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  • 1.
    Abelius, Martina S
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Matthiesen, Leif
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping. Helsingborg Hospital, Helsingborg.
    Duchén, Karel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Nilsson, Lennart J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    The Placental Immune Milieu is Characterized by a Th2- and Anti-Inflammatory Transcription Profile, Regardless of Maternal Allergy, and Associates with Neonatal Immunity2015In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 73, no 5, p. 445-459Article in journal (Refereed)
    Abstract [en]

    PROBLEM: How maternal allergy affects the systemic and local immunological environment during pregnancy and the immune development of the offspring is unclear.

    METHOD OF STUDY: Expression of 40 genes was quantified by PCR arrays in placenta, peripheral blood mononuclear cells (PBMC), and cord blood mononuclear cells (CBMC) from 7 allergic and 12 non-allergic women and their offspring.

    RESULTS: Placental gene expression was dominated by a Th2-/anti-inflammatory profile, irrespectively of maternal allergy, as compared to gene expression in PBMC. p35 expression in placenta correlated with fetal Tbx21 (ρ = -0.88, P < 0.001) and IL-5 expression in PBMC with fetal galectin1 (ρ = 0.91, P < 0.001). Increased expression of Th2-associated CCL22 in CBMC preceded allergy development.

    CONCLUSIONS: Gene expression locally and systemically during pregnancy was partly associated with the offspring's gene expression, possibly indicating that the immunological milieu is important for fetal immune development. Maternal allergy was not associated with an enhanced Th2 immunity in placenta or PBMC, while a marked prenatal Th2 skewing, shown as increased CCL22 mRNA expression, might contribute to postnatal allergy development.

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  • 2.
    Abrahamsson, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. University of Toronto, Canada.
    You Wu, Richard
    University of Toronto, Canada.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gut microbiota and allergy: the importance of the pregnancy period2015In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 77, no 1, p. 214-219Article, review/survey (Refereed)
    Abstract [en]

    Limited microbial exposure is suggested to underlie the increase of allergic diseases in affluent countries, and bacterial diversity seems to be more important than specific bacteria taxa. Prospective studies indicate that the gut microbiota composition during the first months of life influences allergy development, and support the theory that factors influencing the early maturation of the immune system might be important for subsequent allergic disease. However, recent research indicates that microbial exposure during pregnancy may be even more important for the preventative effects against allergic disease. This review gives a background of the epidemiology, immunology, and microbiology literature in this field. It focuses on possible underlying mechanisms such as immune-regulated epigenetic imprinting and bacterial translocation during pregnancy, potentially providing the offspring with a pioneer microbiome. We suggest that a possible reason for the initial exposure of bacterial molecular patterns to the fetus in utero is to prime the immune system and/or the epithelium to respond appropriately to pathogens and commensals after birth.

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  • 3.
    Ahlberg, Emelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Al-Kaabawi, Ahmed
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Thune, Rebecka
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Simpson, Melanie Rae
    Norwegian Univ Sci & Technol NTNU, Norway.
    Pedersen, Sindre Andre
    Norwegian Univ Sci & Technol NTNU, Norway.
    Cione, Erika
    Univ Calabria, Italy.
    Jenmalm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Tingö, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Orebro Univ, Sweden; Orebro Univ, Sweden.
    Breast milk microRNAs: Potential players in oral tolerance development2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1154211Article, review/survey (Refereed)
    Abstract [en]

    Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

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  • 4.
    Aleynick, Mark
    et al.
    Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
    Svensson-Arvelund, Judit
    Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
    Flowers, Christopher R.
    Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, Georgia, USA.
    Marabelle, Aurélien
    Cancer Immunotherapy Program, Gustave Roussy, Villejuif, France.
    Brody, Joshua D.
    1Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;4Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York..
    Pathogen Molecular Pattern Receptor Agonists: Treating Cancer by Mimicking Infection2019In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 21, p. 6283-6294Article in journal (Refereed)
    Abstract [en]

    mmunotherapies such as checkpoint blockade have achieved durable benefits for patients with advanced stage cancer and have changed treatment paradigms. However, these therapies rely on a patient's own a priori primed tumor-specific T cells, limiting their efficacy to a subset of patients. Because checkpoint blockade is most effective in patients with inflamed or "hot" tumors, a priority in the field is learning how to "turn cold tumors hot." Inflammation is generally initiated by innate immune cells, which receive signals through pattern recognition receptors (PRR)–a diverse family of receptors that sense conserved molecular patterns on pathogens, alarming the immune system of an invading microbe. Their immunostimulatory properties can reprogram the immune suppressive tumor microenvironment and activate antigen-presenting cells to present tumors antigens, driving de novo tumor-specific T-cell responses. These features, among others, make PRR-targeting therapies an attractive strategy in immuno-oncology. Here, we discuss mechanisms of PRR activation, highlighting ongoing clinical trials and recent preclinical advances focused on therapeutically targeting PRRs to treat cancer. 

  • 5.
    Aleynick, Mark
    et al.
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Svensson-Arvelund, Judit
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Pantsulaia, Gvantsa
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Kim, Kristy
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Rose, Samuel A.
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA.
    Upadhyay, Ranjan
    Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Yellin, Michael
    Celldex Therapeutics Inc, Hampton, New Jersey, USA.
    Marsh, Henry
    Celldex Therapeutics Inc, Hampton, New Jersey, USA.
    Oreper, Daniel
    Genentech Inc, South San Francisco, California, USA.
    Jhunjhunwala, Suchit
    Genentech Inc, South San Francisco, California, USA.
    Moussion, Christine Carine
    Genentech Inc, South San Francisco, California, USA.
    Merad, Miriam
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
    Brown, Brian D.
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
    Brody, Joshua D.
    Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    Pattern recognition receptor agonists in pathogen vaccines mediate antitumor T-cell cross-priming2023In: Journal for ImmunoTherapy of Cancer, E-ISSN 2051-1426, Vol. 11, no 7, article id e007198Article in journal (Refereed)
    Abstract [en]

    Background Cancer immunotherapies are generallyeffective in patients whose tumors contain a prioriprimed T-cells reactive to tumor antigens (TA). Oneapproach to prime TA-reactive T-cells is to administerimmunostimulatory molecules, cells, or pathogens directlyto the tumor site, that is, in situ vaccination (ISV). Werecently described an ISV using Flt3L to expand and recruitdendritic cells (DC), radiotherapy to load DC with TA, andpattern recognition receptor agonists (PRRa) to activateTA-loaded DC. While ISV trials using synthetic PRRa haveyielded systemic tumor regressions, the optimal method toactivate DCs is unknown.Methods To discover optimal DC activators and increaseaccess to clinical grade reagents, we assessed whetherviral or bacterial components found in common pathogenvaccines are an effective source of natural PRRa(naPRRa). Using deep profiling (155-metric) of naPRRaimmunomodulatory effects and gene editing of specificPRR, we defined specific signatures and molecularmechanisms by which naPRRa potentiate T-cell priming.Results We observed that vaccine naPRRa can be evenmore potent in activating Flt3L-expanded murine andhuman DCs than synthetic PRRa, promoting cross-primingof TA-reactive T-cells. We developed a mechanisticallydiverse naPRRa combination (BCG, PedvaxHIB, Rabies)and noted more potent T-cell cross-priming than withany single naPRRa. The naPRRa triplet—as part of Flt3Lprimed ISV—induced greater intratumoral CD8 T-cellinfiltration, T-cells reactive to a newly defined tumorousneoantigen, durable tumor regressions.Conclusions This work provides rationale for thetranslation of pathogen vaccines as FDA-approved clinicalgrade DC activators which could be exploited as immunestimulants for early phase trials.

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  • 6. Order onlineBuy this publication >>
    Alkaissi, Hammoudi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.

    OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.

    METHODS: MHC II (H-2s) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (Pprc1, Bank1 and Nfkb1) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.

    RESULTS: F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which Rxfp4 (Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with Pprc1 (Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of Nfkb1, Il6 and Tnf than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of Pprc1 and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.

    CONCLUSIONS: By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports Bank1 and Nfkb1 as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports Pprc1 as key regulator and it seems that this gene has a protective role against Hg.

    List of papers
    1. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Open this publication in new window or tab >>Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
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    2016 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 7, p. 920-926Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

    Place, publisher, year, edition, pages
    U.S. Department of Health and Human Services * National Institute of Environmental Health Sciences, 2016
    National Category
    Other Biological Topics
    Identifiers
    urn:nbn:se:liu:diva-131584 (URN)10.1289/ehp.1409284 (DOI)000380749300012 ()26942574 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2016-09-27 Created: 2016-09-27 Last updated: 2021-12-28Bibliographically approved
    2. Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Open this publication in new window or tab >>Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
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    2018 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed) Published
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2018
    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-150265 (URN)10.1371/journal.pone.0199979 (DOI)000438866600014 ()30016332 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2021-12-28
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    Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity
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  • 7.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Univ Autonoma Barcelona, Spain.
    Alvarez, M.
    Univ Leon, Spain.
    Anel-Lopez, L.
    Univ Leon, Spain.
    Guerra, C.
    Univ Leon, Spain.
    Chamorro, C. A.
    Univ Leon, Spain.
    Anel, L.
    Univ Leon, Spain.
    de Paz, P.
    Univ Leon, Spain.
    Martinez-Pastor, F.
    Univ Leon, Spain.
    Effect of length of time post-mortem on quality and freezing capacity of Cantabric chamois (Rupicapra pyrenaica parva) epididymal spermatozoa2018In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 198, p. 184-192Article in journal (Refereed)
    Abstract [en]

    Genome Resource Banks are keystones in the ex-situ conservation of wild species. Post-mortem (PM) collection of epididymal spermatozoa is an opportunistic and valuable source of germplasm, the time from the death of the animal limits its use. Seeking to improve germplasm preservation strategies for the chamois (Rupicapra sp.), the effect of PM time on epididymal sperm quality and freezability was studied using the Cantabrian chamois. Samples were classified according to PM collection time, up to 216 h (refrigerated), and cryopreserved (Tris-citric acid-fructose, 430 mOsm/kg, 15% egg yolk, 8% glycerol; freezing at - 20 degrees C/min). Sperm quality was assessed after recovery and post-thawing (motility by CASA, HOS test, abnormal forms, cytoplasmic droplets, and viability and acrosomal damage by flow cytometry). The sperm mass pH and osmolality showed a positive correlation with time. Total sperm motility dropped after 2 days PM, with progressivity and sperm velocities remained similar up to 3 days PM. Sperm freezability was acceptable, with the post-thawing HOST, motility, progressivity, VAP, VCL, VSL and BCF negatively correlating with PM time. Overall, chamois epidydimal samples were not adequate for preservation after 6 days PM. Freezability capacity could make these spermatozoa suitable for specific ART even if kept refrigerated for several days PM.

  • 8.
    Andersson, Pär
    Linköping University, Faculty of Health Sciences, Engelska: Faculty of Health Sciences, Medical Programme.
    Immunological Effects of TBE Vaccination: Increased Expression of Transcription factor T-bet Indicates Activation of Th1-like Cellular Immunity2007Independent thesis Advanced level (professional degree), 15 credits / 22,5 HE creditsStudent thesis
    Abstract [en]

    Tick-borne encephalitis virus is the cause of much morbidity and sometimes a fatal infection. A vaccine based on formaldehyde inactivated virus is currently the only available way of preventing disease. This vaccine gives a high rate of seroconversion but there are reports of vaccination breakthrough, even in people who have demonstrated a neutralizing antibody response. The T cell response to inactivated TBE vaccine is largely unknown, but could be of importance for the effect of the vaccine. This study characterizes aspects of the T cell response by investigating the expression of two transcription factors, T-bet and GATA-3 with RT-PCR. T-bet is expressed in CD4+ T cells of the Th1 type, while GATA-3 is expressed in CD4+ T cells of the Th2 type. Our data show that vaccination with inactivated TBE vaccine leads to increase in expression of the T-bet gene when cells of vaccinated subjects are cultured with TBE virus. In contrast, the expression of GATA-3 remains unaffected by vaccination. Thus, this study suggests that the inactivated TBE vaccine leads to a Th1-like immune response in humans.

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  • 9.
    Andraos, Rama
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ahmad, Awais
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Wirestam, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Frodlund, Martina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Ronnelid, Johan
    Uppsala Univ, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Screening for autoimmune diseases in apparently healthy antinuclear antibody positive individuals2024In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 11, article id 1455673Article in journal (Refereed)
    Abstract [en]

    Background Anti-nuclear antibodies (ANA) assessed by immunofluorescence (IF) microscopy are associated with systemic autoimmune rheumatic diseases (SARD) and can be detected years before onset of clinical symptoms. Recent data indicate dysregulation of the immune system with increased levels of proinflammatory cytokines, including type I interferons (IFN), in ANA-positive versus ANA-negative individuals. Herein, the aims were to investigate IF-ANA, ANA fine specificities, and IFN-alpha protein levels in relation to self-reported symptoms, as well as clinical signs, of SARD in a large group of healthy blood donors (HBD).Methods Sera from 825 HBD (48.8% females) were included. IF-ANA was assessed, using HEp-2 cells, according to the routine at the accredited laboratory of Clinical Immunology, Link & ouml;ping University Hospital. All samples were analyzed for IgG-ANA fine specificities using addressable laser bead assay (ALBIA) at the same laboratory. IFN-alpha was determined using ELISA. Antibody-positive individuals, and their sex- and age-matched antibody-negative controls, were asked to fill a questionnaire regarding symptoms associated with SARD.Results In total, 130 HBD (15.8%) were positive with IF-ANA and/or ALBIA. Anti-U1RNP was significantly more common among women. Generally, self-reported symptoms correlated poorly with IF-ANA and/or ALBIA results. Two females with high levels of Ro60/SSA, Ro52/SSA and IFN-alpha reported mild sicca symptoms and were diagnosed with Sj & ouml;gren's disease after clinical evaluation.Conclusion A considerable proportion of apparently HBD are autoantibody positive, but without clear association to self-reported symptoms. Nevertheless, the combination of autoantibodies, relevant symptoms and high IFN-alpha levels identified the small proportion of individuals with SARD in the study population.

