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PubMed1989

Complexes of soluble HLA antigens and anti-HLA autoantibodies in human sera: possible role in maintenance of self-tolerance.

The MHC plays an essential role in regulating the process of self-nonself discrimination. T cells recognize nonself antigens only in the context of self-MHC gene products. It is not clear, however, whether B cells are also endowed with immune receptors for self-MHC antigens. We have explored the existence of antibodies against self-MHC antigens (HLA) in the human by analyzing the specificity of anti-HLA antibodies developed by a population of 727 dialysis patients who had been monitored monthly over a period of 3-78 months. Anti-HLA autoantibodies were identified by serum screening in 119 patients. Twenty-five of these 119 patients had not been exposed to alloantigens before, indicating that the production of anti-HLA autoantibodies is not necessarily stimulated by allogeneic HLA antigens. Cross-matching of sera with autologous lymphocytes, confirmed the autoreactive nature of these anti-HLA antibodies which were of IgM or of IgG isotype in approximately equal numbers of patients. The fine specificities of anti-HLA autoantibodies was ascertained in studies which showed that antibodies can be adsorbed, and the eluted, from the membranes of target cells carrying then relevant HLA antigen. Since the antibodies characterized in our studies may be functionally active in vivo we examined the possibility that their level is controlled by anti-idiotypic antibodies or by soluble HLA antigens. We found that the titer of anti-HLA autoantibodies increased significantly if soluble HLA antigens were depleted from the serum. Our data suggest that circulating HLA antigens form immune complexes with anti-HLA autoantibodies and contribute to the maintenance of self-tolerance by inhibiting antibody binding to membrane HLA antigens. The finding that the immune repertoire includes B cells with receptors for self-MHC opens new perspectives for the study of network perturbations in autoimmune diseases.

Antigen-Antibody Complex↗
PubMed1996

T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases.

This paper shows that elimination of a small subpopulation of peripheral T cells can elicit activation/expansion of self-reactive T cells from the remaining T cells and produce a wide spectrum of organ-specific and systemic autoimmune diseases in normal mice; reconstitution of the eliminated T-cell population prevents autoimmune development. This regulatory T-cell population expresses the CD25 molecule, apparently includes 'activated' T cells, and suppresses immune responses to non-self as well as self antigens in an antigen-nonspecific manner. Although the degree of abnormality in the T-cell regulation significantly influences the spectrum, incidence, and severity of autoimmune disease, the T-cell abnormality itself cannot determine the specificities of the elicited autoimmune responses since a comparable degree of abnormality causes different autoimmune diseases depending on the mouse strains used. Host genetic elements thus significantly contribute to determining the specificities. These findings taken together indicate that one aspect of natural self-tolerance is maintained by a T cell-mediated or -dependent control of potentially pathogenic self-reactive T cells in the periphery, and that defective control, caused by environmental insults or genetic abnormalities, suffices to activate self-reactive T cells, eliciting various autoimmune diseases depending on the genetic makeup of the host.

Animals↗
PubMed1997

Autoimmunity: when self-tolerance breaks down.

The spontaneous development of destructive polyarthritis in mice transgenic for an autoreactive T-cell receptor supports the notion that a failure of T-cell self-tolerance can lead to similar diseases in humans, and sheds new light on the role of peripheral tolerance in the avoidance of such pathological immune responses.

Animals↗
PubMed1996

Hierarchical self-tolerance to T cell determinants within the ubiquitous nuclear self-antigen La (SS-B) permits induction of systemic autoimmunity in normal mice.

