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  • 1.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Laukoetter, Mike G.
    Department of General Surgery, University of Muenster, Muenster, Germany.
    Nava, Porfirio
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Lee, Winston Y.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Peatman, Eric
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Severson, Eric A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Flower, Roderick J.
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Perretti, Mauro
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Annexin A1 regulates intestinal mucosal injury, inflammation, and repair2008In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, J Immunol, Vol. 181, no 7, p. 5035-5044Article in journal (Refereed)
    Abstract [en]

    During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.

  • 2.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 1, p. 371-378Article in journal (Refereed)
    Abstract [en]

    IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

  • 3.
    Bengtson, Per
    et al.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lundblad, Arne
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Larson, Göran
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Laboratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden .
    Påhlsson, Peter
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Polymorphonuclear Leukocytes from Individuals Carrying the G329A Mutation in the α1,3-Fucosyltransferase VII Gene (FUT7) Roll on E- and P-Selectins2002In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 169, no 7, p. 3940-3946Article in journal (Refereed)
    Abstract [en]

    We recently identified several individuals carrying a missense mutation (G329A; Arg110-Gln) in the FUT7 gene encoding fucosyltransferase VII. This enzyme is involved in the biosynthesis of the sialyl Lewis x (Lex) epitope on human leukocytes, which has been identified as an important component of leukocyte ligands for E- and P-selectin. No enzyme activity was measurable in expression studies in COS-7 cells using the mutated FUT7 construct. One of the identified individuals carried this mutation homozygously. Flow cytometry analysis of polymorphonuclear leukocytes (PMN) from this individual showed a nearly complete absence of staining with mAbs directed against sialyl Lex and a diminished staining with an E-selectin IgG chimera. However, staining with P-selectin IgG chimera and Abs directed against P-selectin glycoprotein ligand-1 was not affected by the mutation. PMN from the homozygously mutated individual was further analyzed in an in vitro flow chamber assay. The number of rolling PMN and the rolling velocities on both E- and P-selectin were in the range of PMN from nonmutated individuals. FUT4 and FUT7 mRNA was quantified in PMN isolated from individuals carrying the FUT7 mutation. It was found that PMN from both FUT7 homozygously and heterozygously mutated individuals exhibited an elevated expression of FUT4 mRNA compared with PMN from FUT7 nonmutated individuals. The elevated expression of fucosyltransferase IV was reflected as an increased expression of the Lex and CD65s Ags on PMN from these individuals. The significance of the mutation was supported by transfection of BJAB cells.

  • 4.
    Blomgran, Robert
    et al.
    New York University .
    Ernst, Joel D
    New York University .
    Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection2011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 12, p. 7110-7119Article in journal (Refereed)
    Abstract [en]

    Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously published observations that 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis-infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naive M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role of neutrophils in DC migration, we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results revealed a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that makes DCs more effective initiators of naive CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis.

  • 5.
    Båve, Ullvi
    et al.
    Uppsala University, Sweden.
    Magnusson, Mattias
    Swedish University of Agriculture Science, Uppsala, Sweden .
    Eloranta, Maija-Leena
    Swedish University of Agriculture Science, Uppsala, Sweden .
    Perers, Anders
    Swedish University of Agriculture Science, Uppsala, Sweden .
    Alm, Gunnar V.
    Swedish University of Agriculture Science, Uppsala, Sweden .
    Rönnblom, Lars
    Uppsala University, Sweden.
    Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG2003In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 171, no 6, p. 3296-3302Article in journal (Refereed)
    Abstract [en]

    An ongoing production of IFN-alpha may be of etiopathogenic significance in systemic lupus erythematosus (SLE). It may be due to the natural IFN-producing cells (NIPC), also termed plasmacytoid dendritic cells (PDC), activated by immune complexes that contain nucleic acids derived from apoptotic cells. We here examined the role of FcgammaR in the IFN-alpha production in vitro by PBMC induced by the combination of apoptotic U937 cells and autoantibody-containing IgG from SLE patients (SLE-IgG). The Fc portion of the SLE-IgG was essential to induce IFN-alpha production, because Fab fragments or F(ab)(2) were ineffective. Normal, especially heat-aggregated, IgG inhibited the IFN-alpha production, suggesting a role for FcgammaR on PBMC. Using blocking anti-FcgammaR Abs, the FcgammaRIIa,c (CD32) but not FcgammaRI or FcgammaRIII were shown to be involved in the IFN-alpha induction by apoptotic cells combined with SLE-IgG, but not by HSV or CpG DNA. In contrast, the action of all of these inducers was inhibited by the anti-FcgammaRIIa,b,c mAb AT10 or heat-aggregated IgG. Flow cytometric analysis revealed that similar to50% of the BDCA-2-positive PBMC, i.e., NIPC/PDC, expressed low but significant levels of FcgammaRII, as did most of the actual IFN-a producers activated by HSV. RT-PCR applied to NIPC/PDC purified by FACS demonstrated expression of FcgammaRIIa, but not of FcgammaRIIb or FcgammaRIIc. We conclude that FcgammaRIIa on NIPC/PDC is involved in the activation of IFN-alpha production by interferogenic immune complexes, but may also mediate inhibitory signals. The FcgammaRIIa could therefore have a key function in NIPC/PDC and be a potential therapeutic target in SLE.

