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  • 51.
    Mazzurana, L.
    et al.
    Karolinska Inst, Sweden.
    Rao, A.
    Karolinska Inst, Sweden.
    Van Acker, A.
    Karolinska Inst, Sweden.
    Mjösberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    The roles for innate lymphoid cells in the human immune system2018In: Seminars in Immunopathology, ISSN 1863-2297, E-ISSN 1863-2300, Vol. 40, no 4, p. 407-419Article, review/survey (Refereed)
    Abstract [en]

    From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

  • 52.
    Mellergård, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Edström, Måns
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    An Increase in B cell and Cytotoxic NK cell Proportions and Increased T cell Responsiveness in Blood of Natalizumab-treated Multiple Sclerosis Patients2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e81685Article in journal (Refereed)
    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.

  • 53.
    Mirabelli, Pierfrancesco
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Mukwaya, Anthony
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Xeroudaki, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Peebo, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Schaupper, Mira
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7616Article in journal (Refereed)
    Abstract [en]

    Angiogenesis as a pathological process in the eye can lead to blindness. In the cornea, suppression of angiogenesis by anti-VEGF treatment is only partially effective while steroids, although effective in treating inflammation and angiogenesis, have broad activity leading to undesirable side effects. In this study, genome-wide expression was investigated in a suture-induced corneal neovascularization model in rats, to investigate factors differentially targeted by dexamethasone and anti-Vegf. Topical treatment with either rat-specific anti-Vegf, dexamethasone, or normal goat IgG (sham) was given to sutured corneas for 48 hours, after which in vivo imaging, tissue processing for RNA microarray, and immunofluorescence were performed. Dexamethasone suppressed limbal vasodilation (P amp;lt; 0.01) and genes in PI3K-Akt, focal adhesion, and chemokine signaling pathways more effectively than anti-Vegf. The most differentially expressed genes were confirmed by immunofluorescence, qRTPCR and Western blot. Strong suppression of Reg3g and the inflammatory chemokines Ccl2 and Cxcl5 and activation of classical complement pathway factors C1r, C1s, C2, and C3 occurred with dexamethasone treatment, effects absent with anti-Vegf treatment. The genome-wide results obtained in this study provide numerous potential targets for specific blockade of inflammation and angiogenesis in the cornea not addressed by anti-Vegf treatment, as possible alternatives to broad-acting immunosuppressive therapy.

  • 54.
    Mogilenko, Denis A.
    et al.
    Univ Lille, France.
    Haas, Joel T.
    Univ Lille, France.
    Lhomme, Laurent
    Univ Lille, France.
    Fleury, Sebastien
    Univ Lille, France.
    Quemener, Sandrine
    Univ Lille, France.
    Levavasseur, Matthieu
    Univ Lille, France; CHU Lille, France.
    Becquart, Coralie
    Univ Lille, France; CHU Lille, France.
    Wartelle, Julien
    Univ Lille, France.
    Bogomolova, Alexandra
    Univ Lille, France.
    Pineau, Laurent
    Univ Lille, France.
    Molendi-Coste, Olivier
    Univ Lille, France.
    Lancel, Steve
    Univ Lille, France.
    Dehondt, Helene
    Univ Lille, France.
    Gheeraert, Celine
    Univ Lille, France.
    Melchior, Aurelie
    Univ Lille, France.
    Dewas, Cedric
    Univ Lille, France.
    Nikitin, Artemii
    Univ Lille, France.
    Pic, Samuel
    Univ Lille, France.
    Rabhi, Nabil
    Univ Lille, France.
    Annicotte, Jean-Sebastien
    Univ Lille, France.
    Oyadomari, Seiichi
    Tokushima Univ, Japan.
    Velasco-Hernandez, Talia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, 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 Haematology.
    Foretz, Marc
    Univ Paris 05, France; Inst Cochin, France; CNRS, France.
    Viollet, Benoit
    Univ Paris 05, France; Inst Cochin, France; CNRS, France.
    Vukovic, Milica
    Queen Mary Univ London, England.
    Villacreces, Arnaud
    Queen Mary Univ London, England.
    Kranc, Kamil
    Queen Mary Univ London, England.
    Carmeliet, Peter
    VIB, Belgium; Univ Leuven, Belgium.
    Marot, Guillemette
    Univ Lille, France.
    Boulter, Alexis
    Univ Florida, FL 32610 USA.
    Tavernier, Simon
    Univ Ghent, Belgium; Univ Ghent, Belgium.
    Berod, Luciana
    TWINCORE, Germany.
    Longhi, Maria P.
    Queen Mary Univ London, England.
    Paget, Christophe
    Univ Tours, France.
    Janssens, Sophie
    Univ Ghent, Belgium.
    Staumont-Salle, Delphine
    Univ Lille, France; CHU Lille, France.
    Aksoy, Ezra
    Queen Mary Univ London, England.
    Staels, Bart
    Univ Lille, France.
    Dombrowicz, David
    Univ Lille, France.
    Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR2019In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, no 5, p. 1201-Article in journal (Refereed)
    Abstract [en]

    Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondria! reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

  • 55.
    Moreno, Noelia
    et al.
    Centre Invest Sanidad Anim INIA CISA, Spain.
    Mena, Ignacio
    Centre Invest Sanidad Anim INIA CISA, Spain; Icahn School Medical Mt Sinai, NY 10029 USA.
    Angulo, Ivan
    Centre Invest Sanidad Anim INIA CISA, Spain.
    Gomez, Yolanda
    Centre Invest Sanidad Anim INIA CISA, Spain.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. UAB IRTA, Spain.
    Montoya, Maria
    UAB IRTA, Spain; Pirbright Institute, England.
    Caston, Jose R.
    Centre Nacl Biotecnol CSIC, Spain.
    Blanco, Esther
    Centre Invest Sanidad Anim INIA CISA, Spain.
    Barcena, Juan
    Centre Invest Sanidad Anim INIA CISA, Spain.
    Rabbit hemorrhagic disease virus capsid, a versatile platform for foreign B-cell epitope display inducing protective humoral immune responses2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 31844Article in journal (Refereed)
    Abstract [en]

    Virus-like particles (VLPs), comprised of viral structural proteins devoid of genetic material, are tunable nanoparticles that can be chemically or genetically engineered, to be used as platforms for multimeric display of foreign antigens. Here, we report the engineering of chimeric VLPs, derived from rabbit hemorrhagic disease virus (RHDV) for presentation of foreign B-cell antigens to the immune system. The RHDV capsid comprises 180 copies of a single capsid subunit (VP60). To evaluate the ability of chimeric RHDV VLPs to elicit protective humoral responses against foreign antigens, we tested two B-cell epitopes: a novel neutralizing B-cell epitope, derived from feline calicivirus capsid protein, and a well characterized B-cell epitope from the extracellular domain of influenza A virus M2 protein (M2e). We generated sets of chimeric RHDV VLPs by insertion of the foreign B-cell epitopes at three different locations within VP60 protein (which involved different levels of surface accessibility) and in different copy numbers per site. The immunogenic potential of the chimeric VLPs was analyzed in the mouse model. The results presented here indicated that chimeric RHDV VLPs elicit potent protective humoral responses against displayed foreign B-cell epitopes, demonstrated by both, in vitro neutralization and in vivo protection against a lethal challenge.

  • 56.
    Nilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Wilhelms, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Emergency Medicine.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Jaarola, Maarit
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 236-243, article id S0889-1591(16)30549-9Article in journal (Refereed)
    Abstract [en]

    Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

  • 57.
    Nilsson, Bengt-Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Linköping University, Faculty of Health Sciences.
    Strindhall, Jan
    Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Löfgren, Sture
    Department of Microbiology, Ryhov Hospital, Jönköping, Sweden.
    Forsey, Rosalyn
    Unilever Corporate Research, Colworth House, Sharnbrook.
    Thompson, Julie
    LCG Bioscience, Bourn Hall, Bourn, Cambridge.
    Johansson, Boo
    Department of Psychology, Göteborg University, Göteborg, Sweden.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Wikby, Anders
    Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Jönköping, Sweden.
    The Immune Risk Phenotype and IL-6 among Nonagenarians and Associations with Morbidity and Mortality: Findings from the Swedish NONA Immune Longitudinal StudyManuscript (preprint) (Other academic)
    Abstract [en]

    In this NONA immune longitudinal study, we examine 4-year mortality in relation to a set of laboratory parameters, morbidity and cause of death in a population-based sample of oldest-old individuals (n=138). Four groups were constructed based on levels for the CD4/CD8 ratio (above or below one = IRP, immune risk phenotype group) and levels for IL-6 (below or above the median 3.15 pg/mL). 4-year mortality was higher in the “IRP” group (73 %), the “IL-6” group (64 %), and the “Double risk group” (82 %) compared with the “No risk” group (29 %; p-values between .005 and .000). Cognitive dysfunction and dementia were more common in the two groups with elevated IL-6 levels (p-values between .014 and .001), whereas cardiovascular disease tended (p = .081) to be associated with both “IRP” and “IL-6” groups. The most common cause of death was related to cardio- and cerebrovascular disease (59 %,), followed by infection in 15 % of the cases and cancer in 7 %. Despite their strong associations with 4-year mortality, neither IRP nor IL-6 could be linked to any specific cause of death, possibly because both IRP and IL-6 are multi-factorial risk factors, being associated with several different diseases and mechanisms which cause death.

  • 58.
    Nilsson, Line
    et al.
    Aarhus University, Denmark.
    Palm, Fredrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala University, Sweden.
    Norregaard, Rikke
    Aarhus University, Denmark.
    15-Deoxy-Delta(12,14)-prostaglandin J(2) Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction2017In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 3924912Article in journal (Refereed)
    Abstract [en]

    Urinary obstruction is associated with inflammation and oxidative stress, leading to renal dysfunction. Previous studies have shown that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has both antioxidant and anti-inflammatory effects. Using a unilateral ureteral obstruction (UUO) mouse model, we examined the effects of 15d-PGJ(2) on oxidative stress and inflammation in the kidney. Mice were subjected to UUO for 3 days and treated with 15d-PGJ(2). Protein and RNA expression were examined using immunoblotting and qPCR. 15d-PGJ(2) increased NF-E2-related nuclear factor erythroid-2 (Nrf2) protein expression in response to UUO, and heme oxygenase 1 (HO-1), a downstream target of Nrf2, was induced by 15d-PGJ(2). Additionally, 15d-PGJ(2) prevented protein carbonylation, a UUO-induced oxidative stress marker. Inflammation, measured by nuclear NF-kappa B, F4/80, and MCP-1, was increased in response to UUO and further increased by 15d-PGJ(2). Renal injury was aggravated by 15d-PGJ(2) treatment as measured by kidney injury molecule-1 (KIM-1) and cortical caspase 3 content. No effect of 15d-PGJ(2) was observed on renal function in mice subjected to UUO. This study illustrates differentiated functioning of 15d-PGJ(2) on inflammation and oxidative stress in response to obstructive nephropathy. High concentrations of 15d-PGJ(2) protects against oxidative stress during 3-day UUO in mice; however, it aggravates the associated inflammation.