Systemic autoimmune diseases are frequently associated with clustering of high titer autoantibody responses towards nuclear self-antigens. Little is known, however, about the extent of immune tolerance to the target nuclear antigens or the events leading to the complex autoantibody responses that are characteristic of systemic autoimmunity. To address these issues, we have examined the mouse immune response to La autoantigen (mLa) and the homologous human La antigen (hLa), which are components of the La(SS-B)/Ro(SS-A) ribonucleoprotein (RNP) complex targeted in systemic lupus erythematosus and primary Sjögren's syndrome. The findings reveal the presence of hierarchical T cell tolerance involving multiple autodeterminants within the La autoantigen expressed by normal H-2k and H-2a mice. At one end of this spectrum, there was no detectable T or B cell autoimmunity observed in mice that were immunized with the immunodominant mLa287-301 determinant, which differed by a single residue in its core sequence from the homologous but highly immunogenic human La288-302 determinant. Interestingly, the mLa287-301 peptide acted as an altered peptide ligand that specifically antagonized the activation of an hLa288-302-specific T cell hybridoma. In contrast to the tolerogenic mLa287-301 determinant, a range of autoimmune potential was identified among poorly tolerizing, subdominant self-peptides present within mouse La autoantigen. Notably, immunization of normal mice with the autologous subdominant La25-44 and La106-129 determinants resulted in limited or no detectable autoantibody response. In contrast, immunization with the subdominant mouse La13-30 determinant induced a proliferative T cell response associated with the appearance of specific autoantibodies recognizing multiple intrastructural (La) and intermolecular components (Ro) of the murine La/Ro RNP. The findings suggest how diversified autoimmunity might follow initiation of immunity to simple peptide mimics of poorly tolerogenic determinants that are present within ubiquitous self-antigens.

Amino Acid Sequence↗
PubMed1996

Breaking self-tolerance in nonobese diabetic mice.

Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.

Amino Acid Sequence↗
PubMed2005

Monogenic autoimmune diseases - lessons of self-tolerance.

The molecular defects recently identified in the rare monogenic autoimmune diseases (AIDs) have pinpointed critical steps in the pathways that contribute to the development of normal immune responses and self-tolerance. Recent studies of autoimmune polyendocrinopathy syndrome type 1, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, IL-2 receptor alpha-chain deficiency, and, in particular, their corresponding mouse models, have revealed the details of the molecular mechanisms of normal immune tolerance, and exposed how defects in these mechanisms result in human autoimmunity. In addition to a deeper understanding of the immune system, detailed molecular characterization of monogenic AIDs will help us to understand the mechanisms behind common polygenic AIDs and, furthermore, to develop novel therapies and intervention strategies to treat them.

Animals↗
PubMed1990

Intrinsic B-cell hyporesponsiveness accounts for self-tolerance in lysozyme/anti-lysozyme double-transgenic mice.

In double-transgenic mice expressing a gene construct encoding hen egg lysozyme as well as rearranged anti-lysozyme antibody genes, large numbers of anti-lysozyme B cells are present in peripheral lymphoid tissues but are profoundly tolerant. The cellular basis for this form of non-deletional self-tolerance was explored. The tolerant anti-lysozyme B cells from double-transgenic mice were found to produce much less antibody than nontransgenic controls in T-cell-dependent antigen-specific responses, in adoptive transfer in vivo, and in hanging-drop cultures in vitro, as well as in response to stimulation with the nonspecific mitogen lipopolysaccharide. The diminished responsiveness of the tolerant B cells was not due to a reduction in the number of responding B-cell precursors per se nor were suppressor cells detected in titration, depletion, or mixing experiments. Nondeletional tolerance in this model, therefore, appears to result from an intrinsic functional change in the self-reactive B cells themselves.

Animals↗
PubMed2000

The use of HLA A2.1/p53 peptide tetramers to visualize the impact of self tolerance on the TCR repertoire.

p53 is an attractive target for cancer immunotherapy since it is overexpressed in half of all tumors. However, it is also expressed in normal lymphoid tissue, and self tolerance leaves a p53-specific repertoire purged of high avidity CTL. To better understand the mechanism of tolerance and the basis for such low avidity interaction, p53-specific CTL from p53 deficient (p53-) and sufficient (p53+) A2.1/Kb transgenic mice were compared with respect to their ability to bind HLA-A2.1 tetramers containing cognate murine p53 peptide Ag, p53 261-269. Since the murine CD8 molecule cannot interact with human HLA-A2.1, this tests the ability of the TCR to bind the A2.1/peptide complex tetramer. CTL from p53- mice demonstrated strong binding of such A2.1/p53 261-269 tetramers; however, the CTL from tolerant p53+ mice were devoid of tetramer-binding CD8+ T cells. Examination of TCR expression at the clonal level revealed that CTL from p53+ and p53- mice each expressed comparable levels of the p53-specific TCR. These results indicate that normal expression of p53 promotes elimination of T cells expressing TCRs with sufficient affinity to achieve stable binding of the A2.1/p53 261-269 tetramers.

