Multiple paths to loss of anergy and gain of autoimmunity

B cells and autoimmunity: cells of the immune system have the capacity to recognize/neutralize a myriad array of disease-causing pathogens, while simultaneously minimizing damage to self tissue. Obvious breakdowns in this ability to distinguish between self and non-self are evident in multiple forms of autoimmune disease, where B and T cells mount damaging attacks on cells and organs. B cells may directly damage tissue by producing pathogenic antibodies that bind self antigen, fix complement or form immune complexes. Recent evidence also suggests B cells indirectly induce autoimmunity by concentrating low avidity self antigen through the B cell receptor and presenting self-peptides to autoreactive T cells. B cells may also initiate autoimmunity when provided sufficient help from autoreactive T cells that have escaped deletion in the thymus. Here, we will review the role of anergy in maintenance of tolerance and how alterations in the normal balance of positive and negative signals may contribute to the development of autoimmune disease in mouse models and humans.     

Multiple paths to loss of anergy and gain of autoimmunity

B cells and autoimmunity: cells of the immune system have the capacity to recognize/neutralize a myriad array of disease-causing pathogens, while simultaneously minimizing damage to self tissue. Obvious breakdowns in this ability to distinguish between self and non-self are evident in multiple forms of autoimmune disease, where B and T cells mount damaging attacks on cells and organs. B cells may directly damage tissue by producing pathogenic antibodies that bind self antigen, fix complement or form immune complexes. Recent evidence also suggests B cells indirectly induce autoimmunity by concentrating low avidity self antigen through the B cell receptor and presenting self-peptides to autoreactive T cells. B cells may also initiate autoimmunity when provided sufficient help from autoreactive T cells that have escaped deletion in the thymus. Here, we will review the role of anergy in maintenance of tolerance and how alterations in the normal balance of positive and negative signals may contribute to the development of autoimmune disease in mouse models and humans.     

Cross-presentation: inducing CD8 T cell immunity and tolerance

The term cross-presentation denotes the presentation of exogenous (extracellular) antigens to T cells, particularly CD8 T cells. It permits professional antigen-presenting cells which have collected antigens in nonlymphoid tissues to activate naive CD8 T cells in the secondary lymphatic compartment. Thus it allows CD8 T cells to scan nonlymphoid tissues for pathogens without the need of migrating there themselves and may hence be critical for immune responses to tissue-tropic viruses. It may also be essential in the immune response to nonlymphoid tumors. In contrast to the induction of immunogenic responses to pathogens, cross-presentation of self-antigens leads to CD8 T cell tolerance by deletion of autoreactive CD8 T cells. The precise way in which the immune system distinguishes self from foreign is not known, but modification in the cross-presenting antigen-presenting cell, such as that achieved by CD4 T cell help or inflammatory signals, may play a critical role in this process. If the dose of the self-antigen or the avidity of the T cell receptor is too low, cross-presentation fails to remove autoreactive CD8 T cells. Ignoring the self-antigen, these cells recirculate through the secondary lymphatics, unless they are activated, for example, by a cross-reactive virus. Then autoimmunity may be triggered.     

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.     

Induction and maintenance of self tolerance: the role of CD4+CD25+ regulatory T cells

The immune system responds vigorously to invading pathogens (non-self, foreign), while remaining unresponsive (tolerant) to the body's own components and circulating constituents (self). This indifference to self components is a result of finely orchestrated events of thymic negative selection (central tolerance) of developing T cells that are autoaggressive combined with those operative in the periphery (peripheral tolerance) to control the activity of potentially autoreactive T cells that escaped thymic tolerance. Recently, autoimmune regulator expressed in the thymus has been identified as a critical mediator of central tolerance towards tissue-specific antigens. In the periphery, a variety of regulatory T cells are involved in effecting tolerance. There is immense interest and excitement about the newly identified subset of CD4(+)CD25(+) T cells. This is a unique subset of CD4(+) T cells that bear CD25 (IL-2Ralpha chain) on the cell surface in the na?ve state and express FoxP3 as a unique marker. These cells suppress the activity of autoreactive effector T cells primarily via cell-cell contact. The deficiency and/or altered function of CD4(+)CD25(+) T cells is associated with autoimmunity. Mice deficient in FoxP3 (scurfy mice) bear an autoimmune phenotype, and human males with mutations in the corresponding gene express the phenotype of wide-spread autoimmunity, the immune dysregulation, polyendocrinopathy and enteropathy, and X-linked syndrome. In vitro expansion of antigen-specific CD4(+)CD25(+) T cells and their adoptive transfer into patients suffering from autoimmunity is emerging as a promising new therapeutic approach for these debilitating disorders.     