  • 10.
    Aoun, Mike
    et al.
    Karolinska Inst, Sweden.
    Coelho, Ana
    Karolinska Inst, Sweden.
    Kraemer, Alexander
    Karolinska Inst, Sweden.
    Saxena, Amit
    Karolinska Inst, Sweden.
    Sabatier, Pierre
    Karolinska Inst, Sweden.
    Beusch, Christian Michel
    Karolinska Inst, Sweden.
    Loennblom, Erik
    Karolinska Inst, Sweden.
    Geng, Manman
    Xian JiaotongUniv, Peoples R China.
    Do, Nhu-Nguyen
    Karolinska Inst, Sweden; Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany.
    Xu, Zhongwei
    Karolinska Inst, Sweden.
    Zhang, Jingdian
    Karolinska Inst, Sweden.
    He, Yibo
    Karolinska Inst, Sweden.
    Romero Castillo, Laura
    Karolinska Inst, Sweden.
    Abolhassani, Hassan
    Karolinska Univ Hosp, Sweden.
    Xu, Bingze
    Karolinska Inst, Sweden.
    Viljanen, Johan
    Uppsala Univ, Sweden.
    Rorbach, Joanna
    Karolinska Inst, Sweden.
    Fernandez Lahore, Gonzalo
    Karolinska Inst, Sweden.
    Gjertsson, Inger
    Univ Gothenburg, Sweden.
    Kastbom, Alf
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Rheumatology.
    Kihlberg, Jan
    Uppsala Univ, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden; IM Sechenov First Moscow State Med Univ, Russia.
    Burkhardt, Harald
    Fraunhofer Inst Translat Med & Pharmacol, Germany; Fraunhofer Cluster Excellence Immune Mediated Dis, Germany; Goethe Univ, Germany.
    Holmdahl, Rikard
    Karolinska Inst, Sweden; Xian JiaotongUniv, Peoples R China.
    Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice2023In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 220, no 11, article id e20230101Article in journal (Refereed)
    Abstract [en]

    B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

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  • 11.
    Apostolou, Eirini
    et al.
    Univ Athens, Greece; Univ Athens, Greece.
    Moustardas, Petros
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry. Acad Athens, Greece.
    Iwawaki, Takao
    Kanazawa Med Univ, Japan.
    Tzioufas, Athanasios G.
    Univ Athens, Greece; Univ Athens, Greece.
    Spyrou, Ioannis
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry.
    Ablation of the Chaperone Protein ERdj5 Results in a Sjogrens Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 506Article in journal (Refereed)
    Abstract [en]

    Objective: Sjogrens syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods: In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.

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  • 12.
    Apostolou, Eirini
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rizwan, Muhammad
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Moustardas, Petros
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sjögren, Per
    Care Sci & Soc, Sweden; Bragee Clin, Sweden.
    Bertilson, Bo Christer
    Care Sci & Soc, Sweden; Bragee Clin, Sweden.
    Bragée, Björn
    Care Sci & Soc, Sweden; Bragee Clin, Sweden.
    Polo, Olli
    Bragee Clin, Sweden.
    Rosén, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 949787Article in journal (Refereed)
    Abstract [en]

    Background

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

    Methods

    Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

    Results

    At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

    Conclusion

    Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

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  • 13.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Seminal Influence on the Oviduct: Mating and/or semen components induce gene expression changes in the pre-ovulatory functional sperm reservoir in poultry and pigs2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Internal fertilization occurs in birds and eutherian mammals. Foetal development, however, is either extra- respectively intra-corpore (egg vs uterus). In these animal classes, the female genital tract stores ejaculated spermatozoa into a restricted oviductal segment; the functional pre-ovulatory sperm reservoir, where they survive until ovulation/s occur. Paradoxically, this immunologically foreign sperm suspension in seminal fluid/plasma, often microbiologically contaminated, ought to be promptly eliminated by the female local immune defence which, instead, tolerates its presence. The female immune tolerance is presumably signalled via a biochemical interplay of spermatozoa, as well as the peptides and proteins of the extracellular seminal fluid, with female epithelial and immune cells. Such interplay can result in gene expression shifts in the sperm reservoir in relation to variations in fertility. To further aid our understanding of the underlying mechanisms, this thesis studied the proteome of the seminal fluid (using 2D SDS-PAGE and mass spectrometry) including cytokine content (using Luminex and/or ELISA) of healthy, sexually mature and fertile boars and cocks. As well, gene expression changes (using cDNA microarray) in the oviductal sperm reservoirs of sexually-mature females, mated or artificially infused with homologous sperm-free seminal fluid/plasma were studied. Pigs were of commercial, fertility-selected modern breeds (Landrace), while chicken belonged to the ancestor Red Junglefowl (RJF, low egg laying-capacity), a selected egg-layer White Leghorn (WL) and of their Advanced Intercross Line (AIL). Ejaculates were manually collected as single sample in cocks or as the sperm-rich fraction [SRF] and the post- SRF fraction in boars to harvest seminal fluid/plasma for proteome/cytokine and infusion-studies. Oviducts were retrieved for gene-expression analyses via microarray immediately post-mortem (chicken) or at surgery (pig), 24 h after mating or genital infusion. In pigs, the protein-rich seminal plasma showed the highest amounts of cytokines [interferon-γ, interferon gamma-induced protein 10 (IP-10/CXCL10), macrophage derived chemokine (MDC/CCL22), growth-regulated oncogene (GRO/CXCL1), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemo-attractant protein-1 (MCP-1/ CCL2), interleukin (IL)-6, IL-8/CXCL8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-β1-3) in the larger, protein-rich and sperm-poor post-SRF, indicating its main immune signalling influence. Chicken showed also a plethora of seminal fluid proteins with serum albumin and ovotransferrin being conserved through selection/evolution. However, they showed fewer cytokines than pigs, as the anti-inflammatory/immune-modulatory TGF-β2 or the pro-inflammatory CXCL10. The RJF contained fewer immune system process proteins and lacked TGF-β2 compared to WL and AIL, suggesting selection for increased fertility could be associated with higher expression of immune-regulating peptides/proteins. The oviductal sperm reservoir reacted in vivo to semen exposure. In chicken, mating significantly changed the expression of immune-modulatory and pH-regulatory genes in AIL. Moreover, modern fertile pigs (Landrace) and chicken (WL), albeit being taxonomically distant, shared gene functions for preservation of viable sperm in the oviduct. Mating or SP/SF-infusion were able to change the expression of comparable genes involved in pH-regulation (SLC16A2, SLC4A9, SLC13A1, SLC35F1, ATP8B3, ATP13A3) or immune-modulation (IFIT5, IFI16, MMP27, ADAMTS3, MMP3, MMP12). The results of the thesis demonstrate that both mating and components of the sperm-free seminal fluid/plasma elicit gene expression changes in the pre-ovulatory female sperm reservoir of chickens and pigs, some conserved over domestication and fertility-selection.

    List of papers
    1. The Seminal Plasma of the Boar is Rich in Cytokines, with Significant Individual and Intra-Ejaculate Variation
    Open this publication in new window or tab >>The Seminal Plasma of the Boar is Rich in Cytokines, with Significant Individual and Intra-Ejaculate Variation
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    2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 6, p. 523-532Article in journal (Refereed) Published
    Abstract [en]

    Problem The boar, as human, sequentially ejaculates sperm-rich and sperm-poor fractions. Seminal plasma (SP) spermadhesins (PSP-I/PSP-II) induce a primary endometrial inflammatory response in female sows, similar to that elicited by semen deposition in other species, including human. However, the SP is also known to mitigate such response, making it transient to allow for embryo entry to a cleansed endometrium. Although cytokine involvement has been claimed, the exploration of cytokines in different SP fractions is scarce. This study determines Th1, Th2, Th17 and Th3 cytokine profiles in specific ejaculate SP fractions from boars of proven fertility. Methods SP samples from the sperm-rich fraction (SRF) and the sperm-poor post-SRF fraction (post-SRF) of manually collected ejaculates from eight boars (four ejaculates per boar) were analysed by commercial multiplex bead assay kits (Milliplex MAP, Millipore, USA) for interferon-gamma, interferon gamma-induced protein 10, macrophage-derived chemokine, growth-regulated oncogene, granulocyte-macrophage colony-stimulating factor, monocyte chemo-attractant protein-1, interleukins (IL)-6, IL-8, IL-10, IL-15, IL-17 and transforming growth factor (TGF)-beta 1-beta 3. Results Cytokine concentrations differed between the ejaculate fractions among boars, being highest in the post-SRF. Conclusion Boar SP is rich in Th1, Th2, Th17 and Th3 cytokines, with lowest concentrations in the sperm-peak-containing fraction, indicating its main immune influence might reside in the larger, protein-rich sperm-poor post-SRF.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2015
    Keywords
    Ejaculate fractions; immunomodulatory molecules; pig; seminal plasma peptides
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-124497 (URN)10.1111/aji.12432 (DOI)000367669300006 ()26412440 (PubMedID)
    Note

    Funding Agencies|MINECO Madrid (Spain) [AGL2012-39903]; FEDER funds (EU); Formas (Stockholm, Sweden); MECD (Madrid, Spain); Seneca Foundation (Murcia, Spain)

    Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30
    2. Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken
    Open this publication in new window or tab >>Selection for higher fertility reflects in the seminal fluid proteome of modern domestic chicken
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    2017 (English)In: Comparative Biochemistry and Physiology - Part D: Genomics and Proteomics, ISSN 1744-117X, E-ISSN 1878-0407, Vol. 21, p. 27-40Article in journal (Refereed) Published
    Abstract [en]

    The high egg-laying capacity of the modern domestic chicken (i.e. White Leghorn, WL) has arisen from the low egg-laying ancestor Red Junglefowl (RJF) via continuous trait selection and breeding. To investigate whether this long-term selection impacted the seminal fluid (SF)-proteome, 2DE electrophoresis-based proteomic analyses and immunoassays were conducted to map SF-proteins/cytokines in RJF, WL and a 9th generation Advanced Intercross Line (AIL) of RJF/WL-L13, including individual SF (n = 4, from each RJF, WL and AIL groups) and pools of the SF from 15 males of each group, analyzed by 2DE to determine their degree of intra-group (AIL, WL, and RJF) variability using Principal Component Analysis (PCA); respectively an inter-breed comparative analysis of intergroup fold change of specific SF protein spots intensity between breeds. The PCA clearly highlighted a clear intra-group similarity among individual roosters as well as a clear inter-group variability (e.g. between RJF, WL and AIL) validating the use of pools to minimize confounding individual variation. Protein expression varied considerably for processes related to sperm motility, nutrition, transport and survival in the female, including signaling towards immunomodulation. The major conserved SF-proteins were serum albumin and ovotransferrin. Aspartate aminotransferase, annexin A5, arginosuccinate synthase, glutathione S-transferase 2 and l-lactate dehydrogenase-A were RJF-specific. Glyceraldehyde-3-phosphate dehydrogenase appeared specific to the WL-SF while angiotensin-converting enzyme, γ-enolase, coagulation factor IX, fibrinogen α-chain, hemoglobin subunit α-D, lysozyme C, phosphoglycerate kinase, Src-substrate protein p85, tubulins and thioredoxin were AIL-specific. The RJF-SF contained fewer immune system process proteins and lower amounts of the anti-inflammatory/immunomodulatory TGF-β2 compared to WL and AIL, which had low levels- or lacked pro-inflammatory CXCL10 compared to RJF. The seminal fluid proteome differs between ancestor and modern chicken, with a clear enrichment of proteins and peptides related to immune-modulation for sperm survival in the female and fertility.

    Place, publisher, year, edition, pages
    Elsevier, 2017
    Keywords
    Rooster seminal fluid proteome, Cytokines, Egg-laying capacity, Red Junglefowl, White Leghorn, Advanced intercross line, Chicken
    National Category
    Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Genetics and Breeding
    Identifiers
    urn:nbn:se:liu:diva-132624 (URN)10.1016/j.cbd.2016.10.006 (DOI)000395224100004 ()27852008 (PubMedID)
    Note

    Funding agencies: Research Council FORMAS, Stockholm, Sweden [221-2011-512]; Ministerio de Ciencia e Innovacion (Madrid, Spain) [BFU2013-42833-P]

    Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2018-05-02Bibliographically approved
    3. Mating induces the expression of immune- and pH-regulatory genes in the utero-vaginal junction containing mucosal sperm-storage tubuli of hens
    Open this publication in new window or tab >>Mating induces the expression of immune- and pH-regulatory genes in the utero-vaginal junction containing mucosal sperm-storage tubuli of hens
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    2015 (English)In: Reproduction, Vol. 150, no 6, p. 473-483Article in journal (Refereed) Published
    Abstract [en]

    The female chicken, as with other species with internal fertilization, can tolerate the presence of spermatozoa within specialized sperm-storage tubuli (SST) located in the mucosa of the utero-vaginal junction (UVJ) for days or weeks, without eliciting an immune response. To determine if the oviduct alters its gene expression in response to sperm entry, segments from the oviduct (UVJ, uterus, isthmus, magnum and infundibulum) of mated and unmated (control) hens, derived from an advanced inter-cross line between Red Junglefowl and White Leghorn, were explored 24 h after mating using cDNA microarray analysis. Mating shifted the expression of fifteen genes in the UVJ (53.33% immune-modulatory and 20.00% pH-regulatory) and seven genes in the uterus, none of the genes in the latter segment overlapping the former (with the differentially expressed genes themselves being less related to immune-modulatory function). The other oviductal segments did not show any significant changes. These findings suggest sperm deposition causes a shift in expression in the UVJ (containing mucosal SST) and the uterus for genes involved in immune-modulatory and pH-regulatory functions, both relevant for sperm survival in the hen's oviduct.

    Place, publisher, year, edition, pages
    Bioscientifica, 2015
    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-122573 (URN)10.1530/REP-15-0253 (DOI)000365344400004 ()26370241 (PubMedID)
    Note

    Funding agencies: Research Council FORMAS, Stockholm [221-2011-512]; FORMAS [221-2012-667]; VR [621-2011-4802]

    Available from: 2015-11-09 Created: 2015-11-09 Last updated: 2017-02-20
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    Seminal Influence of the Oviduct: Mating and/or semen components induce gene expression changes in the pre-ovulatory functional sperm reservoir in poultry and pigs
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  • 14.
    Azharuddin, Mohammad
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Zhu, Geyunjian Harry
    Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
    Sengupta, Anirban
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Slater, Nigel K.H.
    Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
    Patra, Hirak
    Department of Surgical Biotechnology, University College London, London, UK.
    Nano toolbox in immune modulation and nanovaccines2022In: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 40, no 10, p. 1195-1212Article, review/survey (Refereed)
    Abstract [en]

    Despite the great success of vaccines over two centuries, the conventional strategy is based on attenuated/altered microorganisms. However, this is not effective for all microbes and often fails to elicit a protective immune response, and sometimes poses unexpected safety risks. The expanding nano toolbox may overcome some of the roadblocks in vaccine development given the plethora of unique nanoparticle (NP)-based platforms that can successfully induce specific immune responses leading to exciting and novel solutions. Nanovaccines necessitate a thorough understanding of the immunostimulatory effect of these nanotools. We present a comprehensive description of strategies in which nanotools have been used to elicit an immune response and provide a perspective on how nanotechnology can lead to future personalized nanovaccines.