  • 59.
    Norrman, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Eczema in young children: aspects of clinical investigation and treatment2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Eczema affects at least 20 % of children worldwide, and 1/3 of them also have food allergy. In most children, the food allergy is temporary. Improved clinical management and better understanding of etiological mechanisms underlying the tolerance development are target issues in paediatric research.

    Study design: The thesis is based on two study groups. The first is a large group of children with suspected allergy investigated with skin prick test in a cross-sectional study. The second group is a cohort of infants with eczema and/or suspected food allergy before 2 years of age, investigated prospectively with follow-up to 4.5 years of age.

    Safety of skin prick test (SPT): 5908 children with a mean age of 6.4 years (range: 1 month – 18 years) were investigated with SPT. Seven children, i.e. 0.12%, displayed a generalized allergic reaction (GAR), necessitating pharmacological treatment. Seven children showed a vasovagal reaction (VVR). Risk factors for GAR were age < 1 year (RR 6.28) and eczema (RR 16.98). The risk for VVR was highest among female adolescents, and children investigated with multiple skin pricks.

    The effect of skin care and food elimination on eczema in infants: 123 children, 52 girls and 71 boys, with a mean age of 8.4 months (range: 1-24 months) were recruited due to eczema and/or suspected food allergy. For diagnosis of eczema, the Hanifin and Rajka criteria were used, and for scoring of eczema severity SCORAD. The infants were investigated twice with an interval of 6 weeks. 62% showed positive SPTs. The SCORAD was higher among the sensitized children before treatment compared to not sensitized children. After treatment, i.e. skin care for all and elimination diet for sensitized children, there was no difference regarding eczema severity. Both SPT-positive and SPT-negative children decreased their SCORAD values significantly after treatment. A SPT-negative subgroup, with circulating specific IgE to milk/egg, was only treated with skin care, but these children improved their eczema to the same extent as those also treated with an elimination diet.

    Serum and salivary antibodies and achievement of tolerance Analyses were performed regarding: serum levels of total and egg- and milk-specific IgE antibodies, IgG1 and IgG4 antibodies to β-lactoglobulin (BLG) and ovalbumin (OVA); and salivary levels of total IgA, total SIgA and salivary IgA antibodies to OVA and BLG. Samples were drawn at inclusion, after 6 weeks of intervention (skin care, elimination diet), and at 4.5 years of age. Children sensitized to egg and/or milk who had developed tolerance at 4 ½ years of age had higher levels of IgG4 antibodies to OVA and BLG and also higher IgG4/IgE ratios on inclusion in the study, than those who remained non-tolerant. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative SPT on inclusion. The six-week treatment period did not significantly affect the levels of serum and salivary antibodies.

    Recipes and outcomes of open and double-blinded food challenges in children: After development of recipes for open and blinded challenge with cow’s milk and egg, 52 challenges were performed in 39 children. 4 children, challenged blindly, had a positive outcome of the challenge.

    General conclusions: The risk for generalized allergic reactions at SPT is low among children and teenagers, but allergic reactions do occur, and low age and eczema are risk factors. Vasovagal reactions occur as often as allergic reactions.

    Skin care gives significant improvement of eczema severity. Elimination diet may not be needed in infants with sensitization to milk and/or egg, provided that the skin care is adequate.

    High ratios of serum IgG4/IgE antibodies to food allergens may be associated with faster achievement of clinical tolerance, and may support the concept of benefit from continuing allergen exposure in sensitized children.

    Recipes for masking of cow’s milk and egg in open or blinded food challenges may help to accomplish challenges in young children, often suspicious to unfamiliar tastes or textures.

    List of papers
    1. Adverse reactions to skin prick tests in children: prevalence and possible risk factors
    Open this publication in new window or tab >>Adverse reactions to skin prick tests in children: prevalence and possible risk factors
    2009 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 3, p. 273-278Article in journal (Refereed) Published
    Abstract [en]

    Skin prick test (SPT) is usually considered to be a safe procedure, but recently there have been occasional case reports of generalized allergic reactions. This study was performed to delineate the prevalence of, and evaluate possible risk factors for, adverse reactions to SPT in a prospective study. Altogether 5,908 patients aged ≤18 yr from 11 different pediatric settings were included. The adverse reactions were classified into two groups: (1) Generalized allergic reactions (GAR), (2) Vasovagal reactions (VVR). Adverse reactions were observed in 14 out of 5,908 children examined with SPT. Seven of the adverse reactions were GARs and required medication, yielding a 0.12% risk for GAR. Seven of 14 were VVRs, giving the same risk, 0.12%. Identified risk factors for GAR were low age (<1 yr) (RR 6.28) and active eczema (RR 16.98). For VVR, the risk factors were female sex (RR 7.32) and multiple skin pricks performed on a single patient (p < 0.05). We conclude that GARs do occur, albeit rarely, so the need for proper emergency handling should always be acknowledged. The risk factors suggested may help to identify patients who need extra attention.

    Keywords
    skin tests, allergy and immunology, infant, child, preschool, child, adolescent, adverse effects, risk factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14558 (URN)10.1111/j.1399-3038.2008.00761.x (DOI)
    Available from: 2007-06-19 Created: 2007-06-19 Last updated: 2017-12-13
    2. Significant improvement of eczema with skin care and food elimination in small children
    Open this publication in new window or tab >>Significant improvement of eczema with skin care and food elimination in small children
    Show others...
    2005 (English)In: Acta Paediatrica, ISSN 0803-5253, Vol. 94, no 10, p. 1384-1388Article in journal (Refereed) Published
    Abstract [en]

    Aim: To evaluate common methods of investigation and treatment in children younger than 2 y of age with eczema, with or without sensitization to food allergens.

    Methods: One hundred and twenty-three children younger than 2 y of age with eczema and suspected food allergy were included in this prospective study. The children underwent skin-prick test with cow's milk, fresh hen's egg white and wheat. Specific IgE to milk and egg white was analysed. The eczema extent and severity was estimated with SCORAD before and after treatment. Children with a positive skin-prick test were instructed to exclude that food item from their diet. All children were treated with emollients and topical steroids when needed.

    Results: Sixty-two of the children were skin-prick positive to at least one of the allergens; 62% had mild, 30% moderate and 8% severe eczema at their first visit. After treatment, 90% had mild, 10% moderate and 0% severe eczema. Forty-six per cent of the children had circulating IgE antibodies to milk or egg white. Ten per cent had specific IgE but negative skin-prick test to the same allergen. This subgroup improved their eczema significantly without elimination diet.

    Conclusion: The conventional treatments for children with eczema, i.e. skin care and food elimination, are effective. The beneficial effect of skin care as the first step should not be neglected, and it may not be necessary to eliminate food allergens to relieve skin symptoms in all food-sensitized children with eczema.

    Keywords
    Eczema; food allergy; food elimination; IgE antibodies; skin-prick test
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14559 (URN)10.1080/08035250510036831 (DOI)
    Available from: 2007-06-19 Created: 2007-06-19 Last updated: 2009-05-28
    3. High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
    Open this publication in new window or tab >>High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
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    2009 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, Vol. 5, no 1, p. 35-41Article in journal (Refereed) Published
    Abstract [en]

    Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty-nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme-linked immunosorbent assay and UniCAP® before and after a 6-wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G4 antibodies to ovalbumin and β-lactoglobulin and also higher IgG4/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6-wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG4 and high ratios of IgG4/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.

    Keywords
    food allergy, elimination diet, tolerance, immunoglobulin G4, eczema, children, immunoglobulin E
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13205 (URN)10.1111/j.1399-3038.2008.00738.x (DOI)
    Note
    The fulltext of this work is available at Blackwell-Syergy: Sara Tomičić, Gunilla Norrman, Karin Fälth-Magnusson, Maria C. Jenmalm, Irene Devenney and Malin Fagerås Böttcher, High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life, 2008, Pediatric Allergy and Immunology, (5), 1, 35-41. http://dx.doi.org/10.1111/j.1399-3038.2008.00738.x Copyright: Blackwell-Synergy http://www.blackwellpublishing.com/ Available from: 2009-02-26 Created: 2009-02-26 Last updated: 2010-02-06Bibliographically approved
    4. A new model for low-dose food challenge in children with allergy to milk and egg
    Open this publication in new window or tab >>A new model for low-dose food challenge in children with allergy to milk and egg
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    2006 (English)In: Acta Paediatrica, ISSN 0803-5253, Vol. 95, no 9, p. 1133-1139Article in journal (Refereed) Published
    Abstract [en]

    Background: Atopic eczema and food allergy are common in early childhood. Children seem to gradually develop tolerance to milk and egg, and it is a relief for families when their child can tolerate small amounts of these basic foods, even if larger doses may still cause symptoms. Aim: To develop a model for low-dose oral food challenge, facilitating re-/introduction of milk or egg. Methods: In 39 children sensitized to milk and/or egg, we performed 52 challenges using a new standardized model for low-dose oral food challenge. The recipes were validated for blinding with sensorial tests. Results: Four children challenged to milk had a positive challenge outcome. There were no significant differences with respect to family history, associated atopic manifestations, nutritional supply, eczema severity, or skin-prick test compared with the non-reacting children, but total and specific IgE values were significantly higher. All but two of the non-reacting children were able to introduce milk and egg into their diet without problems.

    Conclusion: We report recipes and a protocol to be used for standardized open and double-blind placebo-controlled low-dose food challenge in young children, enabling the introduction of small amounts of egg and milk into the diet during tolerance development.