Amino Acid Sequence↗
PubMed2005

Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network.

Despite a rapidly accumulating clinical experience with autologous stem cell transplantation (ASCT) as a treatment for severe refractory autoimmune disease, data on the mechanisms by which ASCT induces immune tolerance are still very scarce. In this study it is shown that ASCT restores immunologic self-tolerance in juvenile idiopathic arthritis (JIA) via 2 mechanisms. First, ASCT induces a restoration of the frequency of FoxP3 expressing CD4+CD25bright regulatory T cells (Tregs) from severely reduced numbers before ASCT to normal levels after ASCT. This recovery is due to a preferential homeostatic expansion of CD4+CD25+ Tregs during the lymphopenic phase of immunereconstitution, as measured by Ki67 and CD44 expression, and to a renewed thymopoiesis of naive mRNA FoxP3 expressing CD4+CD25+ Tregs after ASCT. Second, using artificial antigen-presenting cells to specifically isolate self-reactive T cells, we demonstrate that ASCT induces autoimmune cells to deviate from a proinflammatory phenotype (mRNA interferon-gamma [IFN-gamma] and T-bet high) to a tolerant phenotype (mRNA interleukin-10 [IL-10] and GATA-3 high). These data are the first to demonstrate the qualitative immunologic changes that are responsible for the induction of immune tolerance by ASCT for JIA: the restoration of the CD4+CD25+ immune regulatory network and reprogramming of autoreactive T cells.

Antigen-Presenting Cells↗
PubMed1989

The Florey lecture, 1989. Self-tolerance: the key to autoimmunity.

'Horor autotoxicus', as it was termed by Erhlich, is a rare clinical event despite the genetic potential of every individual to mount immune responses to self-antigens. This can be explained by the fact that the developing immune system learns to recognize self-antigens and to tolerate them. The key to autoimmunity therefore lies in unravelling the mechanisms of self-tolerance. Studies of conventional models of unresponsiveness have failed to provide a definitive answer owing to the difficulty in controlling for the large number of antigen-related variables associated with self-tolerance and in following the fate of individual clones of self-reactive lymphocytes which emerge in very low numbers from the pre-immune repertoire. These problems have now been overcome by creation of transgenic mice tolerant to endogenous antigens and containing high frequencies of autoreactive T or B lymphocytes. According to the results obtained to date, different mechanisms of tolerance induction operate for self-reactive T lymphocytes compared with B lymphocytes. Thus self-tolerance in T lymphocytes appears to depend largely on clonal deletion within the thymus. By contrast, self-reactive B lymphocytes are functionally silenced without undergoing deletion provided that the transgenic B lymphocytes express both IgM and IgD on their surfaces. This dichotomy makes good sense given that the T-lymphocyte repertoire once shaped within the thymus is not subject to further mutation whereas antigen receptors on mature B lymphocytes undergo hypermutation in the periphery.

Animals↗
PubMed1998

Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity.

The thymus expresses many genes previously thought to be specific for cell types in other organs. Thus, insulin genes are expressed in rare cells of the thymic medulla. Thymus transplantation demonstrates a functional capability of such expression for self-tolerance induction. Correlative studies suggest that impaired thymic expression confers susceptibility to autoimmune disease.

Animals↗
PubMed2005

CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications.

The treatment of autoimmune diseases using conventional chemical immunosuppressants has short-term effects, imposing the need for chronic treatment with its risks of over-immunosuppression. CD3-specific monoclonal antibodies can restore self-tolerance in a durable fashion after a single short-term treatment, as demonstrated in several experimental models and clinically in recent-onset insulin-dependent diabetes. Disease remission involves first an immediate 'freezing' of the autoimmune response, which is linked to CD3-specific antibody-induced antigenic modulation of CD3-TCR complex at the T lymphocyte surface, followed by 'resetting' of TGF-beta-dependent T-cell mediated immunoregulation. Tolerance induction is demonstrated by persisting disease protection in spite of recovery of full immunocompetence to unrelated antigens.