Mechanisms regulating the development and function of natural regulatory T cells

The key of the immune system is to protect the host from foreign threat posed by pathogens and from the internal threat posed by self-attacking lymphocytes. The ability to discriminate self versus non-self ensures that only “non-self” pathogens, but not the self antigens, are attacked. Such tolerance to “self” arises from the central tolerance mechanisms that include the deletion of thymocytes with high reactivity to self antigens and also the induction of unresponsiveness of autoreactive T cells in the periphery. Natural regulatory T cells (nTregs) directly inhibit effector T cells, and keep their proliferation in control. Apart from preventing autoimmune reactions, Tregs also contribute to peripheral immune homeostasis as evidenced by the excessive lymphocyte accumulation in peripheral lymphoid organs and intestinal inflammation in the absence of nTregs. Here we discuss the molecular aspects of the development and suppressive function of naturally occurring Tregs. Accumulating evidence shows the importance of these Tregs in autoimmunity, tumor immunity, organ transplantation, allergy, and microbial immunity.     

Physiological roles of murine DAP10 adapter protein in tumor immunity and autoimmunity

Summary:  The immune system has evolved to tolerate what is self and reject what is foreign. The recognition of self from non-self is performed by activating and inhibitory receptors, which signal immune cells via adapter molecules, determining the outcome of the immune response. DAP10, a transmembrane adapter protein expressed broadly in hematopoietic cells, associates with NKG2D activating receptor forming a multisubunit complex, which recognizes self-proteins upregulated during tumorigenesis, infection, and autoimmune response. Analysis of immune reactions against syngeneic tumors, as well as autoimmune responses in the DAP10-deficient mice, revealed an important physiological role of DAP10 signaling in maintaining tolerance to self, probably by controlling the development and activation threshold of autoreactive T cells.     

Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy

The immune system is responsible for defending the host from a large variety of potential pathogens, while simultaneously avoiding immune reactivity towards self-components. Self-tolerance has to be tightly maintained throughout several central and peripheral processes; immune checkpoints are imperative for regulating the immunity/tolerance balance. Dendritic cells (DCs) are specialized cells that capture antigens, and either activate or inhibit antigen-specific T cells. Therefore, they play a key role at inducing and maintaining immune tolerance. DCs that suppress the immune response have been called tolerogenic dendritic cells (tolDCs). Given their potential as a therapy to prevent transplant rejection and autoimmune damage, several strategies are under development to generate tolDCs, in order to avoid activation and expansion of self-reactive T cells. In this article, we summarize the current knowledge relative to the main features of tolDCs, their mechanisms of action and their therapeutic use for autoimmune diseases. Based on the literature reviewed, autologous antigen-specific tolDCs might constitute a promising strategy to suppress autoreactive T cells and reduce detrimental inflammatory processes.     

The potential for induction of autoimmune disease by a randomly-mutated self-antigen

The pathology of most autoimmune diseases is well described. However, the exact event that triggers the onset of the inflammatory cascade leading to disease is less certain and most autoimmune diseases are complex idiopathic diseases with no single gene known to be causative. In many cases, a relation to an infectious disease is described, and it is thought that microbes can play a direct role in induction of autoimmunity, for instance by molecular mimicry or bystander activation of autoreactive T cells. In contrast, less attention has been given to the possibility that modified self-antigens can be immunogenic and lead to autoimmunity against wildtype self-antigens. In theory, modified self-antigens can arise by random errors and mutations during protein synthesis and would be recognized as foreign antigens by na?ve B and T lymphocytes. Here, it is postulated that the initial auto-antigen is not a germline self-antigen, but rather a mutated self-antigen. This mutated self-antigen might interfere with peripheral tolerance if presented to the immune system during an infection. The infection lead to bystander activation of na?ve T and B cells with specificity for mutated self-antigen and this can lead to epitopespreading in which T and B cells with specificity for wildtype self-antigens are activated as a result of general inflammation.     