    Keywords
    Atopic eczema; double-blind; food allergy; food challenge; skin-prick test
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14561 (URN)10.1080/08035250500516672 (DOI)
    Available from: 2007-06-19 Created: 2007-06-19 Last updated: 2009-03-30
  • 60.
    Odqvist, Lina
    et al.
    AstraZeneca RandD Gothenburg, Sweden.
    Jevnikar, Zala
    AstraZeneca RandD Gothenburg, Sweden.
    Riise, Rebecca
    AstraZeneca RandD Gothenburg, Sweden.
    Oberg, Lisa
    AstraZeneca RandD Gothenburg, Sweden.
    Rhedin, Magdalena
    AstraZeneca RandD Gothenburg, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Yrlid, Linda
    AstraZeneca RandD Gothenburg, Sweden.
    Jackson, Sonya
    AstraZeneca RandD Gothenburg, Sweden.
    Mattsson, Johan
    AstraZeneca RandD Gothenburg, Sweden.
    Nanda, Sambit
    Univ Dundee, Scotland.
    Cohen, Philip
    Univ Dundee, Scotland.
    Knebel, Axel
    Univ Dundee, Scotland.
    Arthur, Simon
    Univ Dundee, Scotland.
    Thorn, Kristofer
    AstraZeneca RandD Gothenburg, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Alexsson, Andrei
    Uppsala Univ, Sweden.
    Kastbom, Alf
    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.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Bengtsson, Anders
    Lund Univ, Sweden.
    Johansson, Patrik
    AstraZeneca RandD Gothenburg, Sweden.
    Sandling, Johanna K.
    Uppsala 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.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Collins, Barry
    AstraZeneca RandD Gothenburg, Sweden.
    Vaarala, Outi
    AstraZeneca RandD Gothenburg, Sweden; MedImmune LLC, MD 20878 USA.
    Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed)
    Abstract [en]

    Objectives Genetic variations in TNFAIP3 (A20) deubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-kappa B but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-kappa B signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

  • 61.
    Palkovicova, K.
    et al.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Ihnatko, Robert
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Vadovic, P.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Betinova, E.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Skultety, L.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    Frangoulidis, D.
    undeswehr Institute of Microbiology, Neuherbergstr. 11, Munich, Germany.
    Toman, R.
    Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia, Germany.
    A monoclonal antibody specific for a unique biomarker, virenose, in a lipopolysaccharide of Coxiella burnetii2009In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15 Suppl 2, p. 183-4Article in journal (Refereed)
    Abstract [en]

    Q fever is a zoonotic disease caused by Coxiella burnetii. Easy aerosol dissemination, strong environmental persistence and high infectivity make the bacterium a serious threat for humans and animals. A rapid, sensitive and specific test for the infectious agent is still a challenge in the field. C. burnetii expresses a spectrum of amphophilic macromolecules on its surface. Among them, a lipopolysaccharide (LPS) is of particular biological, immunological and medical significance [1]. Upon serial laboratory passages in yolk sacs of embryonated hen eggs, C.

  • 62.
    Parigi, Sara M.
    et al.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Czarnewski, Paulo
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Das, Srustidhar
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Steeg, Christiane
    Bernhard Nocht Institute Trop Med, Germany.
    Brockmann, Leonie
    9 Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
    Fernandez-Gaitero, Sara
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Yman, Victor
    University Hospital, Sweden; Karolinska Institute, Sweden.
    Forkel, Marianne
    Karolinska Institute, Sweden.
    Höög, Charlotte
    Unit for Inflammation, Gastroenterology and Rheumathology, Department of Medicine, Huddinge, Sweden.
    Mjösberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Westerberg, Lisa
    Karolinska Institute, Sweden.
    Färnert, Anna
    University Hospital, Sweden; Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Huber, Samuel
    University of Medical Centre Hamburg Eppendorf, Germany.
    Jacobs, Thomas
    Bernhard Nocht Institute Trop Med, Germany.
    Villablanca, Eduardo J.
    Karolinska Institute, Sweden; University Hospital, Sweden.
    Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 154Article in journal (Refereed)
    Abstract [en]

    A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)(neg)alpha 4 beta 7(+) precursors in the adult murine bone marrow. Expanded Lin(neg)alpha 4 beta 7(+) precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.

  • 63.
    Prakash Chalise, Jaya
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Teresa Pallotta, Maria
    University of Perugia, Italy.
    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.
    Carlsson, Björn
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Iacono, Alberta
    University of Perugia, Italy.
    Namale, Joanitah
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Boon, Louis
    EPIRUS Biopharmaceut Netherlands BV, Netherlands.
    Grohmann, Ursula
    University of Perugia, Italy.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    IDO1 and TGF-beta Mediate Protective Effects of IFN-alpha in Antigen-Induced Arthritis2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 8, p. 3142-3151Article in journal (Refereed)
    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.

  • 64.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Interplay of human macrophages and Mycobacterium tuberculosis phenotypes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) is the pathogen causing tuberculosis (TB), a disease most often affecting the lung. 1.5 million people die annually due to TB, mainly in low-income countries. Usually considered a disease of the poor, also developed nations recently put TB back on their agenda, fueled by the HIV epidemic and the global emergence of drug-resistant Mtb strains. HIV-coinfection is a predisposing factor for TB, and infection with multi-drug resistant and extremely drug resistant strains significantly impedes and lengthens antibiotic treatment, and increases fatality. Mtb is transmitted from a sick individual via coughing, and resident macrophages are the first cells to encounter the bacterium upon inhalation. These cells phagocytose intruders and subject them to a range of destructive mechanisms, aiming at killing pathogens and protecting the host. Mtb, however, has evolved to cope with host pressures, and has developed mechanisms to submerge macrophage defenses. Among these, inhibition of phagosomal maturation and adaptation to the intracellular environment are important features. Mtb profoundly alters its phenotype inside host cells, characterized by altered metabolism and slower growth. These adaptations contribute to the ability of Mtb to remain dormant inside a host during latent TB infection, a state that can last for decades. According to recent estimates, one third of the world’s population is latently infected with Mtb, which represents a huge reservoir for active TB disease. Mtb is also intrinsically tolerant to many antibiotics, and adaptation to host pressures enhances tolerance to first-line TB drugs. Therefore, TB antibiotic therapy takes 6 to 9 months, and current treatment regimens involve a combination of several antibiotics. Patient noncompliance due to therapeutic side effects as well as insufficient penetration of drugs into TB lesions are reasons for treatment failure and can lead to the rise of drug-resistant populations. In view of the global spread of drug-resistant strains, new antibiotics and treatment strategies are urgently needed.

    In this thesis, we studied the interplay of the primary host cell of Mtb, human macrophages, and different Mtb phenotypes. A low-burden infection resulted in restriction of Mtb replication via phagolysosomal effectors and the maintenance of an inactive Mtb phenotype reminiscent of dormant bacteria. Macrophages remained viable for up to 14 days, and profiling of secreted cytokines mirrored a silent infection. On the contrary, higher bacterial numbers inside macrophages could not be controlled by phagolysosomal functions, and intracellular Mtb shifted their phenotype towards active replication. Although slowed mycobacterial replication is believed to render Mtb tolerant to antibiotics, we did not observe such an effect. Mtb-induced macrophage cell death is dependent on ESAT6, a small mycobacterial virulence factor involved in host cell necrosis and the spread of the pathogen. Although well-studied, the fate of ESAT6 inside infected macrophages has been enigmatic. Cultivation of Mtb is commonly carried out in broth containing detergent to avoid aggregation of bacilli due to their waxy cell wall. Altering cultivation conditions revealed the presence of a mycobacterial capsule, and ESAT6 situated on the mycobacterial surface. Infection of macrophages with this encapsulated Mtb phenotype resulted in rapid ESAT6-dependent host cell death, and ESAT6 staining was lost as bacilli were ingested by macrophages. These observations could reflect the earlier reported integration of ESAT6 into membranes followed by membrane rupture and host cell death.

    In conclusion, the work presented in this thesis shows that the phenotype of Mtb has a significant impact on the struggle between the pathogen and human macrophages. Taking the bacterial phenotype into account can lead to the development of drugs active against altered bacterial populations that are not targeted by conventional antibiotics. Furthermore, deeper knowledge on Mtb virulence factors can inform the development of virulence blockers, a new class of antibiotics with great therapeutic potential.

    List of papers
    1. Importance of phagosomal functionality for growth restriction of Mycobacterium tuberculosis in primary human macrophages
    Open this publication in new window or tab >>Importance of phagosomal functionality for growth restriction of Mycobacterium tuberculosis in primary human macrophages
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    2011 (English)In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 3, no 5, p. 508-518Article in journal (Refereed) Published
    Abstract [en]

    The best characterized survival mechanism of Mycobacterium tuberculosis inside the macrophage is the inhibition of phagosomal maturation. Phagosomal maturation involves several steps including fusion with lysosomes and acidification. However, it has not been elucidated which components of phagosomal maturation correlate with growth restriction of virulent mycobacteria in human macrophages, and we aimed to study this. We infected human monocyte-derived macrophages with M. tuberculosis and assessed bacterial replication, translocation of CD63 to the phagosome, and phagosomal acidification. We found that unstimulated macrophages were able to control infection with M. tuberculosis upon inoculation at a low, but not high, multiplicity of infection (MOI). H37Rv and H37Ra infection, at both high and low MOI, led to equally ineffective translocation of CD63 to the phagosome. This was true despite the impaired growth ability of H37Rv at the low MOI and of H37Ra even at the high MOI, indicating that inhibition of CD63 translocation was not sufficient for growth to occur. On the other hand, acidification of mycobacterial phagosomes was more efficient at a low MOI with both mycobacterial strains, consistent with a role for phagosomal acidification in restricting M. tuberculosis growth. Inhibition of the vacuolar H+-ATPase as well as of cathepsin D led to enhanced mycobacterial replication inside the macrophage. We conclude that acidification and related functional aspects of the mature phagosome are important factors for restriction of M. tuberculosis replication in human macrophages.

    Place, publisher, year, edition, pages
    S. Karger, 2011
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-65447 (URN)10.1159/000325297 (DOI)000294572500008 ()21576918 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council|529-2003-5994,2005-7046,2006-5968,2007-2673,2009-3821|Bill and Melinda Gates Foundation||SIDA/SAREC||Ekhaga Foundation||Carl Trygger Foundation||King Gustaf V 80-Year Memorial Foundation||County Council of Ostergotland||Swedish Heart Lung Foundation||Oskar II Jubilee Foundation||Clas Groschinsky Foundation||Soderbergs Foundation||Colorado State University, Fort Collins (NIH, NIAID)|HHSN26620040 0091C|

    Available from: 2011-02-08 Created: 2011-02-08 Last updated: 2018-01-12Bibliographically approved
    2. Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility
    Open this publication in new window or tab >>Replication Rates of Mycobacterium tuberculosis in Human Macrophages Do Not Correlate with Mycobacterial Antibiotic Susceptibility
    Show others...
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112426-Article in journal (Refereed) Published
    Abstract [en]

    The standard treatment of tuberculosis (TB) takes six to nine months to complete and this lengthy therapy contributes to the emergence of drug-resistant TB. TB is caused by Mycobacterium tuberculosis (Mtb) and the ability of this bacterium to switch to a dormant phenotype has been suggested to be responsible for the slow clearance during treatment. A recent study showed that the replication rate of a non-virulent mycobacterium, Mycobacterium smegmatis, did not correlate with antibiotic susceptibility. However, the question whether this observation also holds true for Mtb remains unanswered. Here, in order to mimic physiological conditions of TB infection, we established a protocol based on long-term infection of primary human macrophages, featuring Mtb replicating at different rates inside the cells. During conditions that restricted Mtb replication, the bacterial phenotype was associated with reduced acid-fastness. However, these phenotypically altered bacteria were as sensitive to isoniazid, pyrazinamide and ethambutol as intracellularly replicating Mtb. In support of the recent findings with M. smegmatis, we conclude that replication rates of Mtb do not correlate with antibiotic tolerance.