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  • 15.
    Barathan, Muttiah
    et al.
    University of Malaya, Malaysia.
    Mohamed, Rosmawati
    University of Malaya, Malaysia.
    Vadivelu, Jamuna
    University of Malaya, Malaysia.
    Yen Chang, Li
    University of Malaya, Malaysia.
    Vignesh, Ramachandran
    University of Kuala Lumpur, Malaysia.
    Krishnan, Jayalakshmi
    CUTN, India.
    Sigamani, Panneer
    CUTN, India.
    Saeidi, Alireza
    University of Malaya, Malaysia.
    Ravishankar Ram, M.
    University of Malaya, Malaysia.
    Velu, Vijayakumar
    Emory Vaccine Centre, GA 30329 USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia; CUTN, India; University of Malaya, Malaysia.
    CD8+T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides2017In: Cellular Immunology, ISSN 0008-8749, E-ISSN 1090-2163, Vol. 313Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray (TM) following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-beta 1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-alpha, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence. (C) 2016 Elsevier Inc. All rights reserved.

  • 16.
    Barcenilla, Hugo
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology. Orebro Univ, Sweden; Orebro Univ, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Casas, Rosaura
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+CD8+T Cells in Patients With Recent-Onset Type 1 Diabetes2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 797172Article in journal (Refereed)
    Abstract [en]

    Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naive and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD(65) only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

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  • 17.
    Barcenilla, Hugo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 982Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin producing beta-cells. The time from onset of islet autoimmunity to manifest clinical disease can vary widely in length, and it is fairly uncharacterized both clinically and immunologically. In the current study, peripheral blood mononuclear cells from autoantibody-positive children with high risk for T1D, and from age-matched healthy individuals, were analyzed by mass cytometry using a panel of 32 antibodies. Surface markers were chosen to identify multiple cell types including T, B, NK, monocytes, and DC, and antibodies specific for identification of differentiation, activation and functional markers were also included in the panel. By applying dimensional reduction and computational unsupervised clustering approaches, we delineated in an unbiased fashion 132 phenotypically distinct subsets within the major immune cell populations. We were able to identify an effector memory Treg subset expressing HLA-DR, CCR4, CCR6, CXCR3, and GATA3 that was increased in the high-risk group. In addition, two subsets of NK cells defined by CD16(+) CD8(+) CXCR3(+) and CD16(+) CD8(+) CXCR3(+) CD11c(+) were also higher in the same subjects. High-risk individuals did not show impaired glucose tolerance at the time of sampling, suggesting that the changes observed were not the result of metabolic imbalance, and might be potential biomarkers predictive of T1D.

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  • 18.
    Ben-Akiva, Elana
    et al.
    Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
    Karlsson, Johan
    Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
    Tzeng, Stephany Y.
    Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
    Yu, Hongzhe
    Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
    Green, Jordan J.
    Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States ; Departments of Oncology, Neurosurgery, Ophthalmology, Materials Science & Engineering, and Chemical & Biomolecular Engineering, and the Bloomberg ~ Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
    Delivery strategies for ex vivo and in vivo T-cell reprogramming2022In: Systemic Drug Delivery Strategies / [ed] Lara Milane, Mansoor Amiju, Academic Press , 2022, p. 31-62Chapter in book (Other academic)
    Abstract [en]

    In recent years, the immune system has increasingly been recognized as a critical component to understanding cancer progression and cellular microenvironments. This has led to massive growth in the field of cancer immunotherapy, in which the patient's natural defense mechanisms are harnessed and enhanced to fight cancer. In this field, T-cell engineering has been the most widely studied and developed approach, with checkpoint inhibitors like anti-PD-1 antibody recently showing impressive clinical success for solid tumors and ex vivo engineering of chimeric antigen receptor T-cells making a significant impact on liquid tumors. There has been continued basic and translational research interest in developing engineering technologies for delivery of therapeutic agents to induce T-cell reprogramming both ex vivo and in vivo for cancer immunotherapy. In this chapter, delivery technologies that provide surface stimulation to T-cells (outside-in) as well as technologies that deliver intracellular mediators to T-cells (inside-out) for reprogramming to enhance anti-cancer activity are discussed.

  • 19.
    Bender, A.
    et al.
    Rockefeller University, Laboratory of Cellular Physiology and Immunology, New York 10021, USA..
    Bui, L K
    Rockefeller University, Laboratory of Cellular Physiology and Immunology, New York 10021, USA..
    Feldman, M A
    Rockefeller University, Laboratory of Cellular Physiology and Immunology, New York 10021, USA..
    Larsson, Marie
    Rockefeller University, Laboratory of Cellular Physiology and Immunology, New York 10021, USA..
    Bhardwaj, N
    Rockefeller University, Laboratory of Cellular Physiology and Immunology, New York 10021, USA..
    Inactivated influenza virus, when presented on dendritic cells, elicits human CD8+ cytolytic T cell responses.1995In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 182, no 6, p. 1663-1671Article in journal (Refereed)
    Abstract [en]

    Inactivated or subunit virus preparations have been excellent vaccines for inducing antibody responses. Generation of cytolytic T cell responses, however, is thought to require replicating virus, primarily to provide sufficiently large amounts of cytoplasmic proteins for processing and presentation on major histocompatibility complex class I molecules by antigen-presenting cells. Potent human CD8+ cytolytic T cell responses to live replicating influenza A virus are generated when dendritic cells are used as the antigen-presenting cells. Here, we demonstrate that dendritic cells pulsed with poorly replicating, heat- or ultraviolet-inactivated influenza virus, induce equally strong CD8+ cytolytic T lymphocyte responses. The cytotoxic T lymphocytes are generated in the apparent absence of CD4+ helper cells or exogenous cytokines. Active viral protein synthesis is not required to charge class I molecules on dendritic cells. When pulsed with inactivated virus, < 1% of dendritic cells express nonstructural protein 1, which is only synthesized in the infectious cycle. To be optimally effective, however, the inactivated virus must retain its fusogenic activity, and presumably access the cytoplasm of dendritic cells. The data indicate, therefore, that dendritic cells require only small amounts of viral protein to charge class I molecules, most likely via traditional class I processing pathways. These results reopen the potential use of inactivated virus preparations as immunogens for cytotoxic T lymphocyte responses.

  • 20. Order onlineBuy this publication >>
    Bergström, Ida
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Pro- and anti-inflammatory actions in coronary artery disease: with focus on CD56+ T cells and Annexin A12015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    ¨The atherosclerotic process is considered to be driven by an imbalance between proand anti-inflammatory actions. Still, the inflammatory state in patients with coronary artery disease (CAD) remains to be clarified. Annexin A1 (AnxA1) is a glucocorticoidinduced protein which may have a key role in the anti-inflammatory response as a mediator of glucocorticoid effects.

    The general aim of this thesis was to deepen the knowledge of pro- and antiinflammatory mechanisms in CAD via phenotypic assessments of immune cell subsets, in particular CD56+ T cells, and exploration of AnxA1. The long-term goal is to reveal basic mechanisms that will lead to the development of biomarkers, which may be used for individualized treatment and monitoring.

    The AnxA1 protein was constitutively expressed in both neutrophils and peripheral blood mononuclear cells (PBMCs). However, it varied considerably across PBMC subsets, being most abundantly expressed in monocytes. The AnxA1 expression was also higher in CD56+ T cells than in CD56- T cells.

    The expression of total AnxA1 protein in neutrophils was higher in patients with stable angina (SA) compared with controls. However, this was not accompanied by altered neutrophil activation status. Instead, the neutrophils from patients exhibited an enhanced anti-inflammatory response to exogenous AnxA1, emphasizing the potential of AnxA1 as an inhibitor of neutrophil activity. Only patients with acute coronary syndrome (ACS) showed an increase in cell surface-associated AnxA1.

    CAD patients, independent of clinical presentation, had increased proportions of CD56+ T cells compared with controls, a phenomenon likely to represent immunological aging. The CD56+ T cells were found to exhibit a distinct proinflammatory phenotype compared with CD56- T cells. In all T cell subsets, the expression of cell surface-associated AnxA1 was significantly increased in ACS patients, while it tended to be increased in post-ACS patients. In addition, dexamethasone clearly inhibited activation of CD56+ T cells in in vitro assays, whereas AnxA1 did not. The findings highlight the need to clarify whether the role of AnxA1 is different in T cells than in innate immune cells.

    In PBMCs, the mRNA levels of AnxA1 were increased in CAD patients, particularly in ACS patients. Correspondingly, the monocytes in ACS patients exhibited increased AnxA1 protein levels, both totally and on the cell surface. However, only cell surface-associated AnxA1 in monocytes correlated with the glucocorticoid sensitivity of PBMCs ex vivo. We propose the expression of cell surfaceassociated AnxA1 to be a promising candidate marker of glucocorticoid sensitivity, which needs further investigations in larger cohorts and intervention trials. Furthermore, the fact that PBMCs in post-ACS patients exhibited pro-inflammatory activity but no increase in cell surface-associated AnxA1 allow us to speculate that the glucocorticoid action and/or availability might be insufficient in these patients.

    List of papers
    1. Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
    Open this publication in new window or tab >>Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
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    2010 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 59, no 3, p. 443-440Article in journal (Refereed) Published
    Abstract [en]

    Background: A dysregulated cortisol response in patients with stable coronary artery disease (CAD) is related to systemic inflammatory activity. Moreover, a dysfunctional activation status of neutrophils in CAD has been discussed. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1), a protein mainly expressed by innate immune cells. An altered expression of glucocorticoid receptors (GR) and ANXA1 has been associated with glucocorticoid resistance.

    Methods and Results: Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in neutrophil stimulation assays. The patients showed a flattened diurnal cortisol pattern compared to healthy subjects, involving higher levels in the evening. The neutrophil expression of GRtotal and GRα, as well as the ratio of GRα:GRβ expression was significantly decreased in patients, whereas the GRβ expression did not differ compared to controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 suppressed LTB4-induced ROS production in neutrophils from patients, but not from controls. On the other hand, ANXA1 impaired the LTB4-induced up-regulation of β2-integrins in both patients and controls.

    Conclusion: CAD patients displayed a more flattened diurnal cortisol rhythm caused by higher cortisol levels in the evening compared to healthy subjects. Our findings indicate a chronic overactivation of the hypothalamic-pituitary-adrenal (HPA) axis but give no conclusive evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The data rather point towards an increased anti-inflammatory potential in neutrophils from patients with stable CAD.

    Keywords
    Coronary artery disease, cortisol, neutrophil, glucocorticoid receptor, annexin-1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17247 (URN)10.1016/j.metabol.2009.07.044 (DOI)000276761800021 ()
    Note
    Original Publication: Eva Särndahl, Ida Bergström, Johnny Nijm, Tony Forslund, Mauro Perretti and Lena Jonasson, Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease, 2010, Metabolism: Clinical and Experimental, (59), 3, 443-440. http://dx.doi.org/10.1016/j.metabol.2009.07.044 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2017-12-13
    2. Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease
    Open this publication in new window or tab >>Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease
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    2012 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 2, p. 515-520Article in journal (Refereed) Published
    Abstract [en]

    Objective: There is emerging evidence for CD8(+) T cell alterations in blood from patients with coronary artery disease (CAD). We examined whether the distribution and phenotype of CD8(+)CD56(+) T cells differed according to the clinical manifestation of CAD. less thanbrgreater than less thanbrgreater thanMethods: Patients with acute coronary syndrome (ACS, n = 30), stable angina (SA, n = 34) and controls (n = 36) were included. Blood was collected before and up to 12 months after referral for coronary investigation. CD8(+)CD56(+) T cells were assessed by flow cytometry for expression of surface markers, apoptosis, and intracellular expression of cytokines. less thanbrgreater than less thanbrgreater thanResults: The proportions of CD8(+)CD56(+) T cells were significantly higher in both ACS and SA patients compared with controls, and remained so after 3 and 12 months. This was independent of age, sex, systemic inflammation and cytomegalovirus seropositivity. CD8(+)CD56(+) T cells differed from CD8(+)CD56(-) T cells in terms of lower CD28 expression and fewer apoptotic cells. Both CD8(+) T cell subsets were positive for interferon (IFN)-gamma and tumor necrosis factor, although IFN-gamma was significantly more confined to the CD8(+)CD56(+) T cells. less thanbrgreater than less thanbrgreater thanConclusion: The persistent accumulation of CD8(+)CD56(+) T cells in ACS and SA patients share several features with immunological aging. It also contributes to a larger IFN-gamma(+) pool in blood, and may thereby hypothetically drive the atherosclerotic process in a less favorable direction.

    Place, publisher, year, edition, pages
    Elsevier, 2012
    Keywords
    Acute coronary syndrome, Coronary artery disease, Cytokines, Immune system, Leukocytes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-84895 (URN)10.1016/j.atherosclerosis.2012.07.033 (DOI)000309261400039 ()
    Note

    Funding Agencies|Swedish Research Council||Swedish Heart-Lung Foundation||County Council of Ostergotland, Sweden||Eleanora Demeroutis Foundation, Linkoping, Sweden||Heart Foundation at Linkoping University, Linkoping, Sweden||

    Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2020-01-16
    3. Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells: Potential implications for coronary artery disease
    Open this publication in new window or tab >>Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells: Potential implications for coronary artery disease
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    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Increased proportions of circulating proinflammatory CD56+ T cells have been reported in patients with coronary artery disease (CAD). Yet, little is known about regulation of these cells. In the present study, we investigated the expression and potential role of the glucocorticoid-mediated protein annexin A1 (AnxA1) in CD56+ and CD56-T cell subsets, with focus on CAD.

