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Self Antigens (self + antigen)
Selected AbstractsCovalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouseHEPATOLOGY, Issue 6 2004Jeremy M. Palmer The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by the breakdown of normal immune self tolerance to pyruvate dehydrogenase complex (PDC). How tolerance is broken to such a central and highly conserved self antigen in the initiation of autoimmunity remains unclear. One postulated mechanism is that reactivity arises to an altered form of self antigen with subsequent cross-reactivity to native self. In this murine study, we set out to examine whether sensitization with a covalently modified form of self PDC can give rise to the pattern of breakdown of B-cell and T-cell tolerance to self PDC seen in PBC patients. The notion that altered self can lead to tolerance breakdown was studied by sensitizing SJL/J mice with a covalently modified (biotinylated) preparation of self murine PDC (mP/O-B). Subsequently, antibody and T-cell reactivities to unmodified self mP/O were studied. Sensitization with mP/O-B elicited high-titre, high-affinity antibody responses reactive with both the mP/O-B immunogen and, importantly, native mP/O. In addition, significant MHC class II restricted splenic T-cell responses to native mP/O (i.e., true autoimmune responses) were seen in mP/O-B sensitized animals. The breakdown of T-cell self tolerance to mP/O was not seen in animals sensitized with irrelevant biotinylated antigens. In conclusion, this study provides evidence to support the concept that exposure to covalently modified self PDC can, in the correct proimmune environment, replicate the full breakdown of B-cell and T-cell immune tolerance to PDC seen in PBC. One potential etiological pathway in PBC therefore could be the breakdown of tolerance to self PDC occurring after exposure to self antigen covalently modified in the metabolically active environment of the liver. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;39:1583,1592.) [source] Abortive activation precedes functional deletion of CD8+ T cells following encounter with self-antigens expressed by resting B cells in vivoIMMUNOLOGY, Issue 1 2006Joanne M. Fraser Summary InsHA mice express the haemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8) as a self antigen on pancreatic islet , cells. We have utilized these mice to investigate the ability of resting B cells expressing Kd to induce self-tolerance among naive KdHA-specific clone 4 CD8+ T cells. Adoptive transfer of KdHA-peptide-pulsed resting B cells into clone 4,InsHA recipients resulted in the activation and proliferation of clone 4 CD8+ T cells throughout the peripheral lymphoid tissues. Significantly, proliferation was not associated with the acquisition of T cell effector function; as evidenced by a lack of interferon-, production and the complete absence of any autoimmune pathology even after immunization of recipient mice with PR8. These data demonstrate that resting B cells pulsed with self-epitopes can induce abortive activation of potentially self-reactive naive CD8+ T cells resulting in their functional deletion from the peripheral T-cell repertoire in the absence of any associated autoimmunity. [source] Allogeneic Parenchymal and Hematopoietic Tissues Differ in Their Ability to Induce Deletion of Donor-Reactive T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2003Thomas R. Jones The establishment of immune tolerance to self antigen expressed exclusively in the periphery is a crucial yet incompletely understood feature of the immune system. A dominant concept of peripheral tolerance has been that exposure of T cells to signal one, the TCR,MHC interaction, in the absence of signal two, or costimulation, is a major mechanism of peripheral tolerance. This model suggests that any cell type that expresses MHC-peptide complexes, be they of self or foreign origin, should have the capacity to tolerize antigen-specific T cells when critical costimulatory interactions are interrupted. However, a spectrum of responses, from permanent engraftment to rapid rejection, has been observed in various transplantation models utilizing costimulatory blockade. Therefore we undertook a series experiments to directly assess the tolerogenic potential of donor hematopoietic and parenchymal cells. We find that allogeneic tissues differ profoundly in their ability to promote peripheral tolerance concurrent with combined blockade of B7-CD28 and CD40-CD40L pathways. Non-vascularized and vascularized parenchymal grafts as well as donor-specific transfusions promote varying degrees of donor-specific hyporesponsiveness, but fail to induce donor-reactive T-cell deletion; whereas establishment of stable hematopoietic chimerism promotes specific tolerance mediated by deletion of donor-reactive cells in the periphery. [source] Modulation of peripheral B cell tolerance by CD72 in a murine modelARTHRITIS & RHEUMATISM, Issue 10 2008Daniel Hsieh-Hsin Li Objective B cells play a dominant role in the pathogenesis of several autoimmune diseases, including systemic lupus erythematosus. It is not well understood how B cell signaling contributes to autoantibody production. The goal of this study