    Place, publisher, year, edition, pages
    Public Library of Science, 2014
    National Category
    Clinical Medicine Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-113014 (URN)10.1371/journal.pone.0112426 (DOI)000345250400061 ()25386849 (PubMedID)
    Note

    Funding Agencies|Bill and Melinda Gates Foundation; Swedish Research Council [2009-3821, 2012-3349]; Swedish International Development Cooperation Agency; Swedish Heart-Lung Foundation; King Oscar II Foundation; Carl Trygger Foundation; Clas Groschinsky Foundation

    Available from: 2015-01-12 Created: 2015-01-08 Last updated: 2018-01-11
  • 65.
    Rauch, Katharina S.
    et al.
    Univ Freiburg, Germany; Fac Biol, Germany.
    Hils, Miriam
    Univ Freiburg, Germany; Fac Biol, Germany.
    Menner, Alexandra J.
    Univ Freiburg, Germany; Fac Biol, Germany.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Minguet, Susana
    Univ Freiburg, Germany; Fac Biol, Germany; Univ Freiburg, Germany; Max Planck Inst Immunol and Epigenet, Germany.
    Aichele, Peter
    Univ Freiburg, Germany; Univ Freiburg, Germany.
    Schachtrup, Christian
    Fac Med, Germany.
    Schachtrup, Kristina
    Univ Freiburg, Germany; Fac Biol, Germany.
    Regulatory T cells characterized by low Id3 expression are highly suppressive and accumulate during chronic infection2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 102835-102851Article in journal (Refereed)
    Abstract [en]

    Foxp3(+) regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3(lo) Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3(hi) into Id3(lo) Treg cells and during chronic infection Id3(lo) Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.

  • 66.
    Regnström, K.J.
    et al.
    School of Pharmacy, University of Connecticut, Storrs, CT, USA.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Pharmacogenomics in the evaluation of efficacy and adverse events during clinical development of vaccines2008In: Pharmacogenomics in Drug Discovery and Development: From Bench to Bedside / [ed] Qing Yan, Humana Press, 2008, Vol. 448, p. 469-479Chapter in book (Other academic)
    Abstract [en]

    The understanding of vaccine-induced immune responses in adults and infants is limited. Current vaccination schedules for infants are frequently debated. Especially, the relationship among the timing, the frequency of the dosing, and the generation of an immunological memory are debated. Vaccine antigen-induced cytokine responses to vaccinations given in infancy are of particular interest because little is known about cellular responses in this age, and the information available is based on antibody responses. Pharmacogenomics is ideally suited to study cellular responses related to immune response, in addition, toxicity, inflammation, apoptosis, stress, and oncogenesis can be monitored, since the expression of thousands of genes can be measured in a single experiment. © 2008 Humana Press, a part of Springer Science + Business Media, LLC.

  • 67.
    Saeidi, Alireza
    et al.
    Univ Malaya, Malaysia.
    Zandi, Keivan
    Emory Univ, GA USA.
    Cheok, Yi Ying
    Univ Malaya, Malaysia.
    Saeidi, Hamidreza
    Univ Putra Malaysia, Malaysia.
    Wong, Won Fen
    Univ Malaya, Malaysia.
    Lee, Chalystha Yie Qin
    Univ Malaya, Malaysia.
    Cheong, Heng Choon
    Univ Malaya, Malaysia.
    Yong, Yean Kong
    Univ Malaya, Malaysia; Xiamen Univ Malaysia, Malaysia.
    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 Muthu
    Cent Univ Tamil Nadu, India.
    T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2569Article, review/survey (Refereed)
    Abstract [en]

    T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.

  • 68.
    Sharma, Sumit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Frodlund, Jonas
    Vastervik Hosp, 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.
    Ledin, Torbjörn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Detection of rotavirus- and norovirus-specific IgG memory B cells in tonsils2019In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 91, no 2, p. 326-329Article in journal (Refereed)
    Abstract [en]

    Because rotavirus (RV) and norovirus (NoV) are transmitted through the fecal-oral route, tonsils due to their location within the oropharynx may sample or become infected with these viruses. We investigated if RV and NoV RNA/antigen, or virus-specific memory/plasma B cells can be detected in the tonsils. While neither RV/NoV antigen, nor genomic RNA was detected, 90% (27/30) of tonsils tested had RV- and NoV-specific IgG memory B cells. However, the mechanism explaining how these cells get there (whether because of local induction or homing after induction at other sites) and the role these cells might play during active infection is not yet clear.

  • 69.
    Singh, Susmita K.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Anna-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindestam Arlehamn, Cecilia S.
    La Jolla Institute Allergy and Immunol, CA USA.
    Sette, Alessandro
    La Jolla Institute Allergy and Immunol, CA 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.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells2016In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 186, no 12, p. 3083-3093Article in journal (Refereed)
    Abstract [en]

    HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC) mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB. Human immature DCs coinfected with HIV/Mtb had decreased expression of human leukocyte antigen antigen D related and the costimulatory molecules CD40, CD80, and CD86. In addition, Mtb-infected DCs triggered a significant release of the proinflammatory cytokines IL-6, IL-1 beta, and tumor necrosis factor-alpha, whereas coinfected DCs did not. To assess the DC antigen presentation capacity, we measured interferon-gamma from co-cultures of DCs and autologous Mtb antigen-specific CD4(+) T cells. Interferon-gamma release was significantly reduced when purified protein derivative- and Ag85B-specific CD4(+) T cells had been activated with coinfected DCs compared to Mtb-infected DCs, and this effect was attributed to Mtb antigen processing rather than peptide major histocompatibility complex class II loading. Evaluating autophagy as a measure of vesicular processing and maturation further revealed that HIV efficiently blocks initiation of this pathway during coinfection. Overall, our results demonstrate that HIV impairs Mtb antigen presentation in DCs, thereby suppressing an important cell linking innate and adaptive immune response in TB.

  • 70.
    Smith, Amber R.
    et al.
    University of Kansas, KS 66045 USA.
    Marquez, Rebecca T.
    University of Kansas, KS 66045 USA.
    Tsao, Wei-Chung
    University of Kansas, KS 66045 USA.
    Pathak, Surajit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Roy, Alexandria
    University of Kansas, KS 66045 USA.
    Ping, Jie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Wilkerson, Bailey
    University of Kansas, KS 66045 USA.
    Lan, Lan
    University of Kansas, KS 66045 USA.
    Meng, Wenjian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Neufeld, Kristi L.
    University of Kansas, KS 66045 USA; University of Kansas, KS 66103 USA.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Xu, Liang
    University of Kansas, KS 66045 USA; University of Kansas, KS 66103 USA.
    Tumor suppressive microRNA-137 negatively regulates Musashi-1 and colorectal cancer progression2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 14, p. 12558-12573Article in journal (Refereed)
    Abstract [en]

    Stem cell marker, Musashi-1 (MSI1) is over-expressed in many cancer types; however the molecular mechanisms involved in MSI1 over-expression are not well understood. We investigated the microRNA (miRNA) regulation of MSI1 and the implications this regulation plays in colorectal cancer. MicroRNA miR-137 was identified as a MSI1-targeting microRNA by immunoblotting and luciferase reporter assays. MSI1 protein was found to be highly expressed in 79% of primary rectal tumors (n=146), while miR-137 expression was decreased in 84% of the rectal tumor tissues (n=68) compared to paired normal mucosal samples. In addition to reduced MSI1 protein, exogenous expression of miR-137 inhibited cell growth, colony formation, and tumorsphere growth of colon cancer cells. Finally, in vivo studies demonstrated that induction of miR-137 can decrease growth of human colon cancer xenografts. Our results demonstrate that miR-137 acts as a tumor-suppressive miRNA in colorectal cancers and negatively regulates oncogenic MSI1.

  • 71.
    Stenler, S
    et al.
    Karolinska Cell Therapy Center, Karolinska University Hospital , 141 86 Stockholm , Sweden.
    Lundin, K E
    Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet , SE-141 86 Huddinge , Sweden.
    Hansen, L
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , 171 77 Stockholm , Sweden.
    Petkov, S
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , 171 77 Stockholm , Sweden.
    Mozafari, N
    Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet , SE-141 86 Huddinge , Sweden.
    Isaguliants, M
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , 171 77 Stockholm , Sweden.
    Blomberg, P
    Karolinska Cell Therapy Center, Karolinska University Hospital , 141 86 Stockholm , Sweden.
    Smith, C I E
    Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet , SE-141 86 Huddinge , Sweden.
    Goldenberg, D M
    Immunomedics, Inc.; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey 07950 , USA.
    Chang, C-H
    Immunomedics, Inc.; IBC Pharmaceuticals, Inc., Morris Plains, New Jersey 07950 , USA.
    Ljungberg, K
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , 171 77 Stockholm , 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.
    Wahren, B
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , 171 77 Stockholm , Sweden.
    Immunization with HIV-1 envelope T20-encoding DNA vaccines elicits cross-clade neutralizing antibody responses.2017In: Human Vaccines & Immunotherapeutics, ISSN 2164-5515, E-ISSN 2164-554X, Vol. 13, no 12, p. 2849-2858Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic immunization is expected to induce the expression of antigens in a native form. The encoded peptide epitopes are presented on endogenous MHC molecules, mimicking antigen presentation during a viral infection. We have explored the potential of enfuvirtide (T20), a short HIV peptide with antiviral properties, to enhance immune response to HIV antigens. To generate an expression vector, the T20 sequence was cloned into a conventional plasmid, the novel minicircle construct, and a replicon plasmid. In addition, three conventional plasmids that express the envelope of HIV-1 subtypes A, B and C and contain T20 in their gp41 sequences were also tested.

    RESULTS: All combinations induced HIV-specific antibodies and cellular responses. The addition of T20 as a peptide and as an expression cassette in the three DNA vectors enhanced antibody responses. The highest anti-HIV-1 Env titers were obtained by the replicon T20 construct. This demonstrates that besides its known antiviral activity, T20 promotes immune responses. We also confirm that the combination of slightly divergent antigens improves immune responses.

    CONCLUSIONS: The antiretroviral T20 HIV-1 sequence can be used as an immunogen to elicit binding and neutralizing antibodies against HIV-1. These, or similarly modified gp41 genes/peptides, can be used as priming or boosting components for induction of broadly neutralizing anti-HIV antibodies. Future comparative studies will reveal the optimal mode of T20 administration.

  • 72.
    Stratmann, Johannes
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Gabilondo, Hugo
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. University of Autonoma Madrid, Spain.
    Benito-Sipos, Jonathan
    University of Autonoma Madrid, Spain.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neuronal cell fate diversification controlled by sub-temporal action of Kruppel2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e19311e19311Article in journal (Refereed)
    Abstract [en]

    During Drosophila embryonic nervous system development, neuroblasts express a programmed cascade of five temporal transcription factors that govern the identity of cells generated at different time-points. However, these five temporal genes fall short of accounting for the many distinct cell types generated in large lineages. Here, we find that the late temporal gene castor sub-divides its large window in neuroblast 5-6 by simultaneously activating two cell fate determination cascades and a sub-temporal regulatory program. The sub-temporal program acts both upon itself and upon the determination cascades to diversify the castor window. Surprisingly, the early temporal gene Kruppel acts as one of the sub-temporal genes within the late castor window. Intriguingly, while the temporal gene castor activates the two determination cascades and the sub-temporal program, spatial cues controlling cell fate in the latter part of the 5-6 lineage exclusively act upon the determination cascades.

  • 73.
    Svensson, Judit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lindau, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Mirrasekhian, Elahe
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Lash, Gendie E.
    Newcastle University, England.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. 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.
    The Human Fetal Placenta Promotes Tolerance against the Semiallogeneic Fetus by Inducing Regulatory T Cells and Homeostatic M2 Macrophages2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 4, p. 1534-1544Article in journal (Refereed)
    Abstract [en]

    A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal-placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14(+)CD163(+)CD206(+)CD209(+) phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25(high)CD127(low)Foxp3(+) Tregs in parallel with increased IL-10 production, whereas production of IFN-gamma (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-beta, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance.

  • 74.
    Söderberg (Appelgren), Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic. 

    In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells) in addition to cells of innate immunity can release ET-like structures, in this case consisting of mitochondrial (mt) DNA. mtDNA can act as a damage-associated pattern molecule (DAMP) and promote inflammation, and increased levels of mtDNA has been observed in AAV. Our finding broadens our perspective of the possible roles of T and B cells in immunological responses, and should be further investigated in AAV. In paper IV, we observed reduced frequencies of MZ-like B cells, considered to be innate-like B cells that produce natural antibodies, and of the proposed regulatory B (Breg) cell populations CD24highCD27+ and CD25+CD27+ B cells in patients, particularly in those with active disease. We also observed the phenotypes of these different Breg cell populations to be different from the corresponding cells in HC.

    We hypothesize that the increased activation potential by neutrophils in AAV to produce ROS and undergo NETosis/necrosis contribute to the excessive inflammation as well as an increased antigen load of PR3 and MPO, and that this in combination with dysregulation of innate-like B cells and Breg cells could lead to break of tolerance to these antigens and production of pathogenic autoantibodies. ANCA can in turn activate neutrophils to release NETs, suggesting a vicious circle in disease development.

    List of papers
    1. Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission
    Open this publication in new window or tab >>Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission
    Show others...
    2015 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 54, no 11, p. 2085-2094Article in journal (Refereed) Published
    Abstract [en]

    Objectives. Neutrophil extracellular traps (NETs) have been visualized at the site of ANCA-associated vasculitis (AAV) lesions. Increased levels of NET remnants in the circulation have been reported in some AAV patients with active disease. The aim of the present study was to analyse NET remnants in a larger cohort of AAV patients with varying degrees of disease activity and to elucidate possible factors responsible for remnant variation. Methods. Levels of NET remnants in the circulation of healthy controls (HCs; n =31) and AAV patients (n =93) were determined with ELISA. NET remnants were then correlated with ANCA levels, spontaneous and induced cell death (NETosis/necrosis) in vitro, neutrophil count and corticosteroid therapy. Results. Patients with active disease showed higher levels of circulating NET remnants compared with patients in remission (P=0.026) and HCs (P=0.006). From patients sampled during both remission and active disease, we found increased levels during active disease (P=0.0010). In remission, ANCA-negative patients had higher levels of NET remnants than ANCA-positive patients and a negative correlation was observed between NET remnants and PR3-ANCA (rs = 0.287, P=0.048). NET remnants correlated with neutrophil count in HCs (rs =0.503, P=0.014) but not in patients during remission. Neutrophils from patients showed enhanced spontaneous cell death (P=0.043). Conclusion. We found increased levels of circulating NET remnants in patients with active AAV. Furthermore, AAV patients exhibited an increased propensity for spontaneous cell death. NET remnant levels seem to be positively related to disease activity and neutrophil count, but inversely related to ANCA at least during remission.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS, 2015
    Keywords
    small vessel vasculitis; ANCA-associated vasculitis; neutrophil extracellular trap (NET); NET remnants; ANCA
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123334 (URN)10.1093/rheumatology/kev217 (DOI)000364760700023 ()26170375 (PubMedID)
    Available from: 2015-12-14 Created: 2015-12-11 Last updated: 2019-02-11
    2. Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies
    Open this publication in new window or tab >>Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies
    Show others...
    2014 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 176, no 3, p. 363-372Article in journal (Refereed) Published
    Abstract [en]

    Anti-neutrophil cytoplasmic antibodies (ANCA) are thought to be pathogenic in ANCA-associated vasculitis (AAV) by stimulating polymorphonuclear leucocytes (PMNs) to degranulate and produce reactive oxygen species (ROS). The aim of this study was to investigate if PMNs from AAV patients are stimulated more readily by ANCA compared with PMNs from healthy controls (HCs). Differences in ANCA characteristics that can account for different stimulation potential were also studied. PMNs from five AAV patients and five HCs were stimulated with 10 different immunoglobulins (Ig)Gs, purified from PR3-ANCA-positive patients, and ROS production, degranulation and neutrophil extracellular trap (NET) formation was measured. ANCA levels, affinity and clinical data of the AAV donors were recorded. The results show that PMNs from AAV patients produce more intracellular ROS (P=0 center dot 019), but degranulate to a similar extent as PMNs from HCs. ROS production correlated with NET formation. Factors that may influence the ability of ANCA to activate PMNs include affinity and specificity for N-terminal epitopes. In conclusion, our results indicate that PMNs from AAV patients in remission behave quite similarly to HC PMNs, with the exception of a greater intracellular ROS production. This could contribute to more extensive NET formation and thus an increased exposure of the ANCA autoantigens to the immune system.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2014
    Keywords
    ANCA-associated vasculitis; autoimmunity; degranulation; reactive oxygen species
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-109138 (URN)10.1111/cei.12301 (DOI)000337516700008 ()24666336 (PubMedID)
    Available from: 2014-08-13 Created: 2014-08-11 Last updated: 2018-07-18Bibliographically approved
    3. Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
    Open this publication in new window or tab >>Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C
    Show others...
    2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed) Published
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

    Place, publisher, year, edition, pages
    Washington, DC, United States: National Academy of Sciences, 2018
    Keywords
    CpG-C, DAMP, immune DNA sensing, lymphocyte signaling, mitochondrial DNA release
    National Category
    Basic Medicine Immunology in the medical area
    Research subject
    Economic Information Systems
    Identifiers
    urn:nbn:se:liu:diva-144187 (URN)10.1073/pnas.1711950115 (DOI)000423091400018 ()29295921 (PubMedID)2-s2.0-85042104216 (Scopus ID)
    Funder
    Swedish Cancer Society
    Note

    Funding agencies: Linkoping Medical Society; Linkoping University; ALF grants; Region Ostergotland, Sweden; Linkoping University Cancer; Ingrid Asp Foundation; Swedish Cancer Society

    Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2019-12-09Bibliographically approved
    4. Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis
    Open this publication in new window or tab >>Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis
    2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2242Article in journal (Refereed) Published
    Abstract [en]

    In mice, B1 and marginal zone (MZ) B-cells play an important role in prevention of autoimmunity through production of regulatory cytokines and natural antibodies. There is limited knowledge about the human counterparts of these cells. We therefore investigated functions of MZ-like B-cells and the frequency of circulating MZ-like and Bl-like B-cells in healthy controls (HC), as well as in patients with autoimmune vasculitis to learn more about the role of these cells in autoimmune disease. After stimulation with CpG oligodeoxynucleotides (ODN) of class B in vitro, MZ-like B-cells were the main producers of IgM whereas switched memory B-cells primarily produced IgG and IgA. TNF and IL-10 were produced by both MZ-like and switched memory B-cells. Neither antibody nor TNF/IL-10 production by the B-cell subsets differed between patients and HC. Patients with autoimmune vasculitis, irrespective of disease activity, had lower percentage and absolute numbers of circulating MZ-like B-cells, and lower absolute numbers of B1-like B-cells. The percentage of B1-like B-cells was reduced during active disease. These findings remained significant when the analysis was confined to active treatment-naive patients (disease onset).Our results suggest that human innate-like B-cells might have a physiological role in prevention of autoimmunity.

    Place, publisher, year, edition, pages
    FRONTIERS MEDIA SA, 2018
    Keywords
    marginal-zone (MZ) B-cells; B1 B-cells; innate-like B-cells; natural antibodies; T-cell-independent antibodies; IgM; autoimmunity; anti-neutrophil cytoplasmic autantibody (ANCA) associated vasculitis
    National Category
    Immunology
    Identifiers
    urn:nbn:se:liu:diva-152056 (URN)10.3389/fimmu.2018.02242 (DOI)000446095400001 ()
    Note

    Funding Agencies|Ingrid Asps Foundation; Swedish Society of Nephrology; Swedish Renal Foundation

    Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2020-01-16
  • 75.
    Söderberg, Daniel
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Neutrophil Extracellular Traps in ANCA-Associated Vasculitis2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, no UNSP 256Article, review/survey (Refereed)
    Abstract [en]

    A group of pauci-immune vasculitides, characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of antineutrophil cytoplasmic antibodies (ANCAs), is referred to as ANCA-associated vasculitis (AAV). ANCAs against proteinase 3 (PR3) (PR3-ANCA) or myeloperoxidase (MPO) (MPO-ANCA) are found in over 90% of patients with active disease, and these ANCAs are implicated in the pathogenesis of AAV. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally, it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. AAV patients also possess elevated levels of NETs in the circulation. ANCAs are capable of inducing NETosis in neutrophils, and their potential to do so has been shown to be affinity dependent and to correlate with disease activity. Neutrophils from AAV patients are also more prone to release NETs spontaneously than neutrophils from healthy blood donors. NETs contain proinflammatory proteins and are thought to contribute to vessel inflammation directly by damaging endothelial cells and by activating the complement system and indirectly by acting as a link between the innate and adaptive immune system through the generation of PR3-and MPO-ANCA. Injection of NET-loaded myeloid dendritic cells into mice results in circulating PR3-and MPO-ANCA and the development of AAV-like disease. NETs have also been shown to be essential in a rodent model of drug-induced vasculitis. NETs induced by propylthiouracil could not be degraded by DNaseI, implying that disordered NETs might be important for the generation of ANCAs. NET degradation was also highlighted in another study showing that AAV patients have reduced DNaseI activity resulting in less NET degradation. With this in mind, it might be that prolonged exposure to proteins in the NETs due to the overproduction of NETs and/or reduced clearance of NETs is important in AAV. However, not all ANCAs are pathogenic and some might possibly also aid in the clearance of NETs. A dual role for ANCAs in relation to circulating NET levels has been proposed because a negative correlation was observed between PR3-ANCA and NET remnants in patients in remission.

  • 76.
    Tengdelius, Mattias
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Fucoidan-Mimetic Glycopolymers: Synthesis and Biomedical Applications2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The marine polysaccharide fucoidan has demonstrated several interesting biological properties, for instance being antiviral, anticoagulant, anti-inflammatory, anticancer, and platelet activating. Many of these properties are desirable for various biomedical applications. Yet, there are few reports on fucoidan being used in such applications. The reasons for this are primarily the heterogeneity and low structural reproducibility of fucoidan.

    This thesis describes the synthesis of polymers with pendant saccharides bearing the key structural features of fucoidan. These glycopolymers were synthesized via different radical polymerization techniques yielding polymers of different chain lengths and dispersity. These glycopolymers showed antiviral and platelet activating properties similar to those of natural fucoidan, thus making them fucoidan-mimetic glycopolymers. However, compared to fucoidan from natural sources, the fucoidan-mimetic glycopolymers had homogeneous and reproducible structures making them suitable for biomedical applications.

    Further studies demonstrated that platelet activation, caused by these glycopolymers, showed dose-response curves almost identical to fucoidan. The platelet activation was induced via intracellular signaling and caused platelet surface changes similar to those of fucoidan. Fucoidan-mimetic glycopolymers can therefore be used as unique biomolecular tools for studying the molecular and cellular responses of human platelets.

    Fucoidan-mimetic glycopolymers generally assert their antiviral activity by blocking viral entry to host cells, thus inhibiting spreading of the viral infection but not acting virucidal, i.e. not killing the viruses. Introduction of hydrophobic groups to the polymer’s chain ends improved the antiviral properties significantly and is an important step towards yielding glycopolymers with virucidal properties.

    The fucoidan-mimetic glycopolymers were also applied as capping agents when synthesizing gold nanoparticles. These fucoidan-mimetic glycopolymer coated gold nanoparticles showed improved colloidal stability compared to uncapped gold nanoparticles. Furthermore, the nanoparticles also demonstrated selective cytotoxicity against a human colon cancer cell line over fibroblast cells.

    List of papers
    1. Synthesis and biological evaluation of fucoidan-mimetic glycopolymers through cyanoxyl-mediated free-radical polymerization
    Open this publication in new window or tab >>Synthesis and biological evaluation of fucoidan-mimetic glycopolymers through cyanoxyl-mediated free-radical polymerization
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    2014 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 7, p. 2359-2368Article in journal (Refereed) Published
    Abstract [en]

    The sulfated marine polysaccharide fucoidan has been reported to have health benefits ranging from antivirus and anticancer properties to modulation of high blood pressure. Hence, they could enhance the biological function of materials for biomedical applications. However, the incorporation of fucoidan into biomaterials has been difficult, possibly due to its complex structure and lack of suitable functional groups for covalent anchoring to biomaterials. We have developed an approach for a rapid synthesis of fucoidanmimetic glycopolymer chains through cyanoxyl-mediated free-radical polymerization, a method suitable for chain-end functionalizing and subsequent linkage to biomaterials. The resulting sulfated and nonsulfated methacrylamido alpha-L-fucoside glycopolymers fucoidan-mimetic properties were studied in HSV-1 infection and platelet activation assays. The sulfated glycopolymer showed similar properties to natural fucoidan in inducing platelet activation and inhibiting HSV-1 binding and entry to cells, thus indicating successful syntheses of fucoidan-mimetic glycopolymers.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2014
    National Category
    Chemical Sciences Clinical Medicine Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-109382 (URN)10.1021/bm5002312 (DOI)000339090500003 ()24813544 (PubMedID)
    Available from: 2014-08-15 Created: 2014-08-15 Last updated: 2017-12-05Bibliographically approved
    2. Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles
    Open this publication in new window or tab >>Synthesis and anticancer properties of fucoidan-mimetic glycopolymer coated gold nanoparticles
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    2015 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 51, no 40, p. 8532-8535Article in journal (Refereed) Published
    Abstract [en]

    Gold nanoparticles coated with fucoidan-mimetic glycopolymers were synthesized that displayed good colloidal stability and promising anti-cancer properties. Fucoidan mimetic glycopolymers on their own were nontoxic, while glycopolymer coated gold nanoparticles displayed selective cytotoxicity to human colon cancer cell lines (HCT116) while it was non-toxic to mouse fibroblast cells (NIH3T3).

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2015
    National Category
    Chemical Sciences Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-119269 (URN)10.1039/c5cc02387d (DOI)000354043200034 ()25892661 (PubMedID)
    Note

    Funding Agencies|Swedish Strategic Research StemTherapy

    Available from: 2015-06-12 Created: 2015-06-12 Last updated: 2017-12-04
  • 77.
    Tomičić, Sara
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Environmental and immunological factors associated with allergic disease in children2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Allergic diseases are characterised by dysregulated immune responses. The first manifestation of the atopic phenotype is often food allergy, with symptoms like eczema. Food allergy in children is generally outgrown before 3 years of age, but a temporary food elimination diet is often advocated. The prevalence of allergic diseases has increased in affluent countries during the last decades, possibly as a consequence of a changed lifestyle leading to decreased microbial load.

    Aim: To investigate humoral, mucosal and cell-mediated immunity in association to allergy and allergy development in young children and relate this to environmental factors.

    Subjects: Two cohorts of children were investigated; 1) Children from countries with high (Sweden) and low (Estonia) prevalence of allergy that were followed prospectively from birth to 5 years of age. 2) Infants with eczema and suspected food allergy that were followed prospectively to 4 ½ years of age.

    Methods: Endotoxin levels were analysed in house dust samples. Antibodies were measured in serum and saliva samples with ELISA. Food allergen induced cytokine responses were analysed in mononuclear cells.

    Results: The microbial load, delineated as endotoxin levels, was higher in house dust from Estonia than Sweden and was, in Swedish children, inversely associated with sensitisation and clinical symptoms of allergy. The decreased microbial load in Sweden may have an impact on mucosal immune responses as different IgA antibody patterns were observed in Sweden and Estonian children with much lower secretory (S)IgA antibody levels and high proportion of non-SIgA, i.e. IgA antibodies lacking the secretory component, in the Swedish children. Moreover, low levels of SIgA were associated with clinical symptoms in sensitised children.

    High IgG4 antibody levels to food allergens during infancy were associated with faster tolerance development in food allergic children. Cytokine responses by mononuclear cells after allergen stimulation was upregulated with age in children with prolonged food allergy, but not in children who develop tolerance before 4 ½ years of age, possibly because of the prolonged elimination diet in the former group.

    Summary: Reduced microbial exposure in affluent countries may affect the mucosal immune responses during infancy, possibly resulting in an increased risk of developing allergic disease. High levels of IgG4 antibodies during infancy are associated with faster achievement of tolerance in food allergic children. Allergen elimination during infancy may result in a dysfunctional cytokine response.

    List of papers
    1. Endotoxin levels in Estonian and Swedish house dust and atopy in infancy
    Open this publication in new window or tab >>Endotoxin levels in Estonian and Swedish house dust and atopy in infancy
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    2003 (English)In: Clinical and Experimental Allergy, ISSN 1365-2222, Vol. 33, no 3, p. 295-300Article in journal (Refereed) Published
    Abstract [en]

    Background Immune responses, including those to allergens, may be T helper (Th)2 skewed in newborns. In order to redress the fetal Th1/Th2 imbalance, Th1-stimulating factors, such as bacterial endotoxin, may be required. The increasing prevalence and severity of atopic diseases in industrialized countries, which are in marked contrast with the low prevalence of allergy among children in the formerly socialist countries of Europe, have been suggested to be caused by a reduced microbial stimulation.

    Aim To relate the endotoxin levels in house dust from two countries with a low (Estonia) and a high (Sweden) prevalence of allergy to the development of atopic disease and sensitization in the children during the first 2 years of life.

    Methods The study included 108 children from Tartu, Estonia and 111 children from Linköping, Sweden. Skin prick tests were performed at 3, 6, 12 and 24 months of age, and questionnaires were distributed to the families. At 24 months, a paediatrician examined the children. Dust samples were collected from mattresses and carpets and the endotoxin concentration was determined by a chromogenic Limulus assay.

    Results The endotoxin levels were higher in Estonian than in Swedish house dust (median levels 29 (range 0.25–280) and 14 (range 0.25–99) EU/mg dust, respectively, P < 0.001). Furthermore, the levels were inversely related to the development of atopic disease and sensitization in the Swedish, but not in the Estonian, children.

    Conclusions The low prevalence of atopic disease in Estonia may, at least in part, be related to the high endotoxin levels in this country. The findings support that high levels of endotoxin, or other bacterial products with Th1-stimulating properties, might protect children from developing atopic disease.

    Keywords
    atopy, childhood, endotoxin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13204 (URN)10.1046/j.1365-2222.2003.01562.x (DOI)000181330600006 ()12614441 (PubMedID)
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2013-05-14
    2. High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
    Open this publication in new window or tab >>High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life
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    2009 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, Vol. 5, no 1, p. 35-41Article in journal (Refereed) Published
    Abstract [en]

    Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty-nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme-linked immunosorbent assay and UniCAP® before and after a 6-wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G4 antibodies to ovalbumin and β-lactoglobulin and also higher IgG4/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG4/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6-wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG4 and high ratios of IgG4/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.