    Methods and Results: We included totally 52 healthy individuals, 28 patients with acute coronary syndrome (ACS) and 57 patients with a history of ACS. AnxA1 mRNA expression was assessed in peripheral blood mononuclear cells. AnxA1 protein expression (total and cell surface-associated) was measured by whole blood flow cytometry in circulating CD56+ and CD56- T cell subsets. Furthermore, inhibitory effects of dexamethasone and/or recombinant AnxA1 on cytokine secretion by CD56+ and CD56- T cells were explored in vitro. We found that CD56+ T cells (the majority CD8+), expressed higher levels of AnxA1 mRNA and protein than did CD56- T cells. When comparing CAD patients with healthy controls, significantly higher levels of cell surface-associated AnxA1 expression were seen in patients, most pronounced in ACS patients. In vitro, dexamethasone reduced cytokine secretion by CD56+ T cells, whereas AnxA1 alone had no effect, and AnxA1 combined with dexamethasone abolished the dexamethasone-induced suppressive effects.

    Conclusion: AnxA1 was expressed more abundantly in proinflammatory CD56+ T cells. Patients with ACS exhibited increased levels of cell surface-associated AnxA1, thus indicating increased activation of the AnxA1 pathway. Our data further suggested that AnxA1 might counteract glucocorticoid mediated anti-inflammatory effects in T cells.

    Keywords
    Annexin A1, T cell, CD56, coronary artery disease, acute coronary syndrome
    National Category
    Cardiac and Cardiovascular Systems Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-114121 (URN)
    Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2020-01-16Bibliographically approved
    4. Annexin A1 expression in blood mononuclear cells: a potential marker of glucocorticoid activity in patients with coronary artery disease
    Open this publication in new window or tab >>Annexin A1 expression in blood mononuclear cells: a potential marker of glucocorticoid activity in patients with coronary artery disease
    Show others...
    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    An imbalance between pro- and anti-inflammatory actions is believed to drive progression of atherosclerosis. Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of anti-inflammatory effects of glucocorticoids. Here, we investigated whether expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) was altered in patients with coronary artery disease (CAD) and also related findings to glucocorticoid sensitivity ex vivo.

    We included 57 patients 6-12 months after acute coronary syndrome (ACS), 10 patients with ACS, and healthy controls. AnxA1 mRNA was measured in PBMCs and AnxA1 protein was assessed in monocytes and lymphocyte subsets by flow cytometry. In post-ACS patients and controls, glucocorticoid sensitivity was determined by measuring inhibitory effects of dexamethasone on LPS46 induced cytokine secretion.

    AnxA1 mRNA levels in PBMCs were higher in patients compared with controls, although most pronounced in ACS patients. AnxA1 protein was most abundant in the monocyte fraction. ACS patients exhibited the highest levels of cell surface-associated AnxA1 protein while levels in post-ACS patients and controls were similar. Ex vivo assays showed that PBMCs from post-ACS patients were more prone to release IL-6. Glucocorticoid sensitivity correlated with cell surface-associated AnxA1 protein in peripheral monocytes. Dexamethasone also induced upregulation of AnxA1 mRNA.

    AnxA1 expression in PBMCs is closely associated with glucocorticoid actions and cell surface associated AnxA1 appears to be a marker of glucocorticoid sensitivity. Although still speculative, a “normal” expression of cell surface-associated AnxA1 in post-ACS patients may suggest that glucocorticoid actions in vivo are insufficient to provide adequate anti-inflammatory effects in these patients.

    Keywords
    Annexin A1, monocytes, glucocorticoids, coronary artery disease, acute coronary syndrome
    National Category
    Cardiac and Cardiovascular Systems Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-114122 (URN)
    Available from: 2015-02-10 Created: 2015-02-10 Last updated: 2020-01-16Bibliographically approved
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  • 21.
    Berryman, Meghan A.
    et al.
    Univ Florida, FL 32611 USA.
    Ilonen, Jorma
    Univ Turku, Finland.
    Triplett, Eric W.
    Univ Florida, FL 32611 USA.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Important denominator between autoimmune comorbidities: a review of class II HLA, autoimmune disease, and the gut2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1270488Article, review/survey (Refereed)
    Abstract [en]

    Human leukocyte antigen (HLA) genes are associated with more diseases than any other region of the genome. Highly polymorphic HLA genes produce variable haplotypes that are specifically correlated with pathogenically different autoimmunities. Despite differing etiologies, however, many autoimmune disorders share the same risk-associated HLA haplotypes often resulting in comorbidity. This shared risk remains an unanswered question in the field. Yet, several groups have revealed links between gut microbial community composition and autoimmune diseases. Autoimmunity is frequently associated with dysbiosis, resulting in loss of barrier function and permeability of tight junctions, which increases HLA class II expression levels and thus further influences the composition of the gut microbiome. However, autoimmune-risk-associated HLA haplotypes are connected to gut dysbiosis long before autoimmunity even begins. This review evaluates current research on the HLA-microbiome-autoimmunity triplex and proposes that pre-autoimmune bacterial dysbiosis in the gut is an important determinant between autoimmune comorbidities with systemic inflammation as a common denominator. Graphical representation of central hypothesis.

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  • 22.
    Bhardwaj, Nina
    et al.
    New York University School of Medicine, New York, USA.
    Larsson, Marie
    New York University School of Medicine, New York, USA.
    Dead-cell-associated proteins are an important source of antigens for cross-presentation by dendritic cells2004In: Nature reviews. Immunology, ISSN 1474-1733, E-ISSN 1474-1741, Vol. 4, no 8, p. 656-656Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Bhattacharya, Pradyot
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Khalid, Mohammad
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Svanberg, Cecilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Govender, Melissa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Keita, Åsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Myrelid, Pär
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India.
    Nyström, Sofia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Larsson, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells2020In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e57869Article in journal (Refereed)
    Abstract [en]

    HIV transmission via genital and colorectal mucosa are the most common routes of dissemination. Here, we explored the effects of free and complement-opsonized HIV on colorectal tissue. Initially, there was higher antiviral responses in the free HIV compared to complementopsonized virus. The mucosal transcriptional response at 24 hr revealed the involvement of activated T cells, which was mirrored in cellular responses observed at 96 hr in isolated mucosal T cells. Further, HIV exposure led to skewing of T cell phenotypes predominantly to inflammatory CD4+ T cells, that is Th17 and Th1Th17 subsets. Of note, HIV exposure created an environment that altered the CD8+ T cell phenotype, for example expression of regulatory factors, especially when the virions were opsonized with complement factors. Our findings suggest that HIV-opsonization alters the activation and signaling pathways in the colorectal mucosa, which promotes viral establishment by creating an environment that stimulates mucosal T cell activation and inflammatory Th cells.

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  • 24.
    Blomberg, Jonas
    et al.
    Uppsala Univ, Sweden.
    Gottfries, Carl-Gerhard
    Gottfries Clin AB, Sweden.
    Elfaitouri, Amal
    Benghazi Univ, Libya.
    Rizwan, Muhammad
    Uppsala Univ, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 229Article in journal (Refereed)
    Abstract [en]

    Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

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  • 25. Order onlineBuy this publication >>
    Blomgran, Parmis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammation and tendon healing2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.

    The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.

    First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.

    In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations. 

    List of papers
    1. A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
    Open this publication in new window or tab >>A possible link between loading, inflammation and healing: Immune cell populations during tendon healing in the rat
    2016 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, no 29824Article in journal (Refereed) Published
    Abstract [en]

    Loading influences tendon healing, and so does inflammation. We hypothesized that the two are connected. 48 rats underwent Achilles tendon transection. Half of the rats received Botox injections into calf muscles to reduce mechanical loading. Cells from the regenerating tissue were analyzed by flow cytometry. In the loaded group, the regenerating tissue contained 83% leukocytes (CD45(+)) day 1, and 23% day 10. The M1/M2 macrophage ratio (CCR7/CD206) peaked at day 3, while T helper (CD3(+)CD4(+)) and T-reg cells (CD25(+) Foxp3(+)) increased over time. With Botox, markers associated with down-regulation of inflammation were more common day 5 (CD163, CD206, CD25, Foxp3), and M1 or M2 macrophages and T-reg cells were virtually absent day 10, while still present with full loading. The primary variable, CCR7/CD206 ratio day 5, was higher with full loading (p = 0.001) and the T-reg cell fraction was lower (p amp;lt; 0.001). Free cage activity loading is known to increase size and strength of the tendon in this model compared to Botox. Loading now appeared to delay the switch to an M2 type of inflammation with more T-reg cells. It seems a prolonged M1 phase due to loading might make the tendon regenerate bigger.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2016
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-130383 (URN)10.1038/srep29824 (DOI)000379584000001 ()27405922 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

    Available from: 2016-08-15 Created: 2016-08-05 Last updated: 2022-09-15
    2. Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
    Open this publication in new window or tab >>Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
    2017 (English)In: Muscles, ligaments and Tendons journal, ISSN 2240-4554, Vol. 7, no 2, p. 223-229Article in journal (Refereed) Published
    Abstract [en]

    Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.

    Place, publisher, year, edition, pages
    Rome, Italy: CIC Edizioni Internazionali, 2017
    Keywords
    tendon healing; NSAID; inflammation; rat model; flow cytometry
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-142352 (URN)10.11138/mltj/2017.7.2.223 (DOI)
    Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2022-03-04
    3. Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
    Open this publication in new window or tab >>Systemic corticosteroids improve tendon healing when given after the early inflammatory phase
    2017 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 12468Article in journal (Refereed) Published
    Abstract [en]

    Inflammation initiates tendon healing and then normally resolves more or less completely. Unresolved inflammation might disturb the remodeling process. We hypothesized that suppression of inflammation during the early remodeling phase by systemic dexamethasone treatment can improve healing. 36 rats underwent Achilles tendon transection and were randomized to dexamethasone or saline on days 0-4 after surgery (early inflammatory phase), and euthanasia day 7. Another 54 rats received injections days 5-9 (early remodeling phase) and were euthanized day 12 for mechanical, histological and flow cytometric evaluation. Dexamethasone treatment days 0-4 reduced the cross-sectional area, peak force and stiffness by day 7 to less than half (p amp;lt; 0.001 for all), while material properties (peak stress and elastic modulus) were not significantly affected. In contrast, dexamethasone treatment days 5-9 increased peak force by 39% (p = 0.002) and stiffness by 58% (p amp;lt; 0.001). The cross-sectional area was reduced by 42% (p amp;lt; 0.001). Peak stress and elastic modulus were more than doubled (p amp;lt; 0.001 for both). Semi-quantitative histology at day 12 showed that late dexamethasone treatment improved collagen alignment, and flow cytometry revealed reduced numbers of CD8a(+) cytotoxic T cells in the tendon callus. These results suggest that downregulation of lingering inflammation during the early remodeling phase can improve healing.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2017
    National Category
    Biomaterials Science
    Identifiers
    urn:nbn:se:liu:diva-142175 (URN)10.1038/s41598-017-12657-0 (DOI)000412032600034 ()28963482 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; Ostergotland county (ALF)

    Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2022-09-15
    4. COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    Open this publication in new window or tab >>COX-2 inhibition impairs mechanical stimulation of early tendon healing in rats by reducing the response to microdamage
    2015 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 119, no 5, p. 534-540Article in journal (Refereed) Published
    Abstract [en]

    Early tendon healing can be stimulated by mechanical loading and inhibited by cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs). Therefore, we investigated if impairment of tendon healing by a COX-2 inhibitor (parecoxib) is related to loading. Because loading might infer microdamage, which also stimulates healing, we also investigated if this effect is inhibited by parecoxib. The Achilles tendon was transected in 114 rats. Three degrees of loading were used: full loading, partial unloading, and unloading (no unloading, Botox injections in the plantar flexor muscles, or Botox in combination with tail suspension). For each loading condition, the rats received either parecoxib or saline. In a second experiment, rats were unloaded with Botox, and the tendon was subjected to microdamage by needling combined with either saline or parecoxib. Mechanical testing day 7 showed that there was a significant interaction between loading and parecoxib for peak force at failure (P less than 0.01). However, logarithmic values showed no significant interaction, meaning that we could not exclude that the inhibitory effect of parecoxib was proportionate to the degree of loading. Microbleeding was common in the healing tissue, suggesting that loading caused microdamage. Needling increased peak force at failure (P less than 0.01), and this effect of microdamage was almost abolished by parecoxib (P less than 0.01). Taken together, this suggests that COX-2 inhibition impairs the positive effects of mechanical loading during tendon healing, mainly by reducing the response to microdamage.

    Place, publisher, year, edition, pages
    AMER PHYSIOLOGICAL SOC, 2015
    Keywords
    tendon healing; COX-2; NSAIDs; mechanical stimulation; microdamage
    National Category
    Physiology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-122063 (URN)10.1152/japplphysiol.00239.2015 (DOI)000360694300013 ()26159755 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [K2013-52X-02031-47-5]; Swedish National Centre for Research in Sports; King Gustaf V and Queen Victoria Free Mason Foundation

    Available from: 2015-12-18 Created: 2015-10-19 Last updated: 2019-02-11
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    Inflammation and tendon healing
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  • 26. Order onlineBuy this publication >>
    Boij, Roland
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Aspects of inflammation, angiogenesis and coagulation in preeclampsia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).

    We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.

    A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.

    List of papers
    1. Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
    Open this publication in new window or tab >>Sera from Preeclampsia Patients Elicit Symptoms of Human Disease in Mice and Provide a Basis for an in Vitro Predictive Assay
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    2010 (English)In: AMERICAN JOURNAL OF PATHOLOGY, ISSN 0002-9440, Vol. 177, no 5, p. 2387-2398Article in journal (Refereed) Published
    Abstract [en]

    Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10(-/-) mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fins-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

    Place, publisher, year, edition, pages
    American Society for Investigative Pathology (ASIP), 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62755 (URN)10.2353/ajpath.2010.100475 (DOI)000284182900026 ()
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2016-11-11
    2. Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
    Open this publication in new window or tab >>Biomarkers of Coagulation, Inflammation, and Angiogenesis are Independently Associated with Preeclampsia
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    2012 (English)In: AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, ISSN 1046-7408, Vol. 68, no 3, p. 258-270Article in journal (Refereed) Published
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

    Place, publisher, year, edition, pages
    John Wiley and Sons, 2012
    Keywords
    preeclampsia, coagulation, inflammation, angiogenesis, chemokines, cytokines and early onset preeclampsia
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81815 (URN)10.1111/j.1600-0897.2012.01158.x (DOI)000307440300012 ()
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden)||Futurum (the Research department of County of Jonkoping)||Swedish Research Council|2007-15809-48800-58|Linneaus University (Sweden)||

    Available from: 2012-09-26 Created: 2012-09-24 Last updated: 2023-12-22
    3. Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
    Open this publication in new window or tab >>Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia
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    2015 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 74, no 4, p. 368-378Article in journal (Refereed) Published
    Abstract [en]

    Problem A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Objective Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of study Six-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non-pregnant controls. Results No differences were found in major Treg populations including CD127(low)CD25(+)/CD127(ow)FOXP3(+), resting (FOXP3(dim)CD45RA(+)), and activated (FOXP3(bright)CD45RA(-)) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. Conclusions Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2015
    Keywords
    Early-onset preeclampsia; preeclampsia; pregnancy; regulatory T cells
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:liu:diva-122528 (URN)10.1111/aji.12410 (DOI)000362664200009 ()26118401 (PubMedID)
    Note

    Funding Agencies|FORSS (Medical Research Council of Southeast Sweden); Futurum, academy for Health and Care Jonkoping County Council, Sweden

    Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2023-12-22
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  • 27. Order onlineBuy this publication >>
    Bruno, Valentina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences.
    Clinical and immunological aspects on recurrent pregnancy loss2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Paper I. Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro. Sci Rep 2018. In paper I low molecular weight heparin (LMWH) in vitro effects on activation and polarization of central regulatory immune cells, such as Th cells and macrophages, were assessed, since LMWH has been widely used as an empiric treatment in recurrent pregnancy loss (RPL) and its immunological effects are not fully known. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured without or with LMWH at different concentrations. LMWH exposure induced an activated phenotype of macrophages, with high expression of HLA-DR and CD206 assessed by flow cytometry, associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory Tcells, and intensified IFN-γ secretion. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells, suggesting that potential immunological effects of LMWH may be effective mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage.