was to elucidate the role of CD72 in modulating B cell receptor (BCR),mediated tolerogenic signaling and peripheral B cell tolerance. Methods A mouse model utilizing hen egg lysozyme (HEL) "anergic" B cells was studied. CD72-deficient mice carrying the BCR-specific IgHEL and/or soluble HEL (sHEL) transgenes were generated by breeding IgHEL -transgenic MD4 mice and/or sHEL -transgenic ML5 mice with congenic, CD72-deficient C57BL/6J mice. Normal and anergic B cells were isolated for analyses of B cell signaling. Aged wild-type and CD72-deficient mice were also examined for autoimmune phenomena. Results In the absence of CD72, anergic B cells inappropriately proliferated and survived in response to stimulation with self antigen. Biochemical analyses indicated that in anergic B cells, CD72 dominantly down-regulated BCR signaling to limit the antigen-induced elevation in [Ca2+]i and the activation of NFATc1, NF-,B, MAPK, and Akt. Mechanistically, CD72 was associated with, and regulated, the molecular adaptor Cbl-b in anergic B cells, suggesting that Cbl-b may play a role in mediating the negative effects of CD72 on BCR signaling. Moreover, in aged CD72-deficient mice, spontaneous production of antinuclear and anti,double-stranded DNA autoantibodies and features of lupus-like autoimmune disease were observed. Conclusion CD72 is required to maintain B cell anergy and functions as a regulator of peripheral B cell tolerance. Thus, altered CD72 expression may play a role during the development of systemic lupus erythematosus. [source] Activating and inhibitory Fc, receptors can differentially modulate T cell-mediated autoimmunityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008Mirentxu Abstract The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although Fc,R have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (Fc,RIII) and inhibitory (Fc,RIIb) Fc,R can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While Fc,RIIb,/, mice showed a significant increase in EAE severity, an Fc,RIII deficiency protected mice from disease. In addition, Fc,RIIb,/, mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, Fc,RIII,/, mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for Fc,RIII,/, mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory Fc,R signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression. [source] Recruitment and selection of marginal zone B,cells is independent of exogenous antigensEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005Peter Abstract Marginal zone B (MZ-B) cells of the spleen contribute significantly to the immunity against invasive infections with polysaccharide-encapsulated bacteria. Recent evidence indicates that recruitment and selection of MZ-B,cells occurs on the basis of positive selection constraints that likely operate via B,cell receptor (BCR) signaling. Previous studies have shown that MZ-B,cells carry relatively shorter immunoglobulin (Ig) heavy (H) chain complementarity-determining region,3 (H-CDR3) sequences and express BCR which are thought to be polyreactive. In this scenario, MZ-B,cell selection proceeds via engagement of the BCR with exogenous (i.e. microbial gut flora-derived) and/or endogenous (self) antigens. Here, we studied the influence of exogenous antigens on the selection process of MZ-B,cells using non-genetically manipulated adult germ-free and conventionally reared infant rats. This study was carried out by H-CDR3 spectratype analysis of VH(PC7183)-encoded Ig VHDJH -, transcripts expressed by purified splenic MZ-B,cells and other B,cell subsets. We show that MZ-B,cells in both adult germ-free and conventionally reared infant (14-day-old) rats are H-CDR3-selected cells, providing strong evidence that recruitment and selection of MZ-B,cells is driven by self antigens. [source] Peripheral T,cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunizationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2005Elena Degl'Innocenti Abstract In the tumor-prone transgenic adenocarcinoma mouse prostate (TRAMP) mouse model we followed the fate of the immune response against the SV40 large T,antigen (Tag) selectively expressed in the prostate epithelium during the endogenous transformation from normal cells to tumors. Young (5,7-week-old) male TRAMP mice, despite a dim and patchy expression of Tag overlapping foci of mouse prostate intraepithelial neoplasia, displayed a strong Tag-specific cytotoxic T,lymphocyte (CTL) response after an intradermal injection of peptide-pulsed dendritic cells (DC). This response was weaker than the one found in vaccinated wild-type littermates, and was characterized by a reduced frequency and avidity of Tag-specific CTL. Early DC vaccination also subverted the profound state of peripheral tolerance typically found in TRAMP mice older than 9,10,weeks. The DC-induced CTL response indeed was still detectable in TRAMP mice of 16,weeks, and was associated with histology evidence of reduced disease progression. Our findings suggest that tumor antigens are handled as self antigens, and peripheral tolerance is associated with in situ antigen overexpression and cancer progression. Our data also support a relevant role for DC-based vaccines in controlling the induction of peripheral tolerance