    Keywords
    food allergy, elimination diet, tolerance, immunoglobulin G4, eczema, children, immunoglobulin E
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13205 (URN)10.1111/j.1399-3038.2008.00738.x (DOI)
    Note
    The fulltext of this work is available at Blackwell-Syergy: Sara Tomičić, Gunilla Norrman, Karin Fälth-Magnusson, Maria C. Jenmalm, Irene Devenney and Malin Fagerås Böttcher, High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life, 2008, Pediatric Allergy and Immunology, (5), 1, 35-41. http://dx.doi.org/10.1111/j.1399-3038.2008.00738.x Copyright: Blackwell-Synergy http://www.blackwellpublishing.com/ Available from: 2009-02-26 Created: 2009-02-26 Last updated: 2010-02-06Bibliographically approved
    3. Slow salivary secretory IgA maturation may relate to low microbial pressure and allergic symptoms in sensitized children
    Open this publication in new window or tab >>Slow salivary secretory IgA maturation may relate to low microbial pressure and allergic symptoms in sensitized children
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    2011 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 70, no 6, p. 572-577Article in journal (Refereed) Published
    Abstract [en]

    It is unknown why allergic symptoms do not develop in all sensitized children. We analyzed prospectively the postnatal secretory IgA (SIgA) development and whether high SIgA levels would protect sensitized infants from developing allergic symptoms. Salivary total IgA and SIgA levels were determined by ELISA, and allergy development was investigated at 3, 6, and 12 mo and at 2 and 5 y in two birth cohorts in Estonia (n = 110) and Sweden (n = 91), two geographically adjacent countries with different living conditions and allergy incidence. Total and SIgA levels increased with age, reaching adult levels at the age of 5. Virtually, all salivary IgA in Estonian children was in the secretory form, while a major part of IgA in Swedish saliva lacked the secretory component up to 2 y of age. In Sweden, high levels of salivary IgA without secretory component correlated inversely with house dust endotoxin levels. High SIgA levels were associated with less development of allergic symptoms in sensitized Swedish children. In conclusion, postnatal maturation of the salivary SIgA system proceeds markedly slower in Swedish than Estonian children, possibly as a consequence of low microbial pressure. SIgA may limit allergy-mediated tissue damage at mucosal surfaces in sensitized individuals.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-73314 (URN)10.1203/PDR.0b013e318232169e (DOI)297433900005 ()21857384 (PubMedID)
    Note

    When submitted this article was titled "Slower maturation of the secretory IgA system in Swedish than Estonian children: possibly caused by low microbial pressure and related to expression of allergy in sensitised individuals".

    Available from: 2012-01-03 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
    4. Dysregulated Th1 and Th2 responses in food-allergic children: Does elimination diet contribute to the dysregulation?
    Open this publication in new window or tab >>Dysregulated Th1 and Th2 responses in food-allergic children: Does elimination diet contribute to the dysregulation?
    2010 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 21, no 4, p. 649-655Article in journal (Refereed) Published
    Abstract [en]

    Infants with eczema and sensitization to foods are recommended skin care and, if food allergy is proven, an elimination diet. Although most of these children tolerate foods before 3 yr of age, some children experience prolonged food allergy. To our knowledge, no prospective study has investigated the cytokine profile in food-sensitized eczematous children with prolonged food intolerance. The aim of the study was to prospectively investigate the development of cytokine production induced by food allergen in food-sensitized eczematous children who, at 41/2 yr of age, were allergic or tolerant to egg or milk. Twenty-one eczematous infants, [age 5 (3-10) months; median and range], sensitized to egg and/or milk were included, put on elimination diet and followed prospectively. At 41/2 yr of age, the children were defined as tolerant or allergic to egg and/or milk based on open or double-blind placebo-controlled food challenges. Peripheral blood mononuclear cells (PBMC) were isolated from the children on inclusion, after 6 wk of elimination diet, and at 3 and 41/2 yr of age. Ovalbumin, beta-lactoglobulin and tetanus toxoid-induced IL-4, -5, -10, -13 and IFN-gamma production from PBMC were analyzed with enzyme-linked immunosorbent assay. The IFN-gamma and IL-5 secretion induced by food allergen at 41/2 yr was higher in cell cultures from children who were allergic to egg or milk than in tolerant children. In food-allergic children, the levels of IFN-gamma and IL-5 were higher at 41/2 yr compared with inclusion levels, but this increase was generally not observed in the tolerant children who consumed milk and egg. In conclusion, immune cells from food-allergic children on an elimination diet respond with up-regulated T helper 1 and T helper 2 cytokine secretion induced by food allergen. We hypothesize that allergen elimination may influence the regulatory mechanisms maintaining balanced immune responses to innocuous food antigens.

    Place, publisher, year, edition, pages
    Blackwell Publishing Ltd, 2010
    Keywords
    children; cytokines; elimination diet; food allergy; tolerance
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13207 (URN)10.1111/j.1399-3038.2009.00937.x (DOI)000278526100011 ()
    Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-13
  • 78.
    Ulrich, Jason D.
    et al.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Ulland, Tyler K.
    Washington Univ, MO 63130 USA.
    Mahan, Thomas E.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Song, Wilbur M.
    Washington Univ, MO 63130 USA.
    Zhou, Yingyue
    Washington Univ, MO 63130 USA.
    Reinartz, Mariska
    Washington Univ, MO 63110 USA; Radboud Univ Nijmegen, Netherlands.
    Choi, Seulah
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Jiang, Hong
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Stewart, Floy R.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Anderson, Elise
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    Wang, Yaming
    Washington Univ, MO 63130 USA; Eli Lilly and Co, IN 46285 USA.
    Colonna, Marco
    Washington Univ, MO 63130 USA.
    Holtzman, David M.
    Washington Univ, MO 63110 USA; Washington Univ, MO 63130 USA; Washington Univ, MO 63130 USA.
    ApoE facilitates the microglial response to amyloid plaque pathology2018In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 215, no 4, p. 1047-1058Article in journal (Refereed)
    Abstract [en]

    One of the hallmarks of Alzheimers disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-beta (A beta) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric A beta in the brain. In addition to influencing A beta metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1 Delta E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct A beta morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

  • 79.
    Vazquez Rodriguez, Gabriela
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Abrahamsson, Annelie
    Linköping University, Department of Clinical and Experimental Medicine.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, 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 Oncology.
    Neutrophils Promote Breast Cancer Progression and Metastasis via LFA-1 Integrin2015Conference paper (Other academic)
    Abstract [en]

    Cancer is considered an inflammatory condition where immune cells play an important role in progression and metastasis. Neutrophils may be pro- or antitumorigenic, depending on their phenotype or the number of infiltrating neutrophils in the tumor microenvironment. Massive infiltration of neutrophils in cancer tissue may elicit a cytotoxic effect, leading to tumor regression, whereas a S139 low-grade neutrophil gradient is tumor progressive. Chemokines, cytokines, and growth factors present in the tumor microenvironment, as well as cell-cell interactions mediated by integrins have shown to be determinant steps for cancer cells to break through the endothelial wall and establish metastatic niches. In this work we evaluated the role of lymphocyte functionassociated antigen 1 (LFA-1) integrin in neutrophils-mediated metastasis of estrogen receptor positive breast cancer cells (MCF-7) cells in a tumor xenograft model in zebrafish and in neutrophil infiltration in MCF-7 mammospheres. The metastatic capability of MCF-7 cells was evaluated in presence or absence of human neutrophils and with/without estradiol treatment. Two days old zebrafish embryos were injected into the perivitelline space with labeled MCF-7 cells and human neutrophils, an anti-human LFA-1 antibody (CD11a) was included. We show that estradiol treatment significantly increased the infiltration of neutrophils into MCF-7 mammospheres and this infiltration was significantly reduced by the presence of an anti-human CD11a antibody. Co-injection of MCF-7 cells with neutrophils significantly increased the migration of MCF-7 cells to distant sites in zebrafish and this effect was inhibited by using an anti-human CD11a antibody. We conclude that neutrophils affect the dissemination of breast cancer cells via LFA-1 integrin. Although estradiol increased the number of infiltrating neutrophils into mammospheres exposure to estradiol seemed to have minor effects on the dissemination in the zebrafish.

  • 80.
    Verma, Deepti
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramanarao Parasa, Venkata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martis, Mihaela-Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bhai Mehta, Ratnesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Netea, Mihai
    Radboud University of Nijmegen, Netherlands.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12305Article in journal (Refereed)
    Abstract [en]

    The reason for the largely variable protective effect against TB of the vaccine Bacille Calmette-Guerin (BCG) is not understood. In this study, we investigated whether epigenetic mechanisms are involved in the response of immune cells to the BCG vaccine. We isolated peripheral blood mononuclear cells (PBMCs) from BCG-vaccinated subjects and performed global DNA methylation analysis in combination with functional assays representative of innate immunity against Mycobacterium tuberculosis infection. Enhanced containment of replication was observed in monocyte-derived macrophages from a subgroup of BCG-vaccinated individuals (identified as responders). A stable and robust differential DNA methylation pattern in response to BCG could be observed in PBMCs isolated from the responders but not from the non-responders. Gene ontology analysis revealed that promoters with altered DNA methylation pattern were strongly enriched among genes belonging to immune pathways in responders, however no enrichments could be observed in the non-responders. Our findings suggest that BCG-induced epigenetic reprogramming of immune cell function can enhance anti-mycobacterial immunity in macrophages. Understanding why BCG induces this response in responders but not in nonresponders could provide clues to improvement of TB vaccine efficacy.

  • 81.
    Wendel, Caroline
    Linköping University, Department of Physics, Chemistry and Biology.
    In Vitro Study of Recruitment Ability of Macrophages and Trophoblasts in Early Human Pregnancy2010Independent thesis Advanced level (degree of Master (Two Years)), 40 credits / 60 HE creditsStudent thesis
    Abstract [en]

    The tolerance towards the semi-allogenic foetus is obtained through both systemic and local changes in the maternal immune response. Locally, in the decidua, the cell composition differs from that found in the blood; natural killer (NK) cells and macrophages being the major cell types. Decidual macrophages (dMØ), which are alternatively activated, and trophoblasts, placental cells of foetal origin, are believed to participate in the foetal tolerance at the foetal-maternal interface. To test the recruitment ability of macrophages and trophoblasts, and to test if these cells are responsible for the special cell composition in the decidua, a migration assay was established. In this migration assay peripheral blood mononuclear cells (PBMC) were allowed to migrate through Matrigel-coated transwell inserts into lower wells containing a recruiting stimulus. After testing several conditions, a protocol was established for further use. The results showed that in vitro alternatively activated macrophages, which display many of the surface markers as dMØ, hold a recruiting ability and recruit monocytes. Further there was an indication that trophoblasts also hold a recruiting ability. Neither cell types were shown to recruit NK cells. In conclusion, this study presents a suitable protocol for assessing chemotactic factors and different cell type’s ability to recruit cells from blood. Although the experiments need to be repeated and extended and the recruitment ability of dMØ needs to be evaluated in detail before a final conclusion can be drawn, the preliminary data indicated that macrophages and trophoblasts can recruit monocytes.

  • 82.
    Wirestam, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Biomarkers of disease activity and organ damage in systemic lupus erythematosus2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients.

    High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation. Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated.

    As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels. Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity.

    Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up.

    In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.

    List of papers
    1. Antibodies against High Mobility Group Box protein-1 (HMGB1) versus other anti-nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus
    Open this publication in new window or tab >>Antibodies against High Mobility Group Box protein-1 (HMGB1) versus other anti-nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus
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    2015 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, no 338Article in journal (Refereed) Published
    Abstract [en]

    Introduction: The non-histone nuclear protein high mobility group box protein-1 (HMGB1) is typically associated with nucleosomes, but may shuttle between the nucleus and the cytoplasm, and under some conditions also be released extracellularly and participate in systemic inflammation. Monoclonal HMGB1-targeting antibodies can ameliorate murine polyarthritis and lupus-like disease. Interestingly, autoantibodies against HMGB1 have also been described in patients with systemic lupus erythematosus (SLE), but their clinical implications remain elusive. The main aims of this study were to detect serum anti-HMGB1 antibodies in patients with SLE and relate them to other types of antinuclear antibodies (ANA), and to disease activity. Methods: 188 Swedish SLE patients meeting the 1982 American College of Rheumatology classification criteria and/or the 2012 Systemic Lupus International Collaborating Clinics classification criteria participated in the study. Anti-HMGB1 antibody levels were analysed in patient and control (n = 112) sera by an in-house ELISA using recombinant histidine-tagged HMGB1. SLE sera were also analysed for ANA by immunofluorescence (IF) microscopy (IF-ANA) using fixed HEp-2 cells, and by a line-blot assay for antigen fine-specificities. To quantify antibodies to double-stranded DNA, a fluoroenzyme-immunoassay was employed. Results: At inclusion, 23 % of the SLE patients were anti-HMGB1 antibody positive compared to 5 % of the controls. Anti-HMGB1 antibodies occurred in 49 % of the IF-ANA positive SLE patients, and in 34 % of IF-ANA negative cases (p = 0.004). Levels of anti-HMGB1 antibodies correlated with anti-dsDNA antibody levels (r = 0.49; p less than 0.001). Significant, but less pronounced correlations were found regarding anti-HMGB1 and SLE disease activity index (SLEDAI-2K: r = 0.15; p = 0.04), classical complement function (r = -0.24; p = 0.002) and complement protein C4 (r = -0.23; p = 0.002). Average anti-HMGB1 antibody levels were significantly higher among patients with homogenous +/- other IF-ANA staining patterns (median 180 AU) compared to IF-ANA negative cases (median 83 AU) (p = 0.004). Rabbit anti-HMGB1 antibodies gave rise to cytoplasmic, but not nuclear, staining of HEp-2 cells. Conclusions: We confirm that anti-HMGB1 antibodies are common in SLE and correlate with disease activity variables. Although anti-HMGB1 antibodies measured by ELISA often coincide with nuclear IF-ANA staining, our results indicate that anti-HMGB1 antibodies do not give rise to nuclear staining of the predominantly used commercial HEp-2 cell slides.

    Place, publisher, year, edition, pages
    BIOMED CENTRAL LTD, 2015
    Keywords
    HMGB1; Autoantibodies; SLE; Antinuclear antibodies; Inflammation; Clinical phenotype; Complement proteins
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-123521 (URN)10.1186/s13075-015-0856-2 (DOI)000365252900001 ()26596890 (PubMedID)
    Note

    Funding Agencies|Swedish Society for Medical Research, Region Ostergotland; Swedish Research Council; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz foundation; King Gustaf Vs 80-year foundation

    Available from: 2015-12-22 Created: 2015-12-21 Last updated: 2018-01-10
    2. Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
    Open this publication in new window or tab >>Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
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    2017 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 1, p. 83-91Article in journal (Refereed) Published
    Abstract [en]

    Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)- is typically elevated during SLE flares, and inhibits hepatocyte production of the pentraxin C-reactive protein (CRP), partly explaining the poor correlation between CRP levels and SLE disease activity. The extrahepatically produced pentraxin 3 (PTX3) shares waste disposal functions with CRP, but has not been studied extensively in SLE. We analysed serum PTX3 in SLE, and assessed its interference with IFN- in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN-, and genotyped for three PTX3 single nucleotide polymorphisms reported previously to associate with PTX3 levels. Stimulated PTX3 release was assessed in the presence or absence of IFN- in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (Pamp;lt;00001) and correlated with leucocyte variables. Patients with undetectable IFN- had 29% higher median PTX3 level than patients with detectable IFN- (P=001). PTX3 production by PBMC was inhibited by IFN-, whereas neutrophil degranulation of PTX3 was increased. No differences in PTX3 levels were observed between the SNPs. In conclusion, median serum PTX3 is lower in SLE (especially when IFN- is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN- also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.

    Place, publisher, year, edition, pages
    WILEY, 2017
    Keywords
    biomarkers; interferon-; leucocytes; pentraxin; systemic lupus erythematosus
    National Category
    Immunology
    Identifiers
    urn:nbn:se:liu:diva-138881 (URN)10.1111/cei.12957 (DOI)000402977200008 ()28257596 (PubMedID)
    Note

    Funding Agencies|Swedish Society for Medical Research, Region Ostergotland; Swedish Research Council; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz Foundation; King Gustaf Vs 80-year foundation

    Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2017-09-08
    3. Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
    Open this publication in new window or tab >>Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
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    2017 (English)In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 4, no 1, p. 7article id 000225Article in journal (Refereed) Published
    Abstract [en]

    Objective The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.

    Methods Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.

    Results Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.

    Conclusions In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.

    Place, publisher, year, edition, pages
    BMJ Publishing Group Ltd, 2017. p. 7
    National Category
    Rheumatology and Autoimmunity Neurology Clinical Laboratory Medicine Cardiac and Cardiovascular Systems Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-140711 (URN)10.1136/lupus-2017-000225 (DOI)
    Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved
  • 83.
    Yakymenko Alkaissi, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Bacterial epithelial interaction in intestinal inflammation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The intestine is constantly exposed to bacteria, invading viruses and ingested food. The intestinal barrier serves as a gate preventing passage of harmful components, and at the same time maintaining absorption of nutrients and water. There are over 300 different bacteria species in the human gastrointestinal tract (GI) comprising over 10 times as many cells as the human body. These bacteria are both of commensal and pathogenic strains in which commensal bacteria and antimicrobial peptides have an important role of controlling the intestinal colonization. The intestinal flora is sampled by the membranous cells (M cells) that are present in the follicle associated epithelium (FAE). Antigens encounter immune cells found in Peyer’s patches located in the distal ileum with FAE overlaying them. Due to environmental factors, genetic predisposition, immune dysregulation or dysbiosis the balance can be shifted which, in turn, will lead to the defect in the barrier function, leading to the development of disorders such as Crohn’s disease (CD). CD is a chronic inflammation in the GI tract, often originating in the distal ileum in FAE and associated with an increased number of adherent invasive strains of bacteria. Specifically adherent invasive E.coli (AIEC) that have been isolated from the ileum and colon of CD patients.

    The aim of the present thesis was to study bacterial epithelial interaction during inflammation in in vivo, ex vivo and in vitro models.

    In the first project we found that that Faecalibacterium prausnitzii (FP), possess anti-inflammatory properties in the ileum of an in vivo DSS induced colitis mouse model.

    In the second project, we discovered that infliximab, known to have anti-inflammatory effects by binding soluble TNF and blocking TNF receptors, reduces bacterial transcytosis across colonic biopsies of CD patients and decreases transcytosis and internalization in cell monolayers in vitro. Moreover, we demonstrated that HM427 bacteria, isolated from colonic mucosa of CD patients, uses lipid raft formations to penetrate the barrier under the influence of TNF in an in vitro model.

    In project three, we demonstrated that LF82 bacteria, which is an adherent invasive strain of E.coli that has been isolated from the ileum of CD patients, exploits FAE of CD patients and non-IBD control patients to penetrate the barrier via the CEACAM6 receptor and long polar fimbriae. We further demonstrated that there is an increased expression of CEACM6 receptor in the FAE of CD patients, which leads to increased transcytosis of LF82 compared to non-IBD control group.

    In project four, our results suggested that human α-defensin 5 significantly decreases the passage of LF82 bacteria in an in vitro and ex vivo models. Moreover, we demonstrated that CD patients have a lower expression of human α-defensin 5 in the crypts compared to the non-IBD control patients.

    Taken together, our findings have given a novel insight into the etiology of CD and into the mechanisms involved in bacterial-epithelial interaction in CD.

    List of papers
    1. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis
    Open this publication in new window or tab >>Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis
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    2013 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 10, p. 1136-1144Article in journal (Refereed) Published
    Abstract [en]

    Objective. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. Material and methods. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with Cr-51-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. Results. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in Cr-51-EDTA-passage compared to controls. Cr-51-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. Conclusions. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2013
    Keywords
    dextran sodium sulfate, inflammatory bowel disease, permeability, probiotics, tight junctions
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-99406 (URN)10.3109/00365521.2013.828773 (DOI)000324761000005 ()
    Note

    Funding Agencies|Swedish Research Council|VR-M: K2012-55X-12618-16-3|

    Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2018-04-27
    2. Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
    Open this publication in new window or tab >>Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts
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    2018 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 6, p. 677-684Article in journal (Refereed) Published
    Abstract [en]

    Objective: Infliximab is important in the therapeutic arsenal of Crohn’s disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.

    Materials and methods: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.

    Results: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450–3000); controls 1163(225–1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8–1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.

    Conclusion: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab’s clinical efficacy in colonic CD.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2018
    Keywords
    Inflammatory bowel disease, microbiology, large intestine, intestinal barrier function, adherent invasive E. coli
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:liu:diva-147615 (URN)10.1080/00365521.2018.1458146 (DOI)000438146900008 ()29688802 (PubMedID)
    Note

    Funding agencies: Swedish Research Council-Medicine [VR-MH 2014-02537]; ALF Grants Region Ostergotland

    Available from: 2018-04-27 Created: 2018-04-27 Last updated: 2019-04-30Bibliographically approved
  • 84.
    Yu, Ning
    et al.
    Univ Michigan, MI 48109 USA; Shanghai Skin Dis Hosp, Peoples R China.
    Lambert, Sylviane
    Univ Michigan, MI 48109 USA.
    Bornstein, Joshua
    Univ Michigan, MI 48109 USA.
    Nair, Rajan P.
    Univ Michigan, MI 48109 USA.
    Enerbäck, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology. Univ Michigan, MI 48109 USA.
    Elder, James T.
    Univ Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hlth Syst, MI 48105 USA.
    The Act1 D10N missense variant impairs CD40 signaling in human B-cells2019In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 20, no 1, p. 23-31Article in journal (Refereed)
    Abstract [en]

    The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among amp;lt; 10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-kappa B phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19(+) B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

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