    Paper II. Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomized controlled trial. Sci Rep 2019.

    In paper II we investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomized controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analyzed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17- associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Significantly higher plasma levels of CXCL10 and CXCL11 in treated women were detected at gw 28 and 34, compared to the untreated ones. Thus, a potential proinflammatory effect, linked mainly to Th1 immunity, was shown, suggesting an unfavorable effect of LMWH treatment, since Th1 responsea are responsible for breaking the fetal-maternal immune tolerance.

    Paper III. First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss. Am J Reprod Immunol. 2020.

    In paper III we investigate the “local” immune changes in women with RPL, since they potentially could reveal important mechanisms in RPL. Supernatants from superfluous chorionic villus sampling material culture was used in an ex vivo model, to determinate the immune proteomics profile and to perform functional assays for M2 like macrophages and regulatory T cells polarization, assessed by flow cytometry technique. Chorionic villi, human fetally derived placental tissue, were shown to induce an M2 like-phenotype and an expansion of Treg cells in an ex vivo model, and these immunological properties were maintained despite a history of RPL. Accordingly, no differences in the inflammation proteomic profile were found in RPL, compared to controls. Trophoblasts in an ex vivo model thus maintain tolerogenic and proteomic profile features in successful pregnancies, despite a history of RPL.

    List of papers
    1. Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro
    Open this publication in new window or tab >>Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro
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    2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 4166Article in journal (Refereed) Published
    Abstract [en]

    Low molecular weight heparin (LMWH) is widely used in recurrent miscarriage treatment. The anticoagulant effects are established, while immunological effects are not fully known. Our aim was to assess LMWH effects on activation and polarization of central regulatory immune cells from healthy women, and on placenta tissues from women undergoing elective abortions. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured with or without LMWH. Flow cytometry showed that LMWH exposure induced increased expression of HLA-DR and CD206 in macrophages. This phenotype was associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory T-cells, intensified IFN-gamma secretion and showed a tendency to increase the lymphoblast proportions. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells. Although the biological significancies of these in vitro findings are uncertain and need to be confirmed in vivo, they suggest the possibility that immunological effects of LMWH may be beneficial mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2018
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-147116 (URN)10.1038/s41598-018-22418-2 (DOI)000426825900001 ()29520033 (PubMedID)
    Available from: 2018-04-20 Created: 2018-04-20 Last updated: 2023-12-22
    2. Low-molecular-weight-heparin increases Th1-and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial
    Open this publication in new window or tab >>Low-molecular-weight-heparin increases Th1-and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomised controlled trial
    Show others...
    2019 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 12314Article in journal (Refereed) Published
    Abstract [en]

    Low-molecular-weight heparin (LMWH) is widely used to treat recurrent pregnancy loss (RPL) because of its anti-coagulant effects. Although in vitro studies have suggested additional immunological effects, these are debated. We therefore investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomised controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analysed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. Mixed linear models test on LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p amp;lt; 0.001) and the Th17-associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Subsequent Students t-test showed significantly higher plasma levels of CXCL10 and CXCL11 in treated than untreated women at gw 28 and 34. The consistent increase in the two Th1-associated chemokines suggests a potential proinflammatory and unfavourable effect of LMWH treatment during later stages of pregnancy, when Th1 immunity is known to disrupt immunological tolerance.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2019
    National Category
    General Practice
    Identifiers
    urn:nbn:se:liu:diva-160163 (URN)10.1038/s41598-019-48799-6 (DOI)000482396100028 ()31444404 (PubMedID)
    Note

    Funding Agencies|Stig and Ragna Gorthon foundation, Helsingborg; Thelma Zoegas foundation for medical research, Lund; Medical Research Council of Southeast Sweden [FORSS-159721]; ALF grants, Region Ostergotland, Linkoping University; Skane County Councils Research and Development

    Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2023-12-22
    3. First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss
    Open this publication in new window or tab >>First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss
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    2020 (English)In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 84, no 6, article id e13314Article in journal (Refereed) Published
    Abstract [en]

    Problem While there are several known causes for recurrent pregnancy loss (RPL), about 50% are unexplained (uRPL), and in these cases, an aberrant immune regulation seems to be involved. Although fetally derived trophoblast cells have a key role in immune regulation, it is difficult to study their immune function during pregnancy, and it is not known whether trophoblast function may be an inherent aberration in uRPL or whether it is associated with the outcome of the current pregnancy. Method of study Chorionic villus sampling (CVS) was performed for clinical indications at 12 weeks of gestation. Superfluous materials, divided in small explants, were cultured for 20-24 hours, and supernatants (conditioned medium) were collected from 36 women with singleton normal pregnancies, of whom 9 women had a history of RPL. The secreted immune protein profile was measured by proximity extension assay, and the conditioned medium was further used in functional ex vivo models to assess ability to polarize blood monocytes and CD4(+)T cells into immune regulatory phenotypes, as detected by flow cytometry. Results Conditioned medium from chorionic villi, human fetally derived placental tissue, was able to induce a decidual-type of M2-like macrophages, as well as an expansion of Treg cells ex vivo, both in women with uRPL and in control women. The preserved immunological properties were confirmed by a maintained immune protein profile in RPL compared with controls. Conclusion Trophoblasts in an ex vivo model maintain tolerogenic and proteomic profile features in successful pregnancies, despite a previous history of RPL.

    Place, publisher, year, edition, pages
    WILEY, 2020
    Keywords
    chorionic villus sampling; fetal-maternal immune tolerance; macrophages and regulatory T cells; proteomics; recurrent pregnancy loss
    National Category
    Immunology
    Identifiers
    urn:nbn:se:liu:diva-170064 (URN)10.1111/aji.13314 (DOI)000564551600001 ()32734710 (PubMedID)
    Note

    Funding Agencies|Swedish Research CouncilSwedish Research Council [2018-02776]; Linkoping University; Tor Vergata University; ALF Grants

    Available from: 2020-09-28 Created: 2020-09-28 Last updated: 2021-12-29
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  • 28.
    Burns, R. E.
    et al.
    University of Calif San Diego, CA 92103 USA.
    Gaffney, P. M.
    University of Calif San Diego, CA 92103 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Armien, A. G.
    University of Minnesota, MN 55108 USA.
    Pessier, A. P.
    University of Calif San Diego, CA 92103 USA.
    Systemic Amyloidosis in an African Tiger Snake (Telescopus semiannulatus)2017In: Journal of Comparative Pathology, ISSN 0021-9975, E-ISSN 1532-3129, Vol. 157, no 2-3, p. 136-140Article in journal (Refereed)
    Abstract [en]

    An adult male African tiger snake (Telescopts semiannulatus) was diagnosed with disseminated mycobacteriosis and a hepatic biliary cystadenocarcinoma. Histologically, the spleen was largely replaced by extracellular deposits of eosinophilic, fibrillar to hyaline material. Similar material was also present in the testicular interstitium and occasional blood vessel walls. This material was congophilic with strong green birefringence under polarized light and emitted fluorescence when bound to the luminescent-conjugated oligothiophene, h-FTAA, an amyloid binding probe. Ultrastructurally, deposits were composed of aggregates of haphazardly arranged, non-branching fibrils up to 8 nm in diameter and of indeterminate length. These findings all supported a diagnosis of amyloidosis, most likely amyloid A (AA) type based on concurrent inflammatory disease in this snake. However, immunohistochemistry for serum amyloid A was negative. There are only rare previous reports of amyloidosis in reptiles and many have been incompletely characterized. This case presents a thorough investigation into an occurrence of systemic amyloidosis in a snake, including a novel use of luminescent-conjugated oligothiophene binding in a reptile to confirm the diagnosis. (C) 2017 Elsevier Ltd. All rights reserved.

  • 29. Order onlineBuy this publication >>
    Casado Bedmar, Maria Teresa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Neuro-immuno-regulation of inflammation in the colonic mucosa: Focus on mast cells and eosinophils in bowel disorders2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Intestinal homeostasis is key to control uptake across the mucosa and protect from harmful substances. Disturbances in the bidirectional communication between the gut and the brain are implicated in irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD), being Crohn’s disease (CD) and ulcerative colitis (UC) the two most common IBD subtypes. Although these chronic bowel-relapsing inflammatory disorders present different histopathology, they share similar pathological features. Both IBS and IBD are characterized by a disrupted intestinal barrier function, a pro-inflammatory chronic condition, and an altered gut-brain axis. Despite all the scientific effort, the sequence or exact combination of events that drive these diseases are still unknown, and so is the exact role of every single component. Growing evidence suggests altered neuro-immune interactions as a pathogenic factor.

    The general aim of this thesis was to elucidate the potential involvement of mast cells and eosinophils in IBS and IBD, and the neuro-immune intercellular circuit via vasoactive intestinal polypeptide (VIP) that might exacerbate mucosal inflammation and intestinal barrier disruption.

    Intestinal tissues from IBS, inactive IBD, healthy controls (HC), and murine colitis were collected. Electrophysiological and permeability studies were performed using the ex vivo Ussing chamber technique. Tissues were processed with immunohistological procedures to study cell numbers, activation, location, and interactions in relation to VIP.

    We demonstrated for the very first time an increased transcellular passage of live commensal and pathogenic bacteria through the colonic mucosa of IBS, identifying VIP as a key regulatory molecule together with mast cells activation. In vitro experiments revealed the ability of VIP to activate mast cells. Image analysis identified VIP-mast cells in closer proximity in IBD patients and murine colitis compared to controls. Communication between mast cells and VIP was shown upregulated in IBD and mice colitis via VIP receptor (VPAC)1. Similarities and differences between HC, IBS, and IBD were further studied. Results indicated a pronounced increased intestinal permeability in UC, even during remission, followed by IBS, compared to healthy controls. Surprisingly, permeability results did not correlate with mast cells, but with eosinophil number and activation. A further image analysis suggested an inhibitory effect of eosinophils and VIP on mast cells and an altered interaction between them under inflammatory conditions. Lastly, intestinal VIP levels were shown to increase in IBD patients after the treatment with biological agents and were suggested as a possible biomarker for biological treatment outcome.

    This thesis presents novel insights into the regulation of intestinal permeability, as well as into the pathophysiology of IBD and IBS by demonstrating the importance of neuro-immune interactions between mast cells, VIP, and eosinophils.

    Altogether, our findings have broadened the knowledge of neuro-immune interactions in IBS and IBD and might have the potential to onsight lead to new therapeutic approaches thereby improving the outcomes for patients suffering from these diseases.

    List of papers
    1. Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome
    Open this publication in new window or tab >>Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome
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    2017 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, no 4, p. 948-+Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND amp; AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P amp;lt;.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

    Place, publisher, year, edition, pages
    W B SAUNDERS CO-ELSEVIER INC, 2017
    Keywords
    Intestinal Permeability; Bacteria; Ketotifen; Inflammation
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-142158 (URN)10.1053/j.gastro.2017.06.051 (DOI)000411835200024 ()28711627 (PubMedID)
    Note

    Funding Agencies|Stiftelsen Halsofonden, County Council of Ostergotland; Diarrheal Disease Research Centre, Linkoping University; AFA research foundation; Bengt-Ihre fonden, County Council of Ostergotland; Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Subdireccion General de Investigacion Sanitaria, Ministerio de Economia y Competitividad [FI12/00254]; NIH [R01 DK048351]; [CP10/00502]; [PI13/00935]; [MV16/00028]; [CIBEREHD CB06/04/0021]

    Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2024-01-10
    2. Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis
    Open this publication in new window or tab >>Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis
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    2019 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 31, no 3, article id e13503Article in journal (Refereed) Published
    Abstract [en]

    Background

    Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis.

    Methods

    MCs, VIP, and VIP‐receptors (VPACs) were quantified by immunofluorescence and enzyme‐immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle‐associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non‐IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non‐IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)‐induced colitis and control mice were analyzed likewise.

    Key Results

    FAE‐adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co‐localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP‐stimulation.

    Conclusions and Inferences

    Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC‐VIP‐interactions in this intestinal region.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2019
    Keywords
    Crohns disease; inflammation; neuro-immune interactions; ulcerative colitis
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-154978 (URN)10.1111/nmo.13503 (DOI)000459504300019 ()30407703 (PubMedID)2-s2.0-85056206783 (Scopus ID)
    Note

    Funding Agencies|Swedish Research Council (VR-Medicine and Health) [2014-02537, 2017-02475]; Swedish Foundation For Strategic Research [RB13-016]; Lions Clubs International Foundation; Mattssons Fastighetsutveckling i Stockholm AB

    Available from: 2019-03-08 Created: 2019-03-08 Last updated: 2020-11-17Bibliographically approved
    3. Increased Colonic Epithelial Permeability and Mucosal Eosinophilia in Ulcerative Colitis in Remission Compared With Irritable Bowel Syndrome and Health
    Open this publication in new window or tab >>Increased Colonic Epithelial Permeability and Mucosal Eosinophilia in Ulcerative Colitis in Remission Compared With Irritable Bowel Syndrome and Health
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    2020 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 26, no 7, p. 974-984Article in journal (Refereed) Published
    Abstract [en]

    Background

    Barrier dysfunction is recognized as a pathogenic factor in ulcerative colitis (UC) and irritable bowel syndrome (IBS), but it is unclear to what extent the factors related to barrier dysfunction are disease-specific. The aim of this study was to compare these aspects in UC patients in remission, IBS patients, and healthy controls (HCs).