  • 6.
    Carlsson, Emma
    et al.
    School of Health Sciences, Department of Natural Science and Biomedicine, Jonköping University, Jönköping, Sweden, Division of Medical Diagnostics, Ryhov County Hospital, Jönköping, Sweden.
    Frostell, Anneli
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    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 Paediatrics in Linköping.
    Faresjo, Maria
    School of Health Sciences, Department of Natural Science and Biomedicine, Jonköping University, Jönköping, Sweden, Division of Medical Diagnostics, Ryhov County Hospital, Jonköping, Sweden.
    Psychological stress in children may alter the immune response2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 5, p. 2071-2081Article in journal (Refereed)
    Abstract [en]

    Psychological stress is a public health issue even in children and has been associated with a number of immunological diseases. The aim of this study was to examine the relationship between psychological stress and immune response in healthy children, with special focus on autoimmunity. In this study, psychological stress was based on a composite measure of stress in the family across the domains: 1) serious life events, 2) parenting stress, 3) lack of social support, and 4) parental worries. PBMCs, collected from 5-y-old high-stressed children (n = 26) and from 5-y-old children without high stress within the family (n = 52), from the All Babies In Southeast Sweden cohort, were stimulated with Ags (tetanus toxoid and b-lactoglobulin) and diabetes-related autoantigens (glutamic acid decarboxylase 65, insulin, heat shock protein 60, and tyrosine phosphatase). Immune markers (cytokines and chemokines), clinical parameters (C-peptide, proinsulin, glucose), and cortisol, as an indicator of stress, were analyzed. Children from families with high psychological stress showed a low spontaneous immune activity (IL-5, IL-10, IL-13, IL-17, CCL2, CCL3, and CXCL10; p less than 0.01) but an increased immune response to tetanus toxoid, b-lactoglobulin, and the autoantigens glutamic acid decarboxylase 65, heat shock protein 60, and tyrosine phosphatase (IL-5, IL-6, IL-10, IL-13, IL-17, IFN-g, TNF-A, CCL2, CCL3, and CXCL10; p less than 0.05). Children within the high-stress group showed high level of cortisol, but low level of C-peptide, compared with the control group (p less than 0.05). This supports the hypothesis that psychological stress may contribute to an imbalance in the immune response but also to a pathological effect on the insulin-producing b cells.Copyright © 2014 by The American Association of Immunologists.

  • 7.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Shankar, Esaki M.
    University of Malaya, Malaysia.
    Nyström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Impaired NK Cell Activation and Chemotaxis toward Dendritic Cells Exposed to Complement-Opsonized HIV-12015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 4, p. 1698-1704Article in journal (Refereed)
    Abstract [en]

    Mucosa resident dendritic cells (DCs) may represent one of the first immune cells that HIV-1 encounters during sexual transmission. The virions in body fluids can be opsonized with complement factors because of HIV-mediated triggering of the complement cascade, and this appears to influence numerous aspects of the immune defense targeting the virus. One key attribute of host defense is the ability to attract immune cells to the site of infection. In this study, we investigated whether the opsonization of HIV with complement (C-HIV) or a mixture of complement and Abs (CI-HIV) affected the cytokine and chemokine responses generated by DCs, as well as their ability to attract other immune cells. We found that the expression levels of CXCL8, CXCL10, CCL3, and CCL17 were lowered after exposure to either C-HIV or CI-HIV relative to free HIV (F-HIV). DCs exposed to F-HIV induced higher cell migration, consisting mainly of NK cells, compared with opsonized virus, and the chemotaxis of NK cells was dependent on CCL3 and CXCL10. NK cell exposure to supernatants derived from HIV-exposed DCs showed that F-HIV induced phenotypic activation (e.g., increased levels of TIM3, CD69, and CD25) and effector function (e.g., production of IFN gamma and killing of target cells) in NK cells, whereas C-HIV and CI-HIV did not. The impairment of NK cell recruitment by DCs exposed to complement-opsonized HIV and the lack of NK activation may contribute to the failure of innate immune responses to control HIV at the site of initial mucosa infection.

  • 8.
    Ellegård, Rada
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Crisci, Elisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Burgener, Adam
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Sjöwall, Christoffer
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Rheumatology.
    Birse, Kenzie
    University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
    Westmacott, Garrett
    Public Health Agency of Canada, Winnipeg, Canada.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lifson, Jeffrey D.
    Leidos Biomedical Research, Inc., Frederick, MD, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR32014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 9, p. 4590-4601Article in journal (Refereed)
    Abstract [en]

    Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

  • 9.
    Ericsson, Anna
    et al.
    Lund University.
    Kotarsky, Knut
    Lund University.
    Svensson, Marcus
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Agace, William
    Lund University.
    Functional characterization of the CCL25 promoter in small intestinal epithelial cells suggests a regulatory role for caudal-related homeobox (Cdx) transcription factors2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 6, p. 3642-3651Article in journal (Refereed)
    Abstract [en]

    The chemokine CCL25 is selectively and constitutively expressed in the small intestinal epithelium and plays an important role in mediating lymphocyte recruitment to this site. In this study, we demonstrate that CCL25 expression in murine small intestinal epithelial cells is independent of signaling through the lymphotoxin 0 receptor and is not enhanced by inflammatory stimuli, pathways involved in driving the expression of most other chemokines. We define a transcriptional start site in the CCL25 gene and a region -141 to -5 proximal of exon 1 that is required for minimal promoter activity in the small intestinal epithelial cell lines, MODE-K and mICc12. These cell lines expressed far less CCL25 mRNA than freshly isolated small intestinal epithelial cells indicating that they are missing important factors driving CCL25 expression. The CCL25 promoter contained putative binding sites for,the intestinal epithelial-associated Caudal-related homeobox (Cdx) transcription factors Cdx-1 and Cdx-2, and small intestinal epithelial cells but not MODE-K and mICc12 cells expressed Cdx-1 and Cdx-2. EMSA analysis demonstrated that Cdx proteins were present in nuclear extracts from freshly isolated small intestinal epithelial cells but not in MODE-K or mICcl2 cells, and bound to putative Cdx sites within the CCL25 promoter. Finally, cotransfection of MODE-K cells with Cdx transcription factors significantly increased CCL25 promoter activity as well as endogenous CCL25 mRNA levels. Together these results demonstrate a unique pattern of regulation for CCL25 and suggest a role for Cdx proteins in regulating CCL25 transcription.

  • 10. Grdic, D
    et al.
    Ekman, L
    Schon, K
    Lindgren, K
    Mattsson, J
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Ricciardi-Castagnoli, P
    Lycke, N
    Splenic marginal zone dendritic cells mediate the cholera toxin adjuvant effect: Dependence on the ADP-ribosyltransferase activity of the holotoxin2005In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 175, no 8, p. 5192-5202Article in journal (Refereed)
    Abstract [en]

    The in vivo mechanisms of action of most vaccine adjuvants are poorly understood. In this study, we present data in mice that reveal a series of critical interactions between the cholera toxin (CT) adjuvant and the dendritic cells (DC) of the splenic marginal zone (MZ) that lead to effective priming of an immune response. For the first time, we have followed adjuvant targeting of MZ DC in vivo. We used CT-conjugated OVA and found that the Ag selectively accumulated in MZ DC following i.v. injections. The uptake of Ag into DC was GM1 ganglioside receptor dependent and mediated by the B subunit of CT (CTB). The targeted MZ DC were quite unique in their phenotype: CD11c(+), CD8 alpha(-), CD11b(-), B220(-), and expressing intermediate or low levels of MHC class II and DEC205. Whereas CTB only delivered the Ag to MZ DC, the ADP-ribosyltransferase activity of CT was required for the maturation and migration of DC to the T cell zone, where these cells distinctly up-regulated CD86, but not CD80. This interaction appeared to instruct Ag-specific CD4(+) T cells to move into the B cell follicle and strongly support germinal center formations. These events may explain why CT-conjugated Ag is substantially more immunogenic than Ag admixed with soluble CT and why CTB-conjugated Ag can tolerize immune responses when given orally or at other mucosal sites.

  • 11.
    Hecker, Andreas
    et al.
    University of Giessen, Germany.
    Kuellmar, Mira
    University of Giessen, Germany.
    Wilker, Sigrid
    University of Giessen, Germany.
    Richter, Katrin
    University of Giessen, Germany; University of Giessen, Germany.
    Zakrzewicz, Anna
    University of Giessen, Germany.
    Atanasova, Srebrena
    University of Giessen, Germany.
    Mathes, Verena
    University of Giessen, Germany.
    Timm, Thomas
    University of Giessen, Germany.
    Lerner, Sabrina
    University of Giessen, Germany.
    Klein, Jochen
    Goethe University of Frankfurt, Germany.
    Kaufmann, Andreas
    University of Marburg, Germany.
    Bauer, Stefan
    University of Marburg, Germany.
    Padberg, Winfried
    University of Giessen, Germany.
    Kummer, Wolfgang
    University of Giessen, Germany.
    Janciauskiene, Sabina
    Hannover Medical Sch, Germany.
    Fronius, Martin
    University of Giessen, Germany; University of Otago, New Zealand.
    Schweda, Elke
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lochnit, Guenter
    University of Giessen, Germany.
    Grau, Veronika
    University of Giessen, Germany.
    Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1 beta Release2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 5, p. 2325-2334Article in journal (Refereed)
    Abstract [en]

    IL-1 beta is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1 beta plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1 beta release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1 beta synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1 beta by caspase-1, and release of mature IL-1 beta. Mechanisms controlling IL-1 beta release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1 beta release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits alpha 7, alpha 9, and/or alpha 10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1 beta and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.

  • 12.
    Jenmalm, Maria
    et al.
    SP Biopharma.
    Cherwinski, Holly
    SP Biopharma, Palo Alto USA.
    Bowman, Edward P
    SP Biopharma, Palo Alto USA.
    Phillips, Joseph H
    Eli Lilly and Company, Indianapolis, USA.
    Sedgewick, Jonathon D
    Eli Lilly and Company, Indianapolis, USA.
    Regulation of myeloid cell function through the CD200 receptor2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 1, p. 191-199Article in journal (Refereed)
    Abstract [en]

    Myeloid cells play pivotal roles in chronic inflammatory diseases through their broad proinflammatory, destructive, and remodeling capacities. CD200 is widely expressed on a variety of cell types, while the recently identified CD200R is expressed on myeloid cells and T cells. CD200 deletion in vivo results in myeloid cell dysregulation and enhanced susceptibility to autoimmune inflammation, suggesting that the CD200-CD200R interaction is involved in immune suppression. We demonstrate in this study that CD200R agonists suppress mouse and human myeloid cell function in vitro, and also define a dose relationship between receptor expression and cellular inhibition. IFN-γ- and IL-17-stimulated cytokine secretion from mouse peritoneal macrophages was inhibited by CD200R engagement. Inhibitory effects were not universal, as LPS-stimulated responses were unaffected. Inhibition of U937 cell cytokine production correlated with CD200R expression levels, and inhibition was only observed in low CD200R expressing cells, if the CD200R agonists were further cross-linked. Tetanus toxoid-induced human PBMC IL-5 and IL-13 secretion was inhibited by CD200R agonists. This inhibition was dependent upon cross-linking the CD200R on monocytes, but not on cross-linking the CD200R on CD4+ T cells. In all, we provide direct evidence that the CD200-CD200R interaction controls monocyte/macrophage function in both murine and human systems, further supporting the potential clinical application of CD200R agonists for the treatment of chronic inflammatory diseases. Copyright © 2005 by The American Association of Immunologists, Inc.

  • 13.
    Jensen, Christina T.
    et al.
    Lund University, Sweden.
    Lang, Stefan
    Lund University, Sweden.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Soneji, Shamit
    Lund University, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Lund University, Sweden.
    Identification of Stage-Specific Surface Markers in Early B Cell Development Provides Novel Tools for Identification of Progenitor Populations2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 197, no 5, p. 1937-1944Article in journal (Refereed)
    Abstract [en]

    Whereas the characterization of B lymphoid progenitors has been facilitated by the identification of lineage- nd stage-specific surface markers, the continued identification of differentially expressed proteins increases our capacity to explore normal and malignant B cell development. To identify novel surface markers with stage-specific expression patterns, we explored the reactivity of CD19(+) B cell progenitor cells to Abs targeted to 176 surface proteins. Markers with stage-specific expression were identified using a transgenic reporter gene system subdividing the B cell progenitors into four surface IgM(-) stages. This approach affirmed the utility of known stage-specific markers, as well as identifying additional proteins that selectively marked defined stages of B cell development. Among the stage-specific markers were the cell adhesion proteins CD49E, CD11A, and CD54 that are highly expressed selectively on the most immature progenitors. This work identifies a set of novel stage-specific surface markers that can be used as a complement to the classical staining protocols to explore B lymphocyte development.

  • 14. Kono, DH
    et al.
    Park, MS
    Szydlik, A
    Haraldsson, KM
    Kuan, JD
    Pearson, DL
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Pollard, KM
    Resistance to xenobiotic-induced autoimmunity maps to chromosome 11.2001In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 167, p. 2396-2403Article in journal (Refereed)
  • 15.
    Los, Marek Jan
    et al.
    Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany.
    Khazaie, K.
    Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
    Schulze-Osthoff, Klaus
    Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany; .
    Baeuerle, P. A.
    Tularik Inc., San Francisco, CA, USA.
    Schirrmacher, V.
    Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
    Chlichlia, K.
    Division of Cellular Immunology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
    Human T cell leukemia virus-I (HTLV-I) Tax-mediated apoptosis in activated T cells requires an enhanced intracellular prooxidant state1998In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 161, no 6, p. 3050-3055Article in journal (Refereed)
    Abstract [en]

    We have shown that an estradiol-dependent activation of human T cell leukemia virus-I Tax leads to the inhibition of cell proliferation and to the induction of apoptosis, The present study demonstrates that a hormone-dependent activation of Tax promotes an enhanced prooxidant state in stably transfected Jurkat cells as measured by changes in the intracellular levels of glutathione and H2O2; these changes are followed by apoptotic cell death. Additional stimulation of the CD3/TCR pathway enhances the oxidative and apoptotic effects. Both Tax-mediated apoptosis and oxidative stress can be potently suppressed by antioxidants, as is seen with the administration of recombinant thioredoxin (adult T cell leukemia derived factor) or pyrrolidine dithiocarbamate. Hormone-induced Tax activation induces a long-lasting activation of NF-kappa B, which is a major target of reactive oxygen ntermediates. The long-term exposure of Jurkat cells to hormone eventually results in a selection of cell clones that have lost Tax activity. A subsequent transfection of these apparently "nonresponsive" clones allows the recovery of Tax responses in these cells. Our observations indicate that changes in the intracellular redox status mag be a determining factor in Tax-mediated DNA damage, apoptosis, and selection against the long-term expression of Tax function.