Animals↗
PubMed2005

Thymic transcription of neurohypophysial and insulin-related genes: impact upon T-cell differentiation and self-tolerance.

The thymus is the unique lymphoid organ responsible for the generation of a diverse repertoire of T lymphocytes that are competent against non self-antigens while being tolerant to self-antigens. A vast repertoire of neuroendocrine-related genes is transcribed in the nonlymphoid cellular compartment of the thymus (thymic epithelial cells, dendritic cells and macrophages). The precursors encoded by these genes engage two types of interactions with developing T cells (thymocytes). First, they are not processed in a classical neuroendocrine way but as the source of self-antigens that are presented to pre-T cells by the major histocompatibility complex proteins of the thymus. This presentation could be responsible for the establishment of central T-cell self-tolerance to neuroendocrine functions. Second, they also deliver signal ligands that are able to bind to neuroendocrine-type receptors expressed by thymocytes. This interaction activates several types of intracellular signalling pathways implicated in the developmental process of T lymphocytes. Several experimental arguments support a role for thymic dysfunction as a crucial factor in the development of organ-specific autoimmune endocrinopathies, such as 'idiopathic' central diabetes insipidus and type 1 diabetes mellitus. The rational use of tolerogenic neuroendocrine self-antigens for the prevention/treatment of autoimmune endocrinopathies is currently under investigation.

Animals↗
PubMed1994

Mechanism of self-tolerance and events leading to autoimmune disease and autoantibody response.

This review summarizes recent studies on the mechanisms of self-tolerance and autoimmune disease pathogenesis based primarily on the murine ovarian autoimmune disease models. The ovarian autoimmune disease was induced experimentally by three approaches: (1) transfer of normal T cells into syngeneic athymic nu/nu mice, (2) neonatal thymectomy, or (3) immunization with a well-defined peptide from the ovarian antigen, ZP3. Self-reactive T cells with capacity to elicit autoimmune oophoritis and autoimmune gastritis are not deleted in the neonatal or adult thymus. In the adult spleen, T cells are not pathogenic until regulatory T cells have been depleted. Thus the balance of activity between pathogenic T cells and regulatory T cells appears to determine the tolerance status of the host to self-antigens responsible for these autoimmune diseases. Murine autoimmune disease of the ovaries was found to occur through two independent pathways. The first is by depletion of regulatory T cells, as created by thymectomy within 4 days after birth. Alternatively, pathogenic T cells can be activated through molecular mimicry at the level of T cell peptide. This appears to depend on the sharing between non-ovarian and ovarian peptides of critical amino acid residues required for activation of pathogenic T cells. Finally, when T cells that recognize the ZP3 peptide are activated, endogenous ovarian antigens can spontaneously stimulate B cells to produce antibodies that react with ZP3 domains outside the immunizing T cell peptide.

Animals↗
PubMed2000

Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure.

Arsenic (As) is a human carcinogen. Our prior work showed that chronic (>18 weeks) low level (500 nM) arsenite (As3+) exposure induced malignant transformation in a rat liver epithelial cell line (TRL 1215). In these cells, metallothionein (MT) is hyper-expressible, a trait often linked to metal tolerance. Thus, this study examined whether the adverse effects of arsenicals and other metals were altered in these chronic arsenite-exposed (CAsE) cells. CAsE cells, which had been continuously exposed to 500 nM arsenite for 18 to 20 weeks, and control cells, were exposed to As3+, arsenate (As5+), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), antimony (Sb3+), cadmium (Cd2+), cisplatin (cis-Pt), and nickel (Ni2+) for 24 h and cell viability was determined by metabolic integrity. The lethal concentration for 50% of exposed cells (LC50) for As3+ was 140 microM in CAsE cells as compared to 26 microM in control cells, a 5.4-fold increase in tolerance. CAsE cells were also very tolerant to the acute toxic effects of As5+ (LC50 > 4000 microM) compared to control (LC50 = 180 microM). The LC50 for DMA was 4.4-fold higher in CAsE cells than in control cells, but the LC50 for MMA was unchanged. There was a modest cross-tolerance to Sb3+, Cd2+, and cis-Pt in CAsE cells (LC50 1.5-2.0-fold higher) as compared to control. CAsE cells were very tolerant to Ni2+ (LC50 > 8-fold higher). Culturing CAsE cells in As(3+)-free medium for 5 weeks did not alter As3+ tolerance, implicating an irreversible phenotypic change. Cellular accumulation of As was 87% less in CAsE cells than control and the accumulated As was more readily eliminated. Although accumulating much less As, a greater portion was converted to DMA in CAsE cells. Altered glutathione (GSH) levels were not linked with As tolerance. A maximal induction of MT by Zn produced only a 2.5-fold increase in tolerance to As3+ in control cells. Cell lines derived from MT normal mice (MT+/+) were only slightly more resistant (1.6-fold) to As3+ than cells from MT null mice (MT-/-). These results show that CAsE cells acquire tolerance to As3+, As5+, and DMA. It appears that this self-tolerance is based primarily on reduced cellular disposition of the metalloid and is not accounted for by changes in GSH or MT.

Animals↗
PubMed2001

Restoration of self-tolerance is a feasible approach to control ongoing beta-cell specific autoreactivity: its relevance for treatment in established diabetes and islet transplantation.

Major progress has been made over the last 10 years in understanding the immune mechanisms underlying autoimmune Type I (insulin-dependent) diabetes mellitus. It seems that immunotherapy is the best approach for preventing and/or arresting beta cell destruction. For immunotherapeutic approaches to be clinically applicable to Type I diabetes, they cannot rely on the use of non-specific immunosuppressants. Their relative ineffectiveness over the long term and the risk of recurrence, once the drug is withdrawn, requires permanent drug treatment which augments problems of infection and drug toxicity. One solution is to selectively tackle the pathogenic immune response. Operationally, this requires establishing immunological tolerance, i.e. a state of durable antigen-specific unresponsiveness in the absence of generalised immunosuppression. This review aims to present the rationale and clinical applicability of possible immunointervention strategies in Type I diabetes aimed at restoring self-tolerance to beta cells.

Animals↗
PubMedDate not supplied

Self tolerance is H-2-restricted.

H-2 restriction is an established characteristic of T-cell behaviour and, in effect, it means that mouse T cells are activated against foreign antigens only if those antigens are presented in a membrane association with molecules of the mouse major histocompatibility complex, H-2. Whether T-cell inactivation or tolerance is also H-2-restricted is a question which has been tested directly and indirectly several times in the past. In each case the answer was 'No' but in each case the answer was inconclusive. Doubts arose because of the observation that activation of T cells, in vivo, is an H-2-restricted event which appears unrestricted because of antigen processing by the host. If antigen processing is involved in the induction of tolerance, then tolerance might also be an H-2-restricted process disguised to appear unrestricted. We report here a study designed to minimize antigen processing in which we find that T-cell tolerance induction to 'self' minor histocompatibility (H) antigens is indeed H-2-restricted.

Animals↗
PubMed2005

Natural regulatory T cells and self-tolerance.

The adaptive immune system allows individual organisms to mount defensive reactions against unanticipated pathogens by developmentally creating a diverse repertoire of clonally distributed receptors capable of recognizing a multitude of antigens and then expanding as effector cell populations those that can recognize molecules from the pathogens. To function properly, the system must deal with the problem of randomly generated receptors that can recognize self components. Most solutions to this self-tolerance problem are cell intrinsic and involve the deletion or inactivation of autoreactive cells. However, an extrinsic form of dominant tolerance has been demonstrated that takes the form of CD4(+) regulatory T cells. This perspective discusses why such a mechanism might have evolved and the problems it presents for self-non-self discrimination.

Animals↗