    Methods

    Colonic biopsies were collected from 13 patients with UC in remission, 15 patients with IBS-mixed, and 15 HCs. Ulcerative colitis patients had recently been treated for relapse, and biopsies were taken from earlier inflamed areas. Biopsies were mounted in Ussing chambers for measurements of intestinal paracellular permeability to 51chromium (Cr)-ethylenediaminetetraacetic acid (EDTA). In addition, biopsies were analyzed for mast cells and eosinophils by histological procedures, and plasma tumor necrosis factor (TNF)-α was assessed by ELISA.

    Results

    Ussing chamber experiments revealed an increased 51Cr-EDTA permeability in UC and IBS (P < 0.05). The 51Cr-EDTA permeability was higher in UC compared with IBS (P < 0.005). There were increased numbers of mucosal mast cells and eosinophils in UC and IBS and more eosinophils in UC compared with IBS (P < 0.05). Also, increased extracellular granule content was found in UC compared with HCs (P < 0.05). The 51Cr-EDTA permeability correlated significantly with eosinophils in all groups. Plasma TNF-α concentration was higher in UC compared with IBS and HCs (P < 0.0005).

    Conclusions

    Results indicate a more permeable intestinal epithelium in inactive UC and IBS compared with HCs. Ulcerative colitis patients, even during remission, demonstrate a leakier barrier compared with IBS. Both eosinophil numbers and activation state might be involved in the increased barrier function seen in UC patients in remission.

    Place, publisher, year, edition, pages
    Oxford University Press, 2020
    Keywords
    eosinophils; intestinal permeability; irritable bowel syndrome; mast cells; ulcerative colitis
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-167644 (URN)10.1093/ibd/izz328 (DOI)000544164200013 ()31944236 (PubMedID)2-s2.0-85083096809 (Scopus ID)
    Note

    Funding Agencies|Bengt Ihre research Scholarship; AFA research foundation; Bengt-Ihre fonden, County Council of Ostergotland; Swedish Research Council (VR-Medicine and Health)Swedish Research Council [2017-02475]; Swedish Foundation For Strategic ResearchSwedish Foundation for Strategic Research [RB13-016]; Instituto de Salud Carlos IIIInstituto de Salud Carlos III; Fondo de Investigacion SanitariaInstituto de Salud Carlos III [PI16/00583]; Ministerio de Ciencia, Innovacion y Universidades, Spain [CIBER-EHD CB06/04/0021]

    Available from: 2020-07-20 Created: 2020-07-20 Last updated: 2024-01-10Bibliographically approved
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  • 30.
    Casas, Rosaura
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Dietrich, Fabricia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Barcenilla, Hugo
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Tavira Iglesias, Beatriz
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Endocrinology.
    Achenbach, Peter
    Helmholtz Zentrum Munchen, Germany; Tech Univ Munich, Germany.
    Ludvigsson, Johnny
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients2020In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 11, article id 564921Article in journal (Refereed)
    Abstract [en]

    In spite of intensive treatment Type 1 diabetes leads to serious complications. Preservation of residual beta cell function makes the disease milder, facilitates treatment, prevents complications and increase survival. So far immune interventions have had limited effect, and some serious adverse events and risks. In an open pilot trial we aimed to improve efficacy of GAD-alum treatment using lymph-node administration in combination with oral vitamin D. Here we report the clinical effect and focus on biomarkers for response to treatment. Patients (n = 12) aged 12 to 24 years with recent onset of Type 1 diabetes received 4 mu g GAD-alum into lymph-node at day 30, 60, and 90, and oral Vitamin D 2000 U/d, days 1 to 120. Beta cell function was estimated by Mixed Meal Tolerance Tests. GADA, GADA subclasses, GAD(65)-induced cytokines and proliferation, and T cells markers were analyzed. The treatment was tolerable with no adverse events. Fasting C-peptide and insulin requirement remained stable at 15 months, while HbA1c was lower than baseline. Stimulated C-peptide showed no change at 6 months but declined after 15 months (81% of baseline). Eleven patients remained in partial remission (IDAAC &lt; 9). Patients (n = 9) with better clinical outcome had reduced proportion of IgG1 and increased IgG2, IgG3, and IgG4, increased IL-10 secretion, and reduction of proliferation and CD8(+) T cells activation. Patients with poorer clinical response had higher baseline levels of GAD(65-)induced cytokines and T-cell activation, and an increased ratio of effector/central memory T cells. Intra-lymphatic GAD treatment combined with Vitamin D might preserve beta cell function and improve clinical course in T1D. Patients with less benefit have a different quality of immune response both before and after treatment.

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  • 31.
    Castany Quintana, Silvia
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Batista Rosa, Priscila
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Shionoya, Kiseko
    Linköping University, Department of Biomedical and Clinical Sciences, The Division of Cell and Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, The Division of Cell and Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Social transmission of inflammation in mice2024In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 120, p. 464-470Article in journal (Refereed)
    Abstract [en]

    The ability to detect and respond to sickness in others promotes survival. Here we show that mouse dams respond to immune challenged pups by mirroring their inflammatory response. Dams with pups subjected to immune challenge displayed a marked induction of inflammatory mediators in both the brain and the periphery, accompanied by an increase in maternal behaviors and corticosterone levels. This social transmission of inflammation did not require physical contact, and it contributed to the stress hormone response in the dams. In adult dyads, interaction with an immune challenged cagemate did not elicit robust inflammatory signaling but induced an increased responsiveness to a subsequent immune challenge. The identification of social transmission of inflammation, or inflammatory responsiveness, may open new avenues for research on social behavior, just like the description of similar phenomena such as observational fear and transmitted pain has done.

  • 32.
    Cauvi, D.M.
    et al.
    University of California, San Diego, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Pollard, K. Michael
    The Scripps Research Institute, La Jolla, CA, USA.
    Autoimmune models2015In: Reference module in biomedical sciences, Elsevier, 2015, p. 413-438Chapter in book (Refereed)
    Abstract [en]

    Models of autoimmunity fall into four categories: (a) those induced by immunization with self-antigen, (b) those induced by exogenous agents, (c) those which arise spontaneously, and (d) those which are produced by genetic manipulation. The autoimmunity exhibited by these models covers a spectrum of diseases which fall into the two broad categories, organ-specific and systemic autoimmunity. Animal models of autoimmune diseases have played an essential role in the discovery of many of mechanisms that result in the breaking of self-tolerance. This chapter describes a number of experimental animal models of autoimmunity and the underlying mechanisms that lead to disease.

  • 33.
    Chen, Baoli
    et al.
    Shandong Ctr Dis Control & Prevent, Peoples R China.
    Berglund, Björn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Zhejiang Univ, Peoples R China.
    Wang, Shuang
    Shandong Ctr Dis Control & Prevent, Peoples R China.
    Börjesson, Stefan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Natl Vet Inst SVA, Sweden; Publ Hlth Agcy Sweden, Sweden.
    Bi, Zhenqiang
    Shandong Ctr Dis Control & Prevent, Peoples R China.
    Nilsson, Maud
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection.
    Yin, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Zheng, Beiwen
    Zhejiang Univ, Peoples R China.
    Xiao, Yonghong
    Zhejiang Univ, Peoples R China.
    Bi, Zhenwang
    Shandong Ctr Dis Control & Prevent, Peoples R China; Shandong First Med Univ, Peoples R China.
    Nilsson, Lennart
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection.
    Rapid increase in occurrence of carbapenem-resistant Enterobacteriaceae in healthy rural residents in Shandong Province, China, from 2015 to 20172022In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 28, p. 38-42Article in journal (Refereed)
    Abstract [en]

    Objectives: The global increase in carbapenem-resistant Enterobacteriaceae (CRE) is a growing health concern. Infections caused by CRE are associated with increased mortality and length of hospital stay, emphasising the health and economic burden posed by these pathogens. Although CRE can inhabit the human gut asymptomatically, colonisation with CRE is associated with an increased risk of CRE infection and mortality. In this study, we investigated the occurrence and characteristics of CRE in faecal samples from healthy persons in 12 villages in Shandong Province, China. Methods: Screening for CRE in faecal samples was performed by selective cultivation. Minimum inhibitory concentrations (MICs) of meropenem were determined by the agar dilution method. Multilocus sequence typing (MLST) and carbapenemase gene carriage of the isolates were determined by whole-genome sequencing. Genetic relatedness of Escherichia coli isolates was determined by core genome MLST. Results: CRE carriage increased from 2.4% in 2015 to 13.4% in 2017. Most CRE isolates (93.0%) were E. coli and all carried NDM-type carbapenemases. Sequence types (STs) among the E. coli isolates were diverse. The single most common ST was the highly epidemic strain ST167, which was only observed in 2017. Conclusion: We report a rapid increase in occurrence of CRE (from 2.4% to 13.4%) among faecal samples collected from healthy rural residents of Shandong Province from 2015 to 2017. Colonisation with CRE is known to increase the risk of CRE infection, and the worrying deterioration of the epidemiological situation in the region reported here indicates a need for further monitoring and possible interventions. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

  • 34. Order onlineBuy this publication >>
    Chenna Narendra, Sudeep
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future.

    Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis.

    Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but only in the arthritis phase. In line with this, adoptive transfer of Tregs isolated from IFN-α treated mice to recipient animals in the arthritis phase clearly protected against AIA. The numbers of Tregs were not significantly altered by IFN-α but IFN-α increased the suppressive capacity of Tregs against antigen-induced proliferation. This enhanced suppressive activity of Tregs in the arthritis phase was dependent on the earlier activated enzyme IDO1 during the sensitization phase of AIA. Thus, presence of IFN-α at the time of antigen sensitization activates the enzymatic activity of IDO, which generates Tregs with enhanced suppressive capacity that upon antigen re-challenge prevents inflammation. We have thus identified one example of how immune tolerance can be developed, that may be a future way to combat autoimmunity.

    List of papers
    1. Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    Open this publication in new window or tab >>Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
    2015 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 10, p. e0141863-Article in journal (Refereed) Published
    Abstract [en]

    Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2015
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123070 (URN)10.1371/journal.pone.0141863 (DOI)000363920300089 ()26512984 (PubMedID)
    Note

    Funding Agencies|Vetenskapsradet-Grant [521-2011-3095]; Reumatikerforbundet Grant [155261]; County Council of Ostergotland, Sweden; Linkoping University

    Available from: 2015-12-04 Created: 2015-12-03 Last updated: 2021-06-14
    2. IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Open this publication in new window or tab >>IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis
    Show others...
    2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 8, p. 3142-3151Article in journal (Refereed) Published
    Abstract [en]

    IFN-alpha prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-beta signaling for this anti-inflammatory property of IFN-alpha. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1(-/-), or Ifnar(-/-) mice, treated or not with IFN-alpha or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-beta, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-beta and pDC, respectively. IDO1 expression was determined by RT-PCR, Western blot, and FACS, and enzymatic activity by HPLC. Proliferation was measured by H-3-thymidine incorporation and TGF-beta by RT-PCR and ELISA. WT but not Ido1(-/-) mice were protected from AIA by IFN-alpha, and Kyn, the main IDO1 product, also prevented AIA, both in WTand Ifnar(-/-) mice. Protective treatment with IFN-alpha increased the expression of IDO1 in pDC during AIA, and Ab-mediated depletion of pDC, either during mBSA sensitization or after triggering of arthritis, completely abrogated the protective effect of IFN-alpha. IFN-alpha treatment also increased the enzymatic IDO1 activity (Kyn/tryptophan ratio), which in turn activated production of TGF-beta. Neutralization of enzymatic IDO1 activity or TGF-beta signaling blocked the protective effect of IFN-alpha against AIA, but only during sensitization and not after triggering of arthritis. Likewise, inhibition of the IDO1 enzymatic activity in the sensitization phase, but not after triggering of arthritis, subdued the IFN-alpha-induced inhibition of mBSA-induced proliferation. In conclusion, presence of IFN-alpha at Ag sensitization activates an IDO1/TGF-beta-dependent anti-inflammatory program that upon antigenic rechallenge prevents inflammation via pDC.

    Place, publisher, year, edition, pages
    AMER ASSOC IMMUNOLOGISTS, 2016
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-133121 (URN)10.4049/jimmunol.1502125 (DOI)000387965100018 ()27647832 (PubMedID)
    Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2019-02-11
    3. Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    Open this publication in new window or tab >>Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
    2014 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, no 4, p. 661-666Article in journal (Refereed) Published
    Abstract [en]

    Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

    Place, publisher, year, edition, pages
    Society for Leukocyte Biology, 2014
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102370 (URN)10.1189/jlb.0613320 (DOI)000335346300011 ()24304616 (PubMedID)
    Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
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  • 35.
    Chenna Narendra, Sudeep
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Chalise, Jaya Prakash
    Osaka Univ, Japan.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kalinke, Ulrich
    Zentrum Expt and Klin Infekt Forsch, Germany.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Regulatory T-Cells Mediate IFN-alpha-Induced Resistance against Antigen-Induced Arthritis2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 285Article in journal (Refereed)
    Abstract [en]

    Objective: CD4(+)FoxP3(+)CD25(+) regulatory T-cells (T-regs) are important for preventing tissue destruction. Here, we investigate the role of T-regs for protection against experimental arthritis by IFN-alpha. Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP(+/-) mice [allowing selective depletion of T-regs by diphtheria toxin (DT)] and CD4-Cre(+/-) IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-alpha or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine. T-regs were depleted in DT-treated Foxp3DTReGFP(+/-) mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25(+high)CD4(+) T-regs was tested in vivo by adoptive transfer and ex vivo in cocultures with antigen-stimulated CFSE-stained T-responder (CD25-CD4(+)) cells. IDO was inhibited by 1-methyl tryptophan. Results: Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-alpha. Depletion of T-regs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-alpha and kynurenine against arthritis. IFN-alpha increased the number of T-regs in ex vivo cultures upon antigen recall stimulation but not in naive cells. IFN-alpha also increased the suppressive capacity of T-regs against mBSA-induced T-responder cell proliferation ex vivo and against arthritis when adoptively transferred. The increased suppressive activity against proliferation conferred by IFN-alpha was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-alpha against arthritis. Conclusion: By activating IDO during antigen sensitization, IFN-alpha activates T-regs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-alpha suppresses inflammation.