  • 16.
    Magnusson, Mattias
    et al.
    University of Gothenburg, Sweden.
    Tobes, Raquel
    Granada Centre Europeo Empresas and Innovac, Spain.
    Sancho, Jaime
    Instituto de Parasitologia y Biomedicina López-Neyra, Armilla, Spain.
    Pareja, Eduardo
    Granada Centre Europeo Empresas and Innovac, Spain.
    Cutting edge: Natural DNA repetitive extragenic sequences from Gram-negative pathogens strongly stimulate TLR92007In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 179, no 1, p. 31-35Article in journal (Refereed)
    Abstract [en]

    Bacterial DNA exerts immunostimulatory effects on mammalian cells via the intracellular TLR9. Although broad analysis of TLR9-mediated immunostimulatory potential of synthetic oligonucleotides has been developed, which kinds of natural bacterial DNA sequences are responsible for immunostimulation are not known. This work provides evidence that the natural DNA sequences named repetitive extragenic palindromic (REPs) sequences present in Gram-negative bacteria are able to produce innate immune system stimulation via TLR9. A strong induction of IFN-alpha production by REPs from Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, and Neisseria meningitidis was detected in splenocytes from 129 mice. In addition, the involvement of TLR9 in immune stimulation by REPs was confirmed using B6.129P2-Tlr9(tm1Aki) knockout mice. Considering the involvement of TLRs in Gram-negative septic shock, it is conceivable that REPs play a role in its pathogenesis. This study highlights REPs as a potential novel target in septic shock treatment.

  • 17.
    Mjösberg, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Svensson, Judit
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Johansson, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Hellström, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Boij, Roland
    Ryhov Hospital, Jönköping, Sweden.
    Matthiesen, Leif
    Helsingborg Hospital, Helsingborg, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    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.
    Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17θ-estradiol2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 1, p. 759-769Article in journal (Refereed)
    Abstract [en]

    CD4+CD25high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17β-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4dimCD25high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4+ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17β-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4dimCD25highFoxp3+ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4+CD25 responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-, and IFN- secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • 18.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Long, Min
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway2002In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 168, no 12, p. 6358-6365Article in journal (Refereed)
    Abstract [en]

    In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.

  • 19.
    Perskvist, Nasrin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Zheng, Limin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 164, no 2, p. 959-965Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that human neutrophils play a significant protective role in mycobacteria infection. When encountered with mycobacteria, neutrophils exhibit the typical early bactericidal responses including phagocytosis and generation of reactive oxygen intermediates (ROI), but the underlying mechanisms are largely unknown. The present study shows that stimulation of neutrophils with an attenuated strain of Mycobacterium tuberculosis H37Ra (Mtb) led to a tyrosine kinase-dependent ROI production in these cells. Stimulation with Mtb induces a rapid and transient tyrosine phosphorylation of several proteins, one of which was identified as phospholipase Cγ2 (PLCγ2). Several tyrosine-phosphorylated proteins were associated with the PLCγ2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein. A role for PLCγ2-Shc association in the generation of ROI is supported by the observations that stimulation with Mtb causes the activation of p38 mitogen-activated protein kinase (MAPK), a downstream target of the Shc/Ras signaling cascade, and that the effect of genistein on ROI production coincided with its ability to inhibit both PLCγ2-Shc association and p38 MAPK activation. Moreover, pretreatment of neutrophils with a PLC inhibitor markedly suppresses the Mtb-stimulated ROI production as well as p38 MAPK activation in these cells. Taken together, these results indicate that stimulation of neutrophils with Mtb triggers the tyrosine phosphorylation of PLCγ2 and its association with Shc, and that such association is critical for the Mtb-stimulated ROI production through activating p38 MAPK.

  • 20. Pollard, K Michael
    et al.
    Arnush, Marc
    Hultman, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Kono, Dwight H
    Costimulation requirements of induced murine systemic autoimmune disease2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, no 9, p. 5880-5887Article in journal (Refereed)
    Abstract [en]

    Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligaad (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell Costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.

  • 21.
    Pollard, K. Michael
    et al.
    Scripps Research Institute, CA 92037 USA.
    Escalante, Gabriela M.
    Scripps Research Institute, CA 92037 USA.
    Huang, Hua
    Scripps Research Institute, CA 92037 USA.
    Haraldsson, Katarina M.
    Scripps Research Institute, CA 92037 USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Christy, Joseph M.
    Scripps Research Institute, CA 92037 USA.
    Pawar, Rahul D.
    Scripps Research Institute, CA 92037 USA.
    Mayeux, Jessica M.
    Scripps Research Institute, CA 92037 USA.
    Gonzalez-Quintial, Rosana
    Scripps Research Institute, CA 92037 USA.
    Baccala, Roberto
    Scripps Research Institute, CA 92037 USA.
    Beutler, Bruce
    University of Texas Southwestern Medical Centre Dallas, USA.
    Theofilopoulos, Argyrios N.
    Scripps Research Institute, CA 92037 USA.
    Kono, Dwight H.
    Scripps Research Institute, CA 92037 USA.
    Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN2017In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 199, no 11, p. 3739-3747Article in journal (Refereed)
    Abstract [en]

    Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.

  • 22.
    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.

