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PubMed1995

The role of subsets of CD4+ T cells in autoimmunity.

It is generally considered that T cells which are reactive with self-antigens are effectively eliminated by two processes: clonal deletion and the induction of T cell anergy. More recently, it has been shown that some potentially autoreactive T cells remain unactivated because the self-antigens for which they are specific are not presented on competent antigen-presenting cells. All these mechanisms of self-tolerance may be regarded as passive in the sense that the autoreactive cells are either deleted or are intrinsically non-responsive. If this view of self-tolerance is adopted, then one would predict that rendering animals relatively lymphopoenic should not give rise to autoimmune disease. This prediction is not verified by experiment. Rats rendered relatively lymphopoenic by adult thymectomy followed by repeated low dose gamma-irradiation develop a high incidence of autoimmune diabetes. Furthermore, it has been shown that the reconstitution of these rats with a specific subset of CD4+ T cells from syngeneic donors prevents the development of this disease. The protective cells have the CD45RClow phenotype, they are resistant to adult thymectomy and the majority of them appear to be non-activated in the donor rats. In contrast, the CD45RChigh CD4+ subset does not provide protection from diabetes. Instead, on injection into athymic rats, it gives rise to pathological changes in a variety of organs: stomach, pancreas, liver, thyroid and lung. In addition, the CD45RClow CD4+ subset prevents these manifestations of autoimmunity in these circumstances. Recently, we have shown that CD4+ CD8- thymocytes are a highly potent source of cells that have the ability to control autoimmune diabetes in rats. It appears that the thymus has three distinct functions: positive selection; negative selection; and the generation of a population of cells that seem specialized for the control of autoimmunity.

Animals↗
PubMed1992

Transgenes in autoimmunity.

The ability of transgenic mice to express a specific protein in a specific tissue has enabled the mechanisms of self-tolerance and autoimmunity to be elucidated. Further studies, combined with more sophisticated methods of gene targeting, will provide insights into the pathway leading from loss of self-tolerance to autoimmunity.

Animals↗
PubMed2003

Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis.

BACKGROUND & AIMS: Although considerable effort has been directed toward the mapping of peptide epitopes by autoantibodies, the role of nonprotein molecules has been less well studied. The immunodominant autoantigen in primary biliary cirrhosis (PBC), E2 components of pyruvate dehydrogenase complexes (PDC-E2), has a lipoate molecule bonded to the domain to which autoantibodies are directed. METHODS: We examined sera from patients with PBC (n = 105), primary sclerosing cholangitis (n = 70), and rheumatoid arthritis (n = 28) as well as healthy volunteers (n = 43) for reactivity against lipoic acid. The lipoic acid hapten specificity of the reactive antibodies in PBC sera was determined following incubation of aliquots of the sera with human serum albumin (HSA), lipoylated HSA (HSA-LA), PDC-E2, lipoylated PDC-E2, polyethylene glycol (PEG), lipoylated PEG, free lipoic acid, and synthetic molecular mimics of lipoic acid. RESULTS: Anti-lipoic acid specific antibodies were detected in 81% (79 of 97) of antimitochondrial antibody (AMA)-positive patients with PBC but not in controls. Two previously unreported specificities in AMA-positive sera that recognize free lipoic acid and a carrier-conjugated form of lipoic acid were also identified. CONCLUSIONS: We hypothesize that conjugated form(s) of native or xenobiotic lipoic acid mimics contribute to the initiation and perpetuation of autoimmunity by at first breaking self-tolerance and participating in subsequent determinant spreading. The variability in the immunoreactive carrier/lipoate conjugates provides an experimental framework on which potential mechanisms for the breakdown of self-tolerance following exposure to xenobiotics can be investigated. The data have implications for patients taking lipoic acid as a dietary supplement.

Animals↗
PubMed1976

Antigen inhibition on antibody forming cells at the level of effector cell.

In this study a possibility was examined that the specific antigen might inhibit antibody forming cells in order to know whether a non-T-cell-dependent mechanism of self-tolerance is present or not. If an autoantigen inhibits autoantibody forming cells, this inhibition may be one of the non-T-cell-dependent mechanisms of self-tolerance. Spleen cells from mice which were immunized with sheep red blood cells (SRBC) were incubated with SRBC and after an hour incubation erythrocytes added were removed. After 4 and 8 hr incubation, the plaques against SRBC were assayed by the plaque method. 1) After 8 hr incubation, SRBC reduced the plaque count to about 60% of the control aliquot incubating spleen cells with C3H mouse red blood cells. 2) This inhibition required 1% SRBC suspension, but despite increase in its concentration to more than 1% the degree of the inhibition remained constant. 3) This inhibition seemed to require neither T cells, macrophages nor the cells which display the cytotoxic activity in the antibody dependent cell-mediated cytotoxicity.

Animals↗
PubMed2004

Basic immunology: a primer.

This article is intended to bring practicing physicians up to date on the current state of knowledge regarding the basic components and processes of the immune system. It discusses the role of the immune system and the importance of self-tolerance and describes the main cellular and noncellular entities involved in the immune response. It also details immune processes such as the lymphocyte selection process leading to self tolerance; antigen processing and presentation; cell signaling, activation, and co-stimulation; and the actions of cytokines and other signaling molecules.

Antibody Formation↗
PubMed2001

Transplantation tolerance and autoimmunity after xenogeneic thymus transplantation.

Successful grafting of vascularized xenografts (Xgs) depends on the ability to reliably induce both T cell-independent and -dependent immune tolerance. After temporary NK cell depletion, B cell suppression, and pretransplant infusion of donor Ags, athymic rats simultaneously transplanted with hamster heart and thymus Xgs developed immunocompetent rat-derived T cells that tolerated the hamster Xgs but provoked multiple-organ autoimmunity. The autoimmune syndrome was probably due to an insufficient development of tolerance for some rat organs; for example, it led to thyroiditis in the recipient rat thyroid, but not in simultaneously transplanted donor hamster thyroid. Moreover, grafting a mixed hamster/rat thymic epithelial cell graft could prevent the autoimmune syndrome. These experiments indicate that host-type thymic epithelial cells may be essential for the establishment of complete self-tolerance and that mixed host/donor thymus grafts may induce T cell xenotolerance while maintaining self-tolerance in the recipient.

Animals↗
PubMed1991

MHC class-I transgenic mice.

The introduction of cloned genes into the germline of mice has been proven to be a powerful tool to investigate the role of the respective gene products within the immune system. Here we summarize the transgenic mouse models that have been established with major histocompatibility complex (MHC) class-I genes. Foreign class-I alleles can be expressed in transgenic mice according to their normal expression patterns as authentic self molecules and can function in T-cell responses in the same way as endogenous class-I molecules. Since this is also true for most of the introduced human HLA class-I alleles, there is great interest in establishing mouse models for HLA-linked diseases. A new field of experimental approaches concerning self-tolerance has been opened by tissue specific expression of MHC antigens under specific promoters. Besides negative selection in the thymus, peripheral mechanisms could be identified that induce and maintain self-tolerance.

Animals↗
PubMed1999

The CTLA-4 gene is expressed in placental fibroblasts.

In order to elucidate the mechanisms that ensure survival of the allogeneic fetus, we are investigating the expression pattern of genes that are involved in peripheral self-tolerance in tissues at the maternal-fetal interface. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a negative regulator of T cell activation and may modulate peripheral self-tolerance. Previously, we reported the preferential transmission of maternally-inherited shorter alleles at a 3'-UTR microsatellite locus to liveborn children, but random transmission of paternally-inherited alleles, suggesting that CTLA-4 may be involved in the maintenance of tolerance at the maternal-fetal interface. In this report, we demonstrate that CTLA-4 mRNA and protein are indeed expressed in fetal tissues at the maternal-fetal interface throughout gestation.

Abatacept↗
PubMed1992

Autoimmunity.

The immune system has evolved to protect an organism from the pathogens that invade it but the effector mechanisms involved in mediating this protection are potentially lethal to the host itself. Consequently it is essential that they are not elicited by the host's own tissues and, because biochemically self and non-self are very similar, the immune system has had to develop an exquisite capability to distinguish relatively minor differences. There has been considerable progress recently in understanding how this discrimination is achieved although many questions remain. The problem is important in that the mechanisms that ensure self tolerance occasionally fail. The consequences of this failure are the autoimmune diseases, many of which afflict Man. This article reviews what is known about the way that the immune system normally avoids self reactivity and how breakdown in self tolerance can occur.

Antigen-Presenting Cells↗
PubMed1990

Selection of anti-F protein B-cell repertoires in normal mice.

The hypothesis that self-tolerance to F protein antigen exclusively concerns T cells was tested by determining the frequencies of B lymphocytes producing anti-F antibodies in bone marrow (BM), spleen and peritoneal exudate (PEC) cells from normal, immune or tolerant animals, and in responder and non-responder mouse strains. Using an ELISA spot assay and lipopolysaccharide stimulation, we found that anti-F frequencies were highest in BM and "naturally activated" large spleen cells, followed by resting spleen and PEC cells. Anti-F specificities were also induced among "natural" Ig-secreting cells of normal individuals. Specific immunization of responder mice doubled the splenic frequencies, while tolerization had no effect. Similar results were obtained in BALB/c and A/J mice, while C57BL/6 contained fewer anti-F B cells in spleen, but not in BM. These results support the notion that self-tolerance to F antigen can primarily be ascribed to T cells, but they also show F-antigen-specific selection of B-cell repertoires.

Animals↗
PubMed1996

Costimulation and autoimmunity.

The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in T cell activation and self-tolerance. Recent studies have demonstrated that CTLA-4 is a critical negative regulator of T cell activation and autoreactivity, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. Manipulation of this costimulatory pathway in animal models of autoimmunity has shown an important role for this pathway in both the initiation and progression of autoimmune diseases.

Animals↗
PubMed2002

[Autoimmunity in endocrinology: general principles].

The thymus is a crucial meeting place between the major systems of cell-to-cell communication, the nervous, the endocrine and the immune systems. More specifically, the thymus is the site for establishment of central T cell self-tolerance of neuroendocrine principles. The different factors--genetic, environmental, sexual--that intervene in the pathogenesis of autoimmune endocrinopathies are briefly reviewed here. Current research try to evidence that a thymic dysfunction, a defect in central self-tolerance could play an important role in the development of organ-specific autoimmune diseases, or cell-specific such as type 1 diabetes.

Antigens↗
PubMed1998

Avoidance of self-reactivity results in skewed CTL responses to rare components of synthetic immunogens.

In studying the CTL recognition of peptide determinants derived from the nuclear Ag La (SS-B), we observed significant skewing of the response toward rare components present within the immunogen. Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2Kb-binding peptide comprising human La (hLa) residues 51-58 resulted in class I-restricted cytotoxic T cells that failed to recognize naturally presented hLa 51-58 peptide. Instead, the majority of T hybrids recognized a low abundance (< or = 1%) contaminant present at picomolar concentrations in the original synthesis and identified as a peptide adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51-58 sequence. The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2Kb molecule or to the antagonism of CTL recognizing the unmodified determinant. Rather, the bias in the immune response appeared to be the result of partial self-tolerance to the homologous mouse La 51-58 determinant, which differs from its human counterpart by only a single amino acid at position 1 (T-->I). Accordingly, the CTL response appeared to be focused on "non-self" ligands present within the synthesis, even though they were present at very low concentrations. These observations have significant implications for the use of synthetic peptide vaccines, especially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactivity.

Amino Acid Substitution↗
PubMed2006

PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches.

The thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self-major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor alpha (PDGFRalpha) expression. Depletion of PDGFRalpha+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRalpha+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

Animals↗
PubMedDate not supplied

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes.

BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet beta-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell self-tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat. METHODS: The expression of the mammalian insulin-related genes (Ins, Igf1 and Igf2) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes-resistant BB (BBDR) and diabetes-prone BB (BBDP) rats. RESULTS: RT-PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2-day-old, 5-day-old and 5-week-old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue-specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF-2 protein was significantly lower in BBDP than in BBDR rats (p<0.01). CONCLUSIONS: The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue-specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T-cell development) and the absence of central T-cell self-tolerance of the insulin hormone family (by defective negative selection of self-reactive T-cells).

Aging↗
PubMed1994

T cell anergy.

T cell clonal anergy is a proposed mechanism of immunologic self tolerance in which T cells become functionally inactivated after previous stimulation. MHC class II-restricted antigen presentation by different cell types has been speculated to have a role in determining activation vs. anergy in responding T cells. Human T cells express MHC class II after activation and have been shown to present high concentrations of degraded peptide antigen to autologous T cells resulting in clonal anergy. In contrast to low antigen dose T cell clonal anergy, which occurs in the absence of costimulation, T cell anergy induced by human T cell presentation of antigen results in both primary proliferation and secondary unresponsiveness to high-dose antigenic stimulation. Although clonal anergy was previously thought to prevent autoreactive T cells from ever responding to self antigen presented without costimulation, we postulate that T cell presentation of antigen represents a "fail-safe" mechanism of immunologic self tolerance that would anergize clonally expanded autoreactive T cells when they are surrounded by a high extracellular concentration of degraded self antigen.

Animals↗
PubMed1992

Interleukin-2: a possible trigger for autoimmunity.

High doses of recombinant interleukin-2 (IL-2) may induce autoimmune lesions in patients receiving experimental cancer treatment. In most cases, the manifestation of autoaggression is transient and organ-specific, predominantly affecting the thyroid gland. Only a fraction of the patients are concerned; most individuals (around 90%) do not develop any signs of autoimmunity. Apparently, endogenously hyperproduced IL-2 may also be implicated in the pathogenesis of autoaggression, since active phases of such disparate autoimmune diseases, like multiple sclerosis and systemic lupus erythematosus, are accompanied by elevated IL-2 serum levels. Taking into account that immunological self-tolerance is maintained by several distinct mechanisms, we investigated whether IL-2 would interfere with clonal deletion or clonal anergy in vivo. In several experimental systems, IL-2 failed to abolish clonal deletion in the murine thymus or in the peripheral T-cell compartment. IL-2 did not affect the clonal deletion of self-reactive B cells in the bone marrow either. In contrast, IL-2 was found to be effective in abrogating clonal anergy of non-deleted self-specific T cells. Only in the presence of high frequencies of self-specific, potentially autoreactive T cells, IL-2 induces autoimmune lesions. Thus, IL-2 interferes with a mechanism of self-tolerance that guarantees the inactivation of T cells that for some reason have 'escaped' clonal deletion. If these data, obtained in the murine system, are extrapolated to man, then it may be stated that the T-cell repertoire of most individuals has been completely purged from self-reactive cells. Only in the presence of a non-deleted, anergic, potentially auto-reactive T-cell population, could organ-specific disease be induced by IL-2.

Animals↗