to tumor antigens. [source] CD4 T,cell activation by myelin oligodendrocyte glycoprotein is suppressed by adult but not cord blood CD25+ T,cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003Kajsa Wing Abstract Regulatory T,cells expressing CD25 have been shown to protect rodents from organ-specific autoimmune diseases. Similar CD25+ cells with a memory phenotype exerting suppressive function after polyclonal or allogeneic stimulation are also present in adult human blood. We demonstrate that adult human CD25+ cells regulate the response to myelin oligodendrocyte glycoprotein (MOG), as depletion of CD25+ cells increases responses of PBMC and the addition of purified CD25+ cells suppresses MOG-specific proliferation and IFN-, production of CD4+CD25, T,cells. In contrast, cord blood CD25+ cells do not inhibit responses to self antigens, and only a small subpopulation of cord CD25+ cells expresses the typical phenotype of adult regulatory T,cells (CD45RA, and GITR+) enabling suppression of polyclonal responses. We conclude that activation of self-reactive T,cells in normal healthy individuals is prevented by the presence of self-antigen-specific CD25+ regulatory T,cells and that the majority of these cells mature after birth. [source] Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease lociIMMUNOLOGICAL REVIEWS, Issue 1 2001Marie M. Griffiths Summary: Collagen-induced arthritis (CIA) is a useful model for dissecting the genetic patterns underlying susceptibility to rheumatoid arthritis (RA) and related chronic/inflammatory autoimmune diseases. CIA exhibits three phenotypes characteristic of autoimmune disease pathogenesis: abnormal levels of immune reactivity to self antigens; chronic inflammation of target organs expressing that specific autoantigen; activation and direct participation of invading mononuclear cells and resident tissue fibroblasts in organ damage. Over 25 different quantitative trait loci (QTL) regulating arthritis severity and autoantibody in rats with CIA are mapped. QTL-congenic strains show that certain CIA,QTLs can modulate arthritis independently. These monogenic models are proving to be highly informative for fine mapping and function studies, revealing gender effects and evidence of gene clusters. Recent genome scans of RA populations identified RA-susceptibility loci in chromosome regions homologous to rat chromosomal segments housing CIA,QTLs. Also, CIA,QTLs frequently co-localize with susceptibility QTLs mapped in other rat arthritis models induced with non-immunogenic adjuvant oils and/or in rat autoimmune models of multiple sclerosis and diabetes. Common autoimmunity genes and inflammation genes important to several human diseases are likely being detected in the various rat disease models. Continued dissection of the genetic underpinnings of rat arthritis models should provide candidate genes for investigation in human patients and lead to a clearer understanding of the complex genetics of RA. [source] The T-cell receptor repertoire of regulatory T cellsIMMUNOLOGY, Issue 4 2008Rafal Pacholczyk Summary The CD4+ CD25+ regulatory population of T cells (Treg cells), which expresses the forkhead family transcription factor (Foxp3), is the key component of the peripheral tolerance mechanism that protects us from a variety of autoimmune diseases. Experimental evidence shows that Treg cells recognize a wide range of antigenic specificities with increased reactivity to self antigens, although the affinity of these interactions remains to be further defined. The Treg repertoire is highly diverse with a distinct set of T-cell receptors (TCRs), and yet is overlapping to some extent with the repertoire of conventional T cells (Tconv cells). The majority of Treg cells are generated in the thymus. However, the role of the TCR specificity in directing thymic precursors to become Treg or Tconv cells remains unclear. On the one hand, the higher self reactivity of Treg cells and utilization of different TCRs in Treg and Tconv repertoires suggest that in TCR interactions an initial decision is made about the ,suitability' of a developing thymocyte to become a Treg cell. On the other hand, as Treg cells can recognize a wide range of foreign antigens, have a diverse TCR repertoire, and show some degree of overlap with Tconv cells, the signals through the TCR may be complementary to the TCR-independent process that generates precursors of Treg cells. In this review, we discuss how different features of the Treg repertoire influence our understanding of Treg specificities and the role of self reactivity in the generation of this population. [source] Onset of promiscuous gene expression in murine fetal thymus organ cultureIMMUNOLOGY, Issue 3 2006Renato Sousa Cardoso Summary T-cell differentiation and induction of tolerance to self-antigens occurs mainly in the thymus. Thymic stromal cells, specifically medullary thymic epithelial cells, express a diverse set of genes encoding parenchymal organ-specific proteins. This phenomenon has been termed promiscuous gene expression (PGE) and has been implicated in preventing organ-specific autoimmunity by inducing T-cell tolerance to self antigens. Early thymopoiesis and the critical factors involved in T-cell