  • 23.
    Reyes, Jose L.
    et al.
    University of Calgary, Canada.
    Wang, Arthur
    University of Calgary, Canada.
    Fernando, Maria R.
    University of Calgary, Canada.
    Graepel, Rabea
    University of Calgary, Canada.
    Leung, Gabriella
    University of Calgary, Canada.
    van Rooijen, Nico
    Vrije University of Amsterdam, Netherlands.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    University of Calgary, Canada.
    Splenic B Cells from Hymenolepis diminuta-Infected Mice Ameliorate Colitis Independent of T Cells and via Cooperation with Macrophages2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 1, p. 364-378Article in journal (Refereed)
    Abstract [en]

    Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14(d) (but not 3(d)) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-beta than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-beta and the generation of, or cooperation with, a regulatory macrophage.

  • 24.
    Serrander, Lena
    et al.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Jerström Skarman, Petra
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Witke, Walter
    European Molecular Biology Laboratory Mouse Biology Program, Monterotondo, Italy.
    Lew, Daniel P.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Krause, Karl-Heinz
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nüße, Oliver
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Selective Inhibition of IgG-Mediated Phagocytosis in Gelsolin-Deficient Murine Neutrophils2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 165, no 5, p. 2451-2457Article in journal (Refereed)
    Abstract [en]

    Phagocytosis and the microbicidal functions of neutrophils require dynamic changes of the actin cytoskeleton. We have investigated the role of gelsolin, a calcium-dependent actin severing and capping protein, in peripheral blood neutrophils from gelsolin-null (Gsn) mice. The phagocytosis of complement opsonized yeast was only minimally affected. In contrast, phagocytosis of IgG-opsonized yeast was reduced close to background level in Gsn neutrophils. Thus, gelsolin is essential for efficient IgG- but not complement-mediated phagocytosis. Furthermore, attachment of IgG-opsonized yeast to Gsn neutrophils was reduced (∼50%) but not to the same extent as ingestion (∼73%). This was not due to reduced surface expression of the Fcγ-receptor or its lateral mobility. This suggests that attachment and ingestion of IgG-opsonized yeast by murine neutrophils are actin-dependent and gelsolin is important for both steps in phagocytosis. We also investigated granule exocytosis and several steps in phagosome processing, namely the formation of actin around the phagosome, translocation of granules, and activation of the NADPH-oxidase. All these functions were normal in Gsn neutrophils. Thus, the role of gelsolin is specific for IgG-mediated phagocytosis. Our data suggest that gelsolin is part of the molecular machinery that distinguishes complement and IgG-mediated phagocytosis. The latter requires a more dynamic reorganization of the cytoskeleton.

  • 25.
    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.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    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 the Dendritic Cell-T Cell Axis of Macrophage Activation by Shifting Mycobacterium tuberculosis-Specific CD4 T Cells into a Dysfunctional Phenotype2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 3, p. 816-826Article in journal (Refereed)
    Abstract [en]

    HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. tuberculosis infection in infected macrophages. Coinfection of DCs reduced proliferation of M. tuberculosis Ag-specific CD4 T cells without affecting their viability, led to increased expression of coinhibitory factors CTLA-4, PD-1, and Blimp-1, and decreased expression of costimulatory molecules CD40L, CD28, and ICOS on the T cells. Expression of the regulatory T cell markers FOXP3 and CD25, together with the immunosuppressive cytokines TGF-beta and IL-10, was also significantly increased by coinfection compared with M. tuberculosis single infection. Our data suggest a pattern in which HIV, through its effect on DCs, impairs the ability of M. tuberculosis-specific CD4 T cells to maintain a latent TB within human macrophages, which could play an early role in the subsequent development of TB.

  • 26.
    Spetz, Anna-Lena
    et al.
    Karolinska Institute, Sweden.
    Patterson, Bruce K.
    Northwestern University Medical School, Chicago, USA.
    Lore, Karin
    Karolinska Institute, Sweden.
    Andersson, Jan
    Karolinska Institute, Sweden.
    Holmgren, Lars
    Karolinska Institute, Sweden.
    Functional gene transfer of HIV DNA by an HIV receptor-independent mechanism1999In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 163, no 2, p. 736-742Article in journal (Refereed)
    Abstract [en]

    HIV-1 enters target cells mainly via binding to CD4 and its coreceptors. The presence of HIV-1 in CD4(-) cells suggests, however, that there exist other mechanisms for viral entry, Here it is reported that HIV-1 DNA may be transferred from one cell to another by uptake of apoptotic bodies in a CD4-independent way. This was investigated by coculturing CD4(-), chemokine receptor CCR5(-) and CXCR4(-) human fetal fibroblasts with apoptotic HIV-1-infected HuT78 cells or apoptotic PBMC isolated from HIV-1-infected patients. After 2 wk of coculture, fibroblasts contained HIV-1 DNA and expressed HIV-1 proteins p24 and gp120, Transfer of HIV-1 DNA was verified by coculturing fibroblasts with apoptotic bodies derived from cells infected with a defective HIV-1 virus. These cells contain one integrated copy of a reverse transcriptase (RT)-negative HIV-1 strain (8E5/LAV RT- cells) and consequently cannot produce free virus, Intracellular HIV-1 gag DNA was detected in both fibroblasts and dendritic cells after coculture with apoptotic 8E5/LAV RT- cells. Transfer of viral DNA after uptake of apoptotic bodies mag explain HIV-1 infection of CD4(-) cells in vivo and furthermore may be relevant for Ag presentation.