Idiotypes and autoimmunity

The reports discussed above have increased our knowledge of idiotypes, mainly with respect to additional CRI on autoantibodies and to a relatively new aspect of 'pathogenic idiotypes'. It is obvious that much remains to be discovered about the normal role of idiotypes and how they might be involved in the pathogenesis of autoimmune disorders. The relationship of the idiotypic network to tolerance is a matter of speculation; tolerance implies the ability to distinguish between 'foreign' and self-antigens and it is important to remember that antibody V regions are also self-antigens. Several mechanisms have been proposed to explain immunological tolerance. Originally, it was envisaged that the repertoires of both T and B lymphocytes were in some way purged of potentially self-reactive clones. However, it is now evident that self-reactive lymphocytes do exist but are normally held under control. Finally, it may be that certain self-antigens are simply never exposed to immune surveillance. It seems that the control of self-reactive lymphocytes is central to the question of tolerance. In the absence of autoimmune disease, autoantibodies can be produced, for example, after many infectious diseases or vaccinations. However, this type of perturbation of the immune system is associated with the short-term production of low titres of low-affinity antibodies, generally of the IgM isotype, which are thought to represent germline gene products. Homeostasis is soon re-established, possibly by regulatory T cells interacting with autoreactive B cells through their idiotypic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Avoiding autoimmune disease--T cells know their limits

The molecular mimicry theory has become a dominant paradigm to explain the triggering of autoaggressive T lymphocytes. The basis of the theory is that an immune response is triggered by non-self during infection and subsequent cross-reactive T-cell recognition of a similar self antigen provokes an inflammatory lesion in the target organ. It is clear that we all harbour autoreactive T cells and that T-cell receptor (TCR) cross-reactivity is extensive. Here, I argue that the immune system has evolved mechanisms to limit the risk of an autoaggressive response. Importantly, the strength of TCR stimulation provided by self and non-self antigens will usually differ. Evidence points to a model in which the three pillars of immune tolerance (deletion, anergy-adaptation and regulation) act to limit autoimmune disease from molecular mimicry.     

Emerging role of regulatory T cells in gene transfer

Induction and maintenance of immune tolerance to therapeutic transgene products are key requirements for successful gene replacement therapies. Gene transfer may also be used to specifically induce immune tolerance and thereby augment other types of therapies. Similarly, gene therapies for treatment of autoimmune diseases are being developed in order to restore tolerance to self-antigens. Regulatory T cells have emerged as key players in many aspects of immune tolerance, and a rapidly increasing body of work documents induction and/or activation of regulatory T cells by gene transfer. Regulatory T cells may suppress antibody formation and cytotoxic T cell responses and may be critical for immune tolerance to therapeutic proteins. In this regard, CD4(+)CD25(+) regulatory T cells have been identified as important components of tolerance in several gene transfer protocols, including hepatic in vivo gene transfer. Augmentation of regulatory T cell responses should be a promising new tool to achieve tolerance and avoid immune-mediated rejection of gene therapy. During the past decade, it has become obvious that immune regulation is an important and integral component of tolerance to self-antigens and of many forms of induced tolerance. Gene therapy can only be successful if the immune system does not reject the therapeutic transgene product. Recent studies provide a rapidly growing body of evidence that regulatory T cells (T(reg)) are involved and often play a crucial role in tolerance to proteins expressed by means of gene transfer. This review seeks to provide an overview of these data and their implications for gene therapy.     

Regulation of protein synthesis and autophagy in activated dendritic cells: implications for antigen processing and presentation

Antigenic peptides presented in the context of major histocompatibility complex (MHC) molecules originate from the degradation of both self and non-self proteins. T cells can therefore recognize at the surface of surveyed cells, the self-peptidome produced by the cell itself (mostly inducing tolerance) or immunogenic peptides derived from exogenous origins. The initiation of adaptive immune responses by dendritic cells (DCs), through the antigenic priming of naïve T cells, is associated to microbial pattern recognition receptors engagement. Activation of DCs by microbial product or inflammatory cytokines initiates multiple processes that maximize DC capacity to present exogenous antigens and stimulate T cells by affecting major metabolic and membrane traffic pathways. These include the modulation of protein synthesis, the regulation of MHC and co-stimulatory molecules transport, as well as the regulation of autophagy, that, all together promote exogenous antigen presentation while limiting the display of self-antigens by MHC molecules.     

Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes

Pathogenic autoimmunity requires a combination of inherited and acquired factors. In as much as hormones influence the sexual dimorphism of the immune system, it is possible that they can initiate or accelerate an autoimmune process, and contribute to gender-biased autoimmune disorders. Not only natural hormones, but also endocrine disruptors, such as environmental estrogens, may act in conjunction with other factors to override immune tolerance to self-antigens. In lupus, murine and human studies demonstrate that female sex hormones are implicated in disease pathogenesis. