Antigen-specific responses in autoimmunity and tolerance

Autoantibodies to the hormone insulin arise spontaneously in the insulin autoimmune syndrome and in the prodrome of type I diabetes. Further, administration of insulin to individuals without autoimmune disease routinely results in, antibodies that bind autologoushormone. These observations suggest that physiological levels of hormones, such as insulin, are below critical thresholds for signaling tolerance induction, a state termed clonal ignorance. In contrast, studies from our laboratory on the genetic origins and structure of V genes used by insulin antibodies suggest that the anti-insulin repertoire is tightly regulated. We have shown that B cells in mice harboring an insulin antibody transgene are functionally silenced. These findings verify that tolerance is active for small molecules, even when they are present at low concentrations. Despite, active tolerance, insulin antibodies are sustained in the repertoire of normal animals by several mechanisms, including activation by TI antigen signals, unique display of conformational epitopes, and the recruitment of B cells previously selected by responses to other antigens. This essay reviews our current understanding of escape pathways for anti-insulin B cells.     

B cell tolerance and autoimmunity

Self-tolerance is induced in B cells at various maturational stages by diverse self-antigens B cell tolerance involves multiple mechanisms, ie. clonal deletion, clonal anergy, receptor editing and maturation arrest. The mechanism utilized for self-tolerance depends on both the maturational stage of B cells and the molecular nature of the self-antigens. B cell tolerance is abrogated by various mechanisms such as defects in inhibitory co-receptors, overexpression of CD19, T cell help and defects in the death receptor Fas (CD95). Since all of these molecules regulate B cell apoptosis mediated by either the antigen receptor or Fas, B cell apoptosis may play a role in the induction and maintenance of B cell tolerance. Moreover, environmental factors such as intestinal lipopolysaccharide also play a role in the breakdown of B cell tolerance.     

T cell tolerance and autoimmunity

CD4 T cells are the master controllers of immune responses to protein antigens, and many autoimmune diseases are thought to arise from a breakdown of immunological tolerance in CD4 cells. Peripheral tolerance in CD4 T cells is maintained by several mechanisms, including functional anergy, deletion (death) by apoptosis and suppression by regulatory T lymphocytes (Treg). Using transgenic mouse models, we have explored the roles of these mechanisms in tolerance to cell-associated tissue-restricted self-antigens and secreted systemic self-antigens. Tolerance to a membrane form of the antigen expressed in islet beta cells is maintained by Treg, which block T cell differentiation into pathogenic effectors, and by CTLA-4, which increases the activation threshold of T cells and prevents responses to the self-antigen. A systemically produced soluble form of the antigen induces rapid T cell anergy followed by deletion. The induction of anergy does not require either CTLA-4 or Treg, although in the absence of Treg tolerance can be broken more readily by potent immunogenic signals. Encounter with circulating antigen in T cells induces a state of antigen receptor "desensitization" that is associated with a block in proximal receptor-triggered signals. Thus, different mechanisms play dominant roles in T cell tolerance to different types of self-antigens.     

T cell tolerance and autoimmunity

A functional immune system requires a T cell repertoire that is extremely diverse so as to allow for the elimination of all possible pathogens. However, the production of an immense T cell repertoire also increases the likelihood of generating autoreactive T cells. The immune system must therefore also incorporate a means of silencing or eliminating autoreactive T cells, while minimally sacrificing T cell diversity. The induction and maintenance of T cell unresponsiveness to self antigens is thus defined as T cell tolerance. This review provides an overview of the T cell tolerance mechanisms invoked in the thymus and in the periphery to prevent the induction of autoimmunity. Factors that can influence the induction of tolerance and autoimmunity are also discussed.     

B-cell tolerance checkpoints in health and autoimmunity

The enormous diversity of the antibody repertoire is generated by two mechanisms: recombination of immunoglobulin (Ig) gene variable (V), diversity (D), and joining (J) gene segments during the early stages of B-cell development in the bone marrow and somatic hypermutation (SHM) of functional Ig genes from antigen-activated B cells within secondary lymphoid organs. Diversity by V(D)J recombination and SHM not only provides protective humoral immunity but also generates potentially harmful clones expressing autoantibodies. Under normal circumstances, several mechanisms regulate the removal of autoreactive B cells and defects in central and peripheral B cell tolerance checkpoints are associated with the development of autoimmunity in humans.     

Genes, tolerance and systemic autoimmunity

The characterization of functional CD8(+) inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8(+) T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8(+) Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8(+) Ti.     

T-cell tolerance and autoimmunity in transgenic models of central and peripheral tolerance

Experiments with transgenic mice expressing genes encoding both antigens in defined tissues and T-cell receptor genes of known specificities have enhanced our understanding of the mechanisms involved in the pathogenesis of autoimmune states. They have also shed light on the means by which potentially autoreactive cells may be prevented from exerting their autoaggressive potential. The value of the transgenic approach is that it can overcome the low frequency of peptide-specific T cells occurring in normal animals, and also provide a tissue-specific, cognate antigen that is absent in controls. These factors allow reactive T cells to be isolated or quantified by flow cytometry and their responses to antigen in vitro and in vivo be defined.     

Cell-cycle regulation in immunity, tolerance and autoimmunity

To trigger an effective immune response, lymphocytes must proliferate. In addition to their direct involvement in cell-cycle progression, cell-cycle regulators might thus control immune functions. Recent evidence suggests that these regulators are essential for T-cell function; we argue that their study will provide clues for dissecting anergy and tolerance mechanisms, as well as for intervention in autoimmune diseases.     

B-lymphocyte tolerance and effector function in immunity and autoimmunity

Immunologic Research - B-lymphocytes are integral to host defense against microbial pathogens and are associated with many autoimmune diseases. The B-cell receptor implements B-cell self-tolerance...     

Metabolic control of immune tolerance in health and autoimmunity

The filed that links immunity and metabolism is rapidly expanding. The adipose tissue, by secreting a series of immune regulators called adipokines, represents the common mediator linking metabolic processes and immune system functions. The dysregulation of adipokine secretion, occurring in obese individuals or in conditions of malnutrition or dietary restriction, affects the activity of immune cells resulting in inflammatory autoimmune responses or increased susceptibility to infectious diseases. Alterations of cell metabolism that characterize several autoimmune diseases strongly support the idea that the immune tolerance is also regulated by metabolic pathways. The comprehension of the molecular mechanisms underlying these alterations may lead to the development of novel therapeutic strategies to control immune cell differentiation and function in conditions of autoimmunity.     

Genetic lesions in T-cell tolerance and thresholds for autoimmunity

Summary: The cause of common organ‐specific autoimmune diseases is poorly understood because of genetic and cellular complexity in humans and animals. Recent advances in the understanding of the mechanisms of the defects underlying autoimmune disease in autoimmune polyendocrinopathy syndrome type 1 and non‐obese diabetic mice suggest that failures in central tolerance play a key role in predisposition towards organ‐specific autoimmunity. The lessons from such rare monogenic autoimmune disorders and well‐characterized polygenic traits demonstrate how subtle quantitative trait loci can result in large changes in the susceptibility to autoimmunity. These data allow us to propose a model relating efficiency of thymic deletion to T‐cell tolerance and susceptibility to autoimmunity.     

Peripheral tolerance and autoimmunity: lessons from in vivo imaging

Multi-photon microscopy has taken hold as a widely used technique in immunology, allowing for imaging of the kinetics of immune cell motility and cell–cell interactions, but what have we learned from this technique about the processes involved in peripheral tolerance and autoimmunity? Various studies have now looked at the dynamics of several mechanisms of peripheral T cell tolerance and efforts to examine the dynamics of the autoimmune response at the disease site are also under way. Here, we will discuss the findings of studies that use multi-photon microscopy to examine the dynamics of T cell tolerance in the lymph nodes and of the autoimmune processes involved in models of type 1 diabetes and multiple sclerosis. An emerging theme from these studies is that short T cell-antigen presenting cell interactions can lead to tolerance, and that autoreactive T cell restimulation at the disease site can play an important role in autoimmune disease exacerbation.     

T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens

Summary: We have used transgenic mouse models to examine the mechanisms of tolerance in CD4⁺ T lymphocytes to soluble, systemic and cell‐associated, tissue‐restricted self‐antigens. Anergy to an islet antigen, as a model of a tissue antigen, is dependent on the inhibitory receptor cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), and tissue‐restricted autoimmunity is inhibited by regulatory T lymphocytes. Anergy to a circulating systemic antigen can occur independently of CTLA‐4 signals, and it is induced primarily by a block in proximal receptor‐initiated signals. CD4⁺CD25⁺ regulatory T cells are generated in response to both forms of self‐antigens, but the induction is much more efficient with the tissue antigen. Receptor desensitization can be induced by the systemic antigen even in the absence of regulatory T cells, but tolerance can be broken by immunization much more easily if these cells are absent. Deletion of mature T cells is striking with the systemic antigen; there is little evidence to support peripheral deletion as a mechanism of tolerance to the tissue antigen. Thus, both distinct and overlapping mechanisms account for unresponsiveness to different forms of self‐antigens. These results establish a foundation for searching for genetic influences and pathogenic mechanisms in organ‐specific and systemic autoimmune diseases.     

B and T cell tolerance and autoimmunity in autoantibody transgenic mice

One hallmark of systemic lupus erythematosus (SLE) is the presence of autoantibodies directed at a diverse group of proteins of the U1/Sm small nuclear ribonucleoprotein particles (snRNP). Patients with SLE and murine models of this disease generate high titers of affinity mature, isotype-switched autoantibodies characteristic of T cell-dependent immune responses. In this investigation, we made use of anti-snRNP Ig transgenic mice (2-12 Tg) to track regulation of autoreactive B cells in normal and autoimmune-prone mice. Autoantibody studies demonstrated that the regulation of anti-snRNP B cells is intact in non-autoimmune Tg mice, but not in MRL-lpr/lpr mice. We further utilize autoreactive Tg B cells as antigen-presenting cells (APC) and individual snRNP peptides to assess the presence of autoreactive T cells in the repertoire of non-autoimmune and MRL-lpr/lpr mice. We found that Tg B cells can direct specific T cell tolerance in a non-autoimmune-prone (C57Bl/6) background, whereas the same autoantibody transgene in MRL-lpr/lpr mice drives T cell autoimmunity. Moreover, Tg B cell APC could stimulate autoreactive T cells from wild-type (non-Tg) C57Bl/6 mice, indicating a lack of tolerance induction in the absence of the autoantigenic-presenting B cells. Thus, we have defined dual roles for autoantigen-presenting B lymphocytes in stimulating self-reactive T cells that inhabit the normal repertoire or, under some conditions, providing tolerance signals.     

Induction of oral tolerance in experimental Sjogren's syndrome autoimmunity

Previous studies have showed that immunization with peptides from Ro 60 results in Sjogren's syndrome (SS)-like condition in BALB/c mice. We hypothesized that oral feeding with Ro 60 peptide or Ro 60 would prevent the disease. Four groups (each consisting of 10) of BALB/c mice were used. Group I-III were immunized with Ro 274 peptide. Group IV mice were administered adjuvant only. Group II mice were fed orally with Ro 274 peptide and Group III with Ro 60 for 5 days before immunization. There was a significant reduction in the binding of sera from both Group II and Group III mice to most of the Ro multiple antigenic peptides bound by Group I mice. In Group III mice, salivary flow was maintained above that of the Group I mice (average: 117.5 versus 58.6 microl; t = 2.7; P = 0.02). Salivary infiltrates were drastically decreased in the Ro peptide or Ro 60-fed groups, compared to non-tolerized group. Two of eight mice in Group II and 3/6 mice in Group III had no infiltrates, whereas all eight mice studied in Group I had a significant number of infiltrates. Thus, epitope spreading was prevented, lymphocytic infiltration was blocked and saliva flow was restored by means of oral feeding of either Ro 274 or Ro 60 in this animal model of SS.     

Immuno-ecology: how the microbiome regulates tolerance and autoimmunity

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Immune privilege, T-cell tolerance, and tissue-restricted autoimmunity

The eye is one of several specialized organs/tissues that display immune privilege, i.e. sites that permit foreign tissue grafts to enjoy prolonged (or even indefinite) survival. Immune privilege is an active, rather than a passive, process in which specialized tissues/sites and the immune system collaborate in providing immune protection without the risk of immunopathogenic injury to the tissue itself. Among the mechanisms that have been found to contribute to immune privilege is tolerance of peripheral T cells. Over the past few years, investigators have demonstrated at least four different pathways by which immune privilege can lead to T-cell tolerance: clonal deletion, clonal anergy, immune deviation, and T-cell suppression. In the case of the eye, privilege exists in part because antigens introduced into the eye are captured by distinctive local antigen-presenting cells that migrate via the blood to the spleen. At that site, they generate a stereotypic systemic immune response that is deficient in CD4⁺ T cells that mediate delayed hypersensitivity and that help B cells to secrete complement-fixing antibodies, yet replete with CD8⁺ T cells that function as cytotoxic cells and as regulatory cells. This response, termed anterior chamber associated immune deviation (ACAID), is mediated by antigen-specific regulatory T cells that secrete TGFβ in an autocrine fashion and suppress effector functions of inflammogenic CD4⁺ T cells. Because intraocular inflammation is deleterious to vision, ACAID and immune privilege are considered to be evolutionary adaptations that enable the eye to benefit from immune protection against pathogens without suffering blindness from immune injury.     

B cell tolerance to self in systemic autoimmunity.

After a century of research and despite intensive scrutiny, the origin of autoantibody production remains an enigma. Recently, the essential role of B cells in promoting systemic autoimmunity in mice seems more important than previously thought: self-reactive B cells can be subject to positive selection and a deficiency in serum IgM predisposes to the development of IgG antibodies to autoantigens. Studies of the B cell repertoire expressed in systemic autoimmune diseases have provided important clues. In human lupus, quantitation of this repertoire reveals the presence of an expansion of IgG clonotypes that impart reactivity with disease-related autoantigens. The nucleotide sequences of autoantibodies derived from these patients and expressing nephritogenic idiotopes (present in immune complexes and renal eluates of subjects with active disease) show features of diversification with a high rate of replacement/silent mutations and clustering of the mutations in the hypervariable regions, suggesting than an antigen-driven process plays a role in the generation of pathogenic autoantibodies. Currently, the contributions of apoptosis and of cell receptor signaling to this triggering are being appreciated. Pursuing these and related issues will have an important impact on autoimmune research.