  • 27.
    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.

  • 28.
    Svensson, Judit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Matussek, Andreas
    County Hospital Ryhov.
    Geffers, Robert
    Helmholtz Centre Infect Research.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-102011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 187, no 7, p. 3671-3682Article in journal (Refereed)
    Abstract [en]

    During pregnancy, the maternal immune system is challenged by the presence of the fetus, which must be tolerated despite being semiallogeneic. Uterine mucosal (or decidual) macrophages (Mϕ), one of the major leukocyte populations at the fetal–maternal interface, have been implicated in fetal tolerance, but information regarding their regulation is scarce. In this study, we investigated the role of several factors potentially involved in the differentiation and polarization of decidual Mϕ with an in vitro Mϕ differentiation model. By using flow cytometry, we showed that M-CSF and IL-10 were potent inducers of M2 (immunoregulatory) Mϕ markers expressed on human decidual Mϕ (CD14, CD163, CD206, CD209). In contrast, proinflammatory stimuli, and unexpectedly also the Th2-associated IL-4 and IL-13, induced different patterns of expression, indicating that a Th2-dominated environment is not required for decidual Mϕ polarization. M-CSF/IL-10–stimulated and decidual Mϕ also showed similar cytokine secretion patterns, with production of IL-10 as well as IL-6, TNF, and CCL4. Conversely, the proinflammatory, LPS/IFN-γ–stimulated Mϕ produced significantly higher levels of TNF and no IL-10. We also used a gene array with 420 Mϕ-related genes, of which 100 were previously reported to be regulated in a global gene expression profiling of decidual Mϕ, confirming that M-CSF/IL-10–induced Mϕ are closely related to decidual Mϕ. Taken together, our results consistently point to a central role for M-CSF and in particular IL-10 in the shaping of decidual Mϕ with regulatory properties. These cytokines may therefore play an important role in supporting the homeostatic and tolerant immune milieu required for a successful pregnancy.

  • 29.
    Söderlund, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Svensson, Susanne
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Abrahamsson, Annelie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Bendrik, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Robertson, Jennifer
    McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    McMaster University, Hamilton, Ontario, Canada.
    Olsson, Anna-Karin
    Uppsala University, Sweden .
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 8, p. 4420-4430Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro-and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities. The Journal of Immunology, 2013, 190: 4420-4430.

  • 30.
    Theilgaard-Mönch, Kim
    et al.
    Danmark.
    Knudsen, Steen
    Danmark.
    Follin, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Borregaard, Niels
    Danmark.
    The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 172, no 12, p. 7684-7693Article in journal (Refereed)
    Abstract [en]

    To investigate the cellular fate and function of polymorphonuclear neutrophilic granulocytes (PMNs) attracted to skin wounds, we used a human skin-wounding model and microarray technology to define differentially expressed genes in PMNs from peripheral blood, and PMNs that had transmigrated to skin lesions. After migration to skin lesions, PMNs demonstrated a significant transcriptional response including genes from several different functional categories. The up-regulation of anti-apoptotic genes concomitant with the down-regulation of proapoptotic genes suggested a transient anti-apoptotic priming of PMNs. Among the up-regulated genes were cytokines and chemokines critical for chemotaxis of macrophages, T cells, and PMNs, and for the modulation of their inflammatory responses. PMNs in skin lesions down-regulated receptors mediating chemotaxis and anti-microbial activity, but up-regulated other receptors involved in inflammatory responses. These findings indicate a change of responsiveness to chemotactic and immunoregulatory mediators once PMNs have migrated to skin lesions and have been activated. Other effects of the up-regulated cytokines/chemokines/enzymes were critical for wound healing. These included the breakdown of fibrin clots and degradation of extracellular matrix, the promotion of angiogenesis, the migration and proliferation of keratinocytes and fibroblasts, the adhesion of keratinocytes to the dermal layer, and finally, the induction of anti-microbial gene expression in keratinocytes. Notably, the up-regulation of genes, which activate lysosomal proteases, indicate a priming of skin lesion-PMNs for degradation of phagocytosed material. These findings demonstrate that migration of PMNs to skin lesions induces a transcriptional activation program, which regulates cellular fate and function, and promotes wound healing.

  • 31.
    Verykokakis, Mihalis
    et al.
    University of Chicago, IL 60637 USA University of Chicago, IL 60637 USA .
    Krishnamoorthy, Veena
    University of Chicago, IL 60637 USA .
    Iavarone, Antonio
    Columbia University, NY 10032 USA Columbia University, NY 10032 USA Columbia University, NY 10032 USA .
    Lasorella, Anna
    Columbia University, NY 10032 USA Columbia University, NY 10032 USA Columbia University, NY 10032 USA .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Kee, Barbara L.
    University of Chicago, IL 60637 USA University of Chicago, IL 60637 USA .
    Essential Functions for ID Proteins at Multiple Checkpoints in Invariant NKT Cell Development2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 12, p. 5973-5983Article in journal (Refereed)
    Abstract [en]

    Invariant NKT (iNKT) cells display characteristics of both adaptive and innate lymphoid cells (ILCs). Like other ILCs, iNKT cells constitutively express ID proteins, which antagonize the E protein transcription factors that are essential for adaptive lymphocyte development. However, unlike ILCs, ID2 is not essential for thymic iNKT cell development. In this study, we demonstrated that ID2 and ID3 redundantly promoted iNKT cell lineage specification involving the induction of the signature transcription factor PLZF and that ID3 was critical for development of TBET-dependent NKT1 cells. In contrast, both ID2 and ID3 limited iNKT cell numbers by enforcing the postselection checkpoint in conventional thymocytes. Therefore, iNKT cells show both adaptive and innate-like requirements for ID proteins at distinct checkpoints during iNKT cell development.