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  • 36.
    Cholujová, Dana
    et al.
    Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Jakubíková, Jana
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Kubeš, Miroslav
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Arendacká, Barbora
    Institute of Measurement Science, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sapák, Michal
    Institute of Immunology, Medical Faculty of Comenius University, Sasinkova 4, Bratislava, Slovakia.
    Ihnatko, Robert
    Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, Slovakia.
    Sedlák, Ján
    Laboratory of Tumor Immunology, Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava, Slovakia.
    Comparative study of four fluorescent probes for evaluation of natural killer cell cytotoxicity assays2008In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 213, no 8, p. 629-640Article in journal (Refereed)
    Abstract [en]

    Cytotoxicity is one of the major defence mechanisms against both virus-infected and tumor cells. Radioactive 51chromium (51Cr) release assay is a “gold standard” for assessment of natural killer (NK) cytolytic activity in vitro. Several disadvantages of this assay led us to design alternative tools based on flow cytometry analysis. Four different fluorescent dyes, calcein acetoxymethyl ester (CAM), carboxyfluorescein succinimidyl ester (CFSE), Vybrant DiO (DiO) and MitoTracker Green (MTG) were tested for labeling of NK target K-562 cells. Target staining stability, spontaneous release of fluorochromes and subsequent accumulation in bystander unstained cells were measured using fluorimetry and flow cytometry. Healthy donor peripheral blood mononuclear cells and affinity column purified NK cells were used as effectors coincubated with target K-562 cells at different E:T ratios for 3h and 90min, respectively. Fluorescent probe 7-amino-actinomycin D was used for live and dead cell discrimination. Bland–Altman statistical method was applied to measure true agreement for all CAM–51Cr, CFSE–51Cr, DiO–51Cr and MTG–51Cr pairs analyzed. Based on the data, none of the four proposed methods can be stated equivalent to the standard 51Cr release assay. Considering linear relationships between data obtained with four fluorochromes and 51Cr release assay as well as linear regression analysis with R2=0.9393 value for CAM–51Cr pair, we found the CAM assay to be the most closely related to the 51Cr assay.

  • 37.
    Crespo-Felez, I.
    et al.
    University of Leon, Spain.
    Castaneda-Sampedro, A.
    University of Leon, Spain.
    Sanchez, D. I.
    University of Leon, Spain.
    Fernandez-Alegre, E.
    University of Leon, Spain.
    Alvarez-Rodriguez, Manuel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Dominguez, J. C.
    University of Leon, Spain.
    Morrell, J. M.
    Swedish University of Agriculture Science, Sweden.
    Martinez-Pastor, F.
    University of Leon, Spain; University of Leon, Spain.
    Effect of Single Layer Centrifugation Porcicoll (70%, 80% and 90%) or supplementation with reduced glutathione, seminal plasma and bovine serum albumin on frozen-thawed boar sperm2017In: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 187, p. 167-173Article in journal (Refereed)
    Abstract [en]

    Selecting the optimal sperm population is essential for success with reproductive techniques. Porcicoll (formerly Androcoll-P) is a colloid formulation for selection of high-quality boar spermatozoa by single layer centrifugation (SLC). To date, most studies have been carried out with fresh semen and large volumes. We carried out 2 experiments to test the use of Porcicoll for thawed boar semen in small volumes. In Experiment 1, cryopreserved semen doses were thawed, split in 200-pL aliquots and layered on 1 mL of Porcicoll 70%, 80% or 90%, or buffer without colloid. We assessed sperm recovery (the proportion of the loading dose that appeared in the pellet, %), and the physiology of the selected spermatozoa (flow cytometry: Viability, apoptotic changes, capacitation, mitochondrial activity, intracellular reactive oxygen species). The most suitable proportion was Porcicoll 80%, allowing acceptable sperm recovery (16.9 4.2%, compared to 70% (35.4% 3.0, p amp;lt; 0.001) and 90% (8.2% 3.0, P = 0.001), and improved quality (mitochondrial activity: Porcicoll 80%: 77.7 1% vs Control: 60.3 0.7%, P amp;lt; 0.05). In Experiment 2, we compared 3 supplements to Porcicoll 80%: 500 mM reduced glutathione (GSH), 20% seminal plasma (SP) and 0.5% bovine serum albumin (BSA). Supplementation with GSH or BSA did not cause relevant changes relative to Control. In contrast, SP induced membrane and acrosomal changes resembling capacitation, which might preclude its use in some applications, and decreased recovery (5.5% 1.9 vs. 24.3% 1.2 Control; P amp;lt; 0.001). However, it could be useful prior to other applications such as in vitro fertilisation. Overall, Porcicoll is an effective colloid for isolating a high-quality population from thawed boar sperm, 80% being a balanced option for good recovery and high quality. Supplements could be useful depending on the proposed use of the spermatozoa.

  • 38. Order onlineBuy this publication >>
    Cros, Olivier
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Structural properties of the mastoid using image analysis and visualization2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mastoid, located in the temporal bone, houses an air cell system whose cells have a variation in size that can go far below current conventional clinical CT scanner resolution. Therefore, the mastoid air cell system is only partially represented in a CT scan. Where the conventional clinical CT scanner lacks level of minute details, micro-CT scanning provides an overwhelming amount of ne details. The temporal bone being one of the most complex in the human body, visualization of micro-CT scanning of this boneawakens the curiosity of the experimenter, especially with the correct visualization settings.

    This thesis first presents a statistical analysis determining the surface area to volume ratio of the mastoid air cell system of human temporal bone, from micro-CT scanning using methods previously applied for conventional clinical CT scans. The study compared current results with previous studies, with successive downsampling the data down to a resolution found in conventional clinical CT scanning. The results from the statistical analysis showed that all the small mastoid air cells, that cannot be detected in conventional clinical CT scans, do heavily contribute to the estimation of the surface area, and in consequence to the estimation of the surface area to volume ratio by a factor of about 2.6. Such a result further strengthens the idea of the mastoid to play an active role in pressure regulation and gas exchange.

    Discovery of micro-channels through specific use of a non-traditional transfer function was then reported, where a qualitative and a quantitative pre-analysis were performed and reported. To gain more knowledge about these micro-channels, a local structure tensor analysis was applied where structures are described in terms of planar, tubular, or isotropic structures. The results from this structural tensor analysis suggest these microchannels to potentially be part of a more complex framework, which hypothetically would provide a separate blood supply for the mucosa lining the mastoid air cell system.

    The knowledge gained from analysing the micro-channels as locally providing blood to the mucosa, led to the consideration of how inflammation of the mucosa could impact the pneumatization of the mastoid air cell system. Though very primitive, a 3D shape analysis of the mastoid air cell system was carried out. The mastoid air cell system was first represented in a compact form through a medial axis, from which medial balls could be used. The medial balls, representative of how large the mastoid air cells can be locally, were used in two complementary clustering methods, one based on the size diameter of the medial balls and one based on their location within the mastoid air cell system. From both quantitative and qualitative statistics, it was possible to map the clusters based on pre-defined regions already described in the literature, which opened the door for new hypotheses concerning the effect of mucosal inflammation on the mastoid pneumatization.

    Last but not least, discovery of other structures, previously unreported in the literature, were also visually observed and briefly discussed in this thesis. Further analysis of these unknown structures is needed.

    List of papers
    1. Determination of the mastoid surface area and volume based on micro-CT scanning of human temporal bone: Geometrical parameters dependence on scanning resolutions
    Open this publication in new window or tab >>Determination of the mastoid surface area and volume based on micro-CT scanning of human temporal bone: Geometrical parameters dependence on scanning resolutions
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    2016 (English)In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 340, p. 127-134Article in journal (Refereed) Published
    Abstract [en]

    The mastoid air cell system (MACS) with its large complex of interconnected air cells reflects an enhanced surface area (SA) relative to its volume (V), which may indicate that the MACS is adapted to gas exchange and has a potential role in middle ear pressure regulation. Thus, these geometric parameters of the MACS have been studied by high resolution clinical CT scanning. However, the resolution of these scans is limited to a voxel size of around 0.6 mm in all dimensions, and so, the geometrical parameters are also limited. Small air cells may appear below the resolution and cannot be detected. Such air cells may contribute to a much higher SA than the V, and thus, also the SA/V ratio. More accurate parameters are important for analysis of the function of the MACS including physiological modeling.

    Our aim was to determine the SA, V, and SA/V ratio in MACS in human temporal bones at highest resolution by using micro-CT-scanning. Further, the influence of the resolution on these parameters was investigated by downsampling the data. Eight normally aerated temporal bones were scanned at the highest possible resolution (30-60 μm). The SA was determined using a triangular mesh fitted onto the segmented MACS. The V was determined by summing all the voxels containing air. Downsampling of the original data was applied four times by a factor of 2.

    The mean SA was 194 cm2, the mean V was 9 cm3, and the mean SA/V amounted to 22 cm-1. Decreasing the resolution resulted in a non-linear decrement of SA and SA/V, whereas V was mainly independent of the resolution.

    The current study found significantly higher SA and SA/V compared with previous studies using clinical CT scanning at lower resolutions. These findings indicate a separate role of the MACS compared with the tympanum, and the results are important for a more accurate modeling of the middle ear physiology.

    Keywords
    Mastoid air cells; medical imaging; micro-CT; surface area; volume
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:liu:diva-122176 (URN)10.1016/j.heares.2015.12.005 (DOI)000386417900016 ()
    Available from: 2015-10-23 Created: 2015-10-23 Last updated: 2019-12-02Bibliographically approved
    2. Micro-channels in the mastoid anatomy. Indications of a separate blood supply of the air cell system mucosa by micro-CT scanning
    Open this publication in new window or tab >>Micro-channels in the mastoid anatomy. Indications of a separate blood supply of the air cell system mucosa by micro-CT scanning
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    2013 (English)In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 301, p. 60-65Article in journal (Refereed) Published
    Abstract [en]

    The mastoid air cell system has traditionally been considered to have a passive role in gas exchange and pressure regulation of the middle ear possibly with some acoustic function. However, more evidence has focused on the mucosa of the mastoid, which may play a more active role in regulation of middle ear pressure.

    In this study we have applied micro-CT scanning on a series of three human temporal bones. This approach greatly enhances the resolution (40–60 μm), so that we have discovered anatomical details, which has not been reported earlier. Thus, qualitative analysis using volume rendering has demonstrated notable micro-channels connecting the surface of the compact bone directly to the mastoid air cells as well as forming a network of connections between the air cells. Quantitative analysis on 2D slices was employed to determine the average diameter of these micro-channels (158 μm; range = 40–440 μm) as well as their density at a localized area (average = 75 cm−2; range = 64–97 cm−2).

    These channels are hypothesized to contain a separate vascular supply for the mastoid mucosa. However, future studies of the histological structure of the micro-channels are warranted to confirm the hypothesis. Studies on the mastoid mucosa and its blood supply may improve our knowledge of its physiological properties, which may have important implications for our understanding of the pressure regulation of the middle ear.

    Place, publisher, year, edition, pages
    Elsevier, 2013
    Keywords
    mastoid, micro CT, middle ear
    National Category
    Otorhinolaryngology Radiology, Nuclear Medicine and Medical Imaging Medical Image Processing
    Identifiers
    urn:nbn:se:liu:diva-92813 (URN)10.1016/j.heares.2013.03.002 (DOI)000320478100009 ()23518400 (PubMedID)
    Available from: 2013-05-22 Created: 2013-05-22 Last updated: 2017-12-06Bibliographically approved
    3. Structural Analysis of Micro-channels in Human Temporal Bone
    Open this publication in new window or tab >>Structural Analysis of Micro-channels in Human Temporal Bone
    2015 (English)In: IEEE 12th International Symposium on Biomedical Imaging (ISBI), 2015 IEEE 12th International Symposium on, Institute of Electrical and Electronics Engineers (IEEE), 2015, p. 9-12Conference paper, Published paper (Refereed)
    Abstract [en]

    Recently, numerous micro-channels have been discovered in the human temporal bone by micro-CT-scanning. Preliminary structure of these channels has suggested they contain a new separate blood supply for the mucosa of the mastoid air cells, which may have important functional implications. This paper proposes a structural analysis of the microchannels to corroborate this role. A local structure tensor is first estimated. The eigenvalues obtained from the estimated local structure tensor were then used to build probability maps representing planar, tubular, and isotropic tensor types. Each tensor type was assigned a respective RGB color and the full structure tensor was rendered along with the original data. Such structural analysis provides new and relevant information about the micro-channels but also their connections to mastoid air cells. Before carrying a future statistical analysis, a more accurate representation of the micro-channels in terms of local structure tensor analysis using adaptive filtering is needed.

    Place, publisher, year, edition, pages
    Institute of Electrical and Electronics Engineers (IEEE), 2015
    Series
    IEEE International Symposium on Biomedical Imaging, ISSN 1945-7928
    Keywords
    Human temporal bone, mastoid, microchannels, quadrature filters, structure tensor, visualization
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:liu:diva-122177 (URN)10.1109/ISBI.2015.7163804 (DOI)000380546000003 ()978-1-4799-2374-8 (ISBN)
    Conference
    IEEE 12th International Symposium on Biomedical Imaging (ISBI), 2015 IEEE 12th International Symposium on, 16-19 April, New York, USA
    Available from: 2015-10-23 Created: 2015-10-23 Last updated: 2017-05-10Bibliographically approved
    4. Enhancement of micro-channels within the human mastoid bone based on local structure tensor analysis
    Open this publication in new window or tab >>Enhancement of micro-channels within the human mastoid bone based on local structure tensor analysis
    2016 (English)In: Image Proceessing Theory, Tools and Apllications, IEEE, 2016Conference paper, Published paper (Refereed)
    Abstract [en]

    Numerous micro-channels have recently been discovered in the human temporal bone by x-ray micro-CT-scanning. After a preliminary study suggesting that these micro-channels form a separate blood supply for the mucosa of the mastoid air cells, a structural analysis of the micro-channels using a local structure tensor was carried out. Despite the high-resolution of the micro-CT scan, presence of noise within the air cells along with missing information in some micro-channels suggested the need of image enhancement. This paper proposes an adaptive enhancement of the micro-channels based on a local structure analysis while minimizing the impact of noise on the overall data. Comparison with an anisotropic diffusion PDE based scheme was also performed.