differentiation can be reproduced in vitro by murine fetal thymus organ culture (FTOC), which mimics the natural thymic microenvironment. To evaluate the occurrence of PGE in FTOC, gene expression profiling during in vitro thymic development in BALB/c mice was performed using a set of nylon cDNA microarrays containing 9216 sequences. The statistical analysis of the microarray data (sam program) revealed the temporal repression and induction of 57 parenchymal and seven lymphoid organ-specific genes. Most of the genes analysed are repressed during early thymic development (15,17 days post-coitum). The expression of the autoimmune regulator (AIRE) gene at 16 days post-coitum marks the onset of PGE. This precedes the induction of parenchymal organ genes during the late developmental phase at 20 days post-coitum. The mechanism of T-cell tolerance induction begins during fetal development and continues into adulthood. Our findings are significant because they show a fine demarcation of PGE onset, which plays a central role in induction of T-cell tolerance. [source] CD4+CD25hi regulatory T-cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasiaINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Johan W. Molling Abstract CD4+CD25hiCTLA4+FoxP3+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self antigens and increased circulating frequencies have been reported in various types of cancers. Circulating invariant natural killer T-cells (iNKT) are reduced in cancer patients and low iNKT frequency is related to poor prognosis. It is not yet clear whether high Treg numbers and low iNKT cell numbers pose an increased risk for the progression of premalignant lesions or whether Treg and iNKT cell numbers are influenced by dysplasia. We therefore studied prospectively the relation between iNKT cell and Treg frequencies and the natural course of human papillomavirus type 16 (HPV16) induced pre-malignant cervical dysplasia in 82 patients who participated in a nonintervention cohort study of women with abnormal cytology. Treg frequencies were significantly increased in women who had persistent HPV16 infection. Within the HPV16 persistence group there was no difference in Treg frequencies among patients who developed a CIN3 lesion and patients who did not progress to CIN3. Furthermore, Treg frequencies were increased in patients who had detectable HPV16 E7 specific IL-2 producing T-helper cells, which suggests a causal role of HPV infection in Treg development in parallel with HPV16 specific T helper cells. No evidence was found for a role for iNKT cells in persistence of HPV16 and progression of HPV16 induced CIN lesions. However, HPV-persistence-associated Tregs may explain the inefficacy of concomitant persistence associated immunity and may contribute to subsequent progression to neoplasia. © 2007 Wiley-Liss, Inc. [source] Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 6 2009Ian K. Campbell Objective Autoimmune regulator (Aire) promotes the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study was undertaken to determine whether loss of central tolerance renders Aire-deficient (Aire,/,) mice more susceptible to the induction of autoimmune arthritis. Methods Medullary TECs were isolated from Aire,/, and wild-type C57BL/6 mice for gene expression analysis. Collagen-induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) in adjuvant. Cellular and humoral immune responses to CII were evaluated. Chimeric mice were created by reconstituting lymphocyte-deficient mice with either Aire,/, or wild-type CD4 T cells and wild-type B cells. Results Wild-type, but not Aire,/,, mTECs expressed the CII gene Col2a1. Aire,/, mice developed more rapid and severe CIA, showing elevated serum anti-CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire,/, mice; however, Aire,/, CD4 T cells were more efficient at stimulating wild-type B cells to produce anti-CII IgG following immunization of chimeric mice with CII. Conclusion Our findings indicate that Aire-dependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire,/, mice manifests as increased CD4 T cell help to B cells for cross-reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross-reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity. [source] Dendritic cells in the recognition of intestinal microbiotaCELLULAR MICROBIOLOGY, Issue 4 2006Jan Hendrik Niess Summary Mucosal dendritic cells (DCs) constantly survey the luminal microenvironment which contains commensal microbiota and potentially harmful organisms regulating pathogen recognition and adaptive as well as innate defense activation. Distinct mechanisms are beginning to emerge by which intestinal antigen sampling and handling is achieved ensuring specificity and contributing to redundancy in pathogen detection. Distinct DC subsets are associated with these mechanisms and regulate specific innate or adaptive immune responses to help distinguish between commensal microbiota, pathogens and self antigens. Understanding DC biology in the mucosal immune system may contribute to the unraveling of infection routes of intestinal pathogens and may aid in developing novel vaccines and therapeutic strategies for the treatment of infectious and inflammatory diseases. [source] | ||||||||||