  • 32.
    Wang, Duncheng
    et al.
    Sunnybrook Research Institute.
    Claus, Carol L.
    Sunnybrook Research Institute.
    Rajkumar, Paula
    Sunnybrook Research Institute.
    Braunstein, Marsela
    Sunnybrook Research Institute.
    Moore, Amanda J.
    Sunnybrook Research Institute.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Anderson, Michele K.
    Sunnybrook Research Institute.
    Context-Dependent Regulation of Hematopoietic Lineage Choice by HEBAlt2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 185, no 7, p. 4109-4117Article in journal (Refereed)
    Abstract [en]

    Hematopoietic development is controlled by combinatorial interactions between E-protein transcription factors and other lineage regulators that operate in the context of gene-regulatory networks. The E-proteins HEB and E2A are critical for T cell and B cell development, but the mechanisms by which their activities are directed to different genes in each lineage are unclear. We found that a short form of HEB, HEBAlt, acts downstream of Delta-like (DL)-Notch signaling to promote T cell development. In this paper, we show that forced expression of HEBAlt in mouse hematopoietic progenitors inhibited B cell development, but it allowed them to adopt a myeloid fate. HEBAlt interfered with the activity of E2A homodimers and with the expression of the transcription factor Pax5, both of which are critical for B cell development. However, when combined with DL-Notch signaling, HEBAlt enhanced the generation of T cell progenitors at the expense of myeloid cells. The longer form of HEB, HEBCan, also inhibited E47 activity and Pax5 expression, but it did not collaborate with DL-Notch signaling to suppress myeloid potential. Therefore, HEBAlt can suppress B cell or myeloid potential in a context-specific manner, which suggests a role for this factor in maintaining T lineage priming prior to commitment.

  • 33. Wolfraim, Larence A
    et al.
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    James, Zakiya
    Fernandez, Tania
    Letterio, John J
    p21Cip1 and p27Kip1 act in synergy to alter the sensitivy of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness2004In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 173, p. 3093-3102Article in journal (Refereed)
  • 34.
    Yien Tan, Hong
    et al.
    University of Malaya, Malaysia.
    Kong Yong, Yean
    University of Malaya, Malaysia.
    Shankar, Esaki M.
    University of Malaya, Malaysia; University of Malaya, Malaysia.
    Paukovics, Geza
    Macfarlane Burnet Institute Medical Research and Public Heatlh, Australia.
    Ellegård, Rada
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kamarulzaman, Adeeba
    University of Malaya, Malaysia.
    French, Martyn A.
    University of Western Australia, Australia; Royal Perth Hospital, Australia.
    Crowe, Suzanne M.
    Macfarlane Burnet Institute Medical Research and Public Heatlh, Australia; Alfred Hospital, Australia; Monash University, Australia.
    Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome2016In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, p. 4052-4063Article in journal (Refereed)
    Abstract [en]

    Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

  • 35.
    Zandi, Sasan
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Månsson, Robert
    Department for Biomedicin and Surgery Linköping University.
    Tsapogas, Panagiotis
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Zetterblad, Jenny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    Bryder, David
    Department for Immunology Lund University, Sweden.
    Sigvardsson, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology .
    EBF1 is essential for B-lineage priming and establishment of a transcription factor network in common lymphoid progenitors2008In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 181, no 5, p. 3364-3372Article in journal (Refereed)
    Abstract [en]

    Development of B-lymphoid cells in the bone marrow is a process under strict control of a hierarchy of transcription factors. To understand the development of a B-lymphoid-restricted functional network of transcription factors, we have investigated the cell autonomous role of the transcription factor EBF1 in early B cell development. This revealed that even though transplanted EBF1-deficient fetal liver cells were able to generate common lymphoid progenitors (CLPs) as well as B220(+)CD43(+)AA4.1(+) candidate precursor B cells, none of these populations showed signs of B lineage priming. The isolated CLPs were able to generate T lymphocytes in vitro supporting the idea that the phenotype of EBF1-deficient mice is restricted to the development of the B lineage. Furthermore, EBF deficient CLPs displayed a reduction in Ig H chain recombination as compared with their wild-type counterpart and essentially lacked transcription of B-lineage-associated genes. Among the genes displaying reduced expression in the EBF1 deficient CLPs were the transcription factors Pax5, Pou2af1 (OcaB), and FoxO1 that all appear to be direct genetic targets for EBF1 because their promoters contained functional binding sites for this factor. This leads us to suggest that EBF1 regulates a transcription factor network crucial for B lineage commitment.

1 - 35 of 35
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