    Place, publisher, year, edition, pages
    IEEE, 2016
    Series
    International Conference on Image Processing Theory Tools and Applications (IPTA), E-ISSN 2154-512X
    Keywords
    Micro-channels, Structure tensor analysis, Image enhancement, Adaptive filtering, Human temporal bone, Mastoid bone
    National Category
    Medical Engineering
    Identifiers
    urn:nbn:se:liu:diva-134434 (URN)10.1109/IPTA.2016.7821019 (DOI)000393589800071 ()9781467389105 (ISBN)9781467389112 (ISBN)
    Conference
    6th International Conference on Image Processing Theory Tools and Applications (IPTA), Oulu, Finland, 12-15 December 2016
    Note

    Funding agencies: Obel Family Foundation (Denmark)

    Available from: 2017-02-13 Created: 2017-02-13 Last updated: 2017-06-21
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  • 39.
    Depelsenaire, Alexandra C. I.
    et al.
    Vaxxas Pty Ltd, Australia.
    Witham, Katey
    Vaxxas Pty Ltd, Australia.
    Veitch, Margaret
    Univ Queensland, Australia.
    Wells, James W.
    Univ Queensland, Australia.
    Anderson, Christopher D.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lickliter, Jason D.
    Nucleus Network Pty Ltd, Australia.
    Rockman, Steve
    Seqirus Pty Ltd, Australia; Univ Melbourne, Australia.
    Bodle, Jesse
    Seqirus Pty Ltd, Australia.
    Treasure, Peter
    Peter Treasure Stat Serv Ltd, England.
    Hickling, Julian
    Tandem Ltd, England.
    Fernando, Germain J. P.
    Vaxxas Pty Ltd, Australia; Univ Queensland, Australia.
    Forster, Angus H.
    Vaxxas Pty Ltd, Australia.
    Cellular responses at the application site of a high-density microarray patch delivering an influenza vaccine in a randomized, controlled phase I clinical trial2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 7, article id e0255282Article in journal (Refereed)
    Abstract [en]

    Microarray patches (MAPs) have the potential to be a safer, more acceptable, easier to use and more cost-effective method for administration of vaccines when compared to the needle and syringe. Since MAPs deliver vaccine to the dermis and epidermis, a degree of local immune response at the site of application is expected. In a phase 1 clinical trial (ACTRN 12618000112268), the Vaxxas high-density MAP (HD-MAP) was used to deliver a monovalent, split inactivated influenza virus vaccine into the skin. HD-MAP immunisation led to significantly enhanced humoral responses on day 8, 22 and 61 compared with IM injection of a quadrivalent commercial seasonal influenza vaccine (Afluria Quadrivalent (R)). Here, the aim was to analyse cellular responses to HD-MAPs in the skin of trial subjects, using flow cytometry and immunohistochemistry. HD-MAPs were coated with a split inactivated influenza virus vaccine (A/Singapore/GP1908/2015 [H1N1]), to deliver 5 mu g haemagglutinin (HA) per HD-MAP. Three HD-MAPs were applied to the volar forearm (FA) of five healthy volunteers (to achieve the required 15 mu g HA dose), whilst five control subjects received three uncoated HD-MAPs (placebo). Local skin response was recorded for over 61 days and haemagglutination inhibition antibody titres (HAI) were assessed on days 1, 4, 8, 22, and 61. Skin biopsies were taken before (day 1), and three days after HD-MAP application (day 4) and analysed by flow-cytometry and immunohistochemistry to compare local immune subset infiltration. HD-MAP vaccination with 15 mu g HA resulted in significant HAI antibody titres compared to the placebo group. Application of uncoated placebo HD-MAPs resulted in mild erythema and oedema in most subjects, that resolved by day 4 in 80% of subjects. Active, HA-coated HD-MAP application resulted in stronger erythema responses on day 4, which resolved between days 22-61. Overall, these erythema responses were accompanied by an influx of immune cells in all subjects. Increased cell infiltration of CD3(+), CD4(+), CD8(+) T cells as well as myeloid CD11b(+) CD11c(+) and non-myeloid CD11b(-) dendritic cells were observed in all subjects, but more pronounced in active HD-MAP groups. In contrast, CD19(+)/CD20(+) B cell counts remained unchanged. Key limitations include the use of an influenza vaccine, to which the subjects may have had previous exposure. Different results might have been obtained with HD-MAPs inducing a primary immune response. In conclusion, influenza vaccine administered to the forearm (FA) using the HD-MAP was well-tolerated and induced a mild to moderate skin response with lymphocytic infiltrate at the site of application.

  • 40.
    Devito, Claudia
    et al.
    Swedish Inst Infect Dis Control, Sweden; HD Dept Clin Virol, Sweden.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Falkeborn, Tina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ohlin, Mats
    Lund Univ, Sweden.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Broliden, Kristina
    Karolinska Inst, Sweden.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro2018In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed)
    Abstract [en]

    The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

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  • 41.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Ernestam, Sofia
    Karolinska Univ Hosp, Sweden.
    Forsblad-DElia, Helena
    Umea Univ, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Lindstrom, Ulf
    Gothenburg Univ, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Uptake of rheumatology biosimilars in the absence of forced switching2018In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 5, p. 499-504Article in journal (Refereed)
    Abstract [en]

    Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

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  • 42.
    Eberhardson, Michael
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Mag- tarmmedicinska kliniken. Karolinska Inst, Sweden.
    Levine, Yaakov A.
    Karolinska Inst, Sweden; SetPoint Med, CA 91355 USA.
    Tarnawski, Laura
    Karolinska Inst, Sweden.
    Olofsson, Peder S.
    Karolinska Inst, Sweden; Feinstein Inst Med Res, NY USA.
    The brain-gut axis, inflammatory bowel disease and bioelectronic medicine2021In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 33, no 6, p. 349-356Article, review/survey (Refereed)
    Abstract [en]

    The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults. An abundance of neutrophils is seen in the inflammatory lesions, but adaptive immunity is also an important player in the chronicity of the disease. There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity. The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention. In this review, we discuss the role of the inflammatory reflex in gut inflammation and the recent advances in the treatment of IBD by intervening with the brain-gut axis through bioelectronic devices.

  • 43. Order onlineBuy this publication >>
    Edström, Måns
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Regulation of immunity in Multiple Sclerosis: CD4+ T cells and the influence of natalizumab2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsing-remitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4+ T cells have been shown to be of importance in disease pathology. A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.

    The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4+ T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4+ T cells in vitro.

    We showed an imbalance in the mRNA expression of CD4+ T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated GATA3 and FOXP3 expression was decreased in RR-MS. Given the reciprocally inhibitory nature of TH subsets, this might imply not only diminished function of TH2 and TREG cells but also a permissive state of harmful TH1 and TH17 cells. The size of the peripheral TREG population was unaltered in RR-MS. When analysed in detail, activated and resting TREG were distinguished, showing clear differences in FOXP3 and CD39 expression. Furthermore, when investigating these subpopulations functionally, the ability of activated TREG to suppress proliferation of responder T cells was found to be decreased in RR-MS patients compared to controls. To further investigate this defect, the global gene expression of TREG was compared between patients and controls. Gene set enrichment analysis revealed an enrichment (over-expression) of chemokine receptor signalling genes in RR-MS TREG, possibly suggesting a role for  chemokines in TREG function.

    A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. Furthermore, T cells from patients with MS displayed decreased responsiveness towards antigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.

    The importance of CD4+ T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4+ T cell differentiation were enriched for many, not only immunerelated, diseases. Furthermore, global CD4+ T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4+ T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.

    In conclusion, our results demonstrate an imbalance of peripheral CD4+ T cells in MS, along with a functional deficiency in the case of TREG. Taken together, these aberrations might result in differentiation and activation of harmful TH1 and TH17 cells, resulting in CNS tissue damage. The importance of CD4+ T cells was further demonstrated by the finding that genes associated with CD4+ T cell differentiation constitute a pleiotropic module common to a number of diseases. Investigation of natalizumab revealed drastic changes in the peripheral lymphocyte compartment caused by treatment. It also appears as treatment might influence the responsiveness of peripheral T cells to antigens. In addition, by using CD4+ T cell transcriptomics after in vitro drug exposure, prediction of treatment outcome may be possible.

    List of papers
    1. Transcriptional characteristics of CD4+ T cells in multiple sclerosis: relative lack of suppressive populations in blood
    Open this publication in new window or tab >>Transcriptional characteristics of CD4+ T cells in multiple sclerosis: relative lack of suppressive populations in blood
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    2011 (English)In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 17, no 1, p. 57-66Article in journal (Refereed) Published
    Abstract [en]

    Background:Multiple sclerosis (MS) is hypothetically caused by autoreactive Th1 and Th17 cells, whereas Th2 and regulatory T cells may confer protection. The development of Th subpopulations is dependant on the expression of lineage-specific transcription factors.

    Objective:The aim of this study was to assess the balance of CD4+T cell populations in relapsing-remitting MS.

    Methods:Blood mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 was assessed in 33 patients with relapsing-remitting MS and 20 healthy controls. In addition, flow cytometry was performed to assess T lymphocyte numbers.

    Results:In relapsing-remitting MS, diminished expression of FOXP3 (Treg) was found (p < 0.05), despite normal numbers of CD4+CD25hiTreg. Immunoregulatory EBI3 and Th2-associated GATA3 ([a-z]+) was also decreased in MS (p < 0.005 and p < 0.05, respectively). Expression of TBX21 (Th1) and RORC (Th17) did not differ between patients and controls. Similar changes were observed when analysing beta-interferon treated (n = 12) or untreated (n = 21) patients. Analysis of transcription factor ratios, comparing TBX21/GATA3 and RORC/FOXP3, revealed an increase in the RORC/FOXP3 ratio in patients with relapsing-remitting MS (p < 0.005).

    Conclusion:Our findings indicate systemic defects at the mRNA level, involving downregulation of beneficial CD4+phenotypes. This might play a role in disease development by permitting activation of harmful T cell populations.

    Place, publisher, year, edition, pages
    Sage Publications, 2011
    Keywords
    EBI3, FOXP3, multiple sclerosis, RORC, T cells, transcription factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-64758 (URN)10.1177/1352458510381256 (DOI)000285867200006 ()20847001 (PubMedID)
    Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2024-01-25
    2. Regulatory T cells in Multiple Sclerosis – Indications of impaired function of suppressive capacity and a role for chemokines
    Open this publication in new window or tab >>Regulatory T cells in Multiple Sclerosis – Indications of impaired function of suppressive capacity and a role for chemokines
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    2014 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND Regulatory T cells (Treg) are critical for immune regulation and homeostasis. In multiple sclerosis (MS), the function of these cells has been shown to be impaired, although the underlying mechanism has yet to be shown. In the current study, we aimed to characterize and assess the phenotypical, functional and transcriptional characteristics of memory and naïve Treg in MS patients and controls.

    MATERIAL AND METHODS 27 patients with relapsing-remitting disease were included, along with 29 healthy controls. Flow cytometry was used for detailed phenotyping of Treg subpopulations CD4+CD45RA+/- and CD4dimCD25++ and their expression of FOXP3, CD39 and HELIOS. CFSE (proliferation marker) and CD69 (activation marker) were used to investigate the functional capacity of Treg. A microarray was employed for genome-wide transcriptional characterization of isolated Treg.

    RESULTS CD4+CD45RA–CD25++ activated Treg displayed a higher expression of FOXP3 and CD39 than resting CD4+CD45RA+CD25+ Treg, while no significant phenotypical differences were observed in Treg subpopulations between patients and controls. However, a lower anti-proliferative capacity was observed in activated Treg of MS patients compared with those of controls (p<0.05), while suppression of activation was similar to controls. Gene set enrichment analysis (GSEA) of microarray data revealed enrichment for the GO gene set ‘chemokine receptor binding’ in MS Treg.

    CONCLUSION Although numerical phenotypical assessment of resting and activated Tregs did not reveal any significant difference between patients and controls, functional co-culturing experiments showed an impaired function in activated Treg of MS patients. Furthermore, GSEA revealed immune-related gene sets overexpressed in Treg of MS patients, possibly containing clues to the functional impairment. In particular over-activity in chemokine signalling in Treg would be of interest for further investigation.

    Keywords
    EBI3, FOXP3, multiple sclerosis, RORC, T cells, transcription factors
    National Category
    Clinical Medicine Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-108908 (URN)
    Available from: 2014-07-11 Created: 2014-07-11 Last updated: 2020-01-16Bibliographically approved
    3. An Increase in B cell and Cytotoxic NK cell Proportions and Increased T cell Responsiveness in Blood of Natalizumab-treated Multiple Sclerosis Patients
    Open this publication in new window or tab >>An Increase in B cell and Cytotoxic NK cell Proportions and Increased T cell Responsiveness in Blood of Natalizumab-treated Multiple Sclerosis Patients
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    2013 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 12, article id e81685Article in journal (Refereed) Published
    Abstract [en]

    Background

    Changes in the peripheral blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks.

    Objectives

    To assess changes in circulating lymphocyte subpopulation compositions and T-cell responses during natalizumab treatment.

    Material and methods

    A broad panel of markers for blood lymphocyte populations, including states of activation and co-stimulation as well as T-cell responses to recall antigens and mitogens, was assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment.

    Results

    Absolute numbers of all major populations of lymphocytes increased after treatment, most markedly for NK- and B-cells. The fraction of both memory and presumed regulatory B-cell subsets increased, as did CD3-CD56dim cytotoxic NK-cells, whereas CD3-CD56bright regulatory NK-cells decreased. Treatment was also associated with a restored T-cell responsiveness to recall antigens and mitogens.

    Conclusions

    Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK- and B-cells. This supports reduction of lymphocyte extravasation as a main mode of action, although the differential composition of lymphocyte subpopulations suggests cell-signalling effects may also be operative. The systemic increase in T-cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses become correspondingly decreased.

    Place, publisher, year, edition, pages
    San Francisco, USA: Public Library of Science, 2013
    Keywords
    Multiple sclerosis, natalizumab, flow cytometry, T-cells, NK-cells, B-cells, lymphocyte proliferation
    National Category
    Neurology Immunology in the medical area
    Identifiers
    urn:nbn:se:liu:diva-84268 (URN)10.1371/journal.pone.0081685 (DOI)000327944500088 ()24312575 (PubMedID)2-s2.0-84891420120 (Scopus ID)
    Available from: 2012-10-03 Created: 2012-10-03 Last updated: 2024-01-25Bibliographically approved
    4. Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
    Open this publication in new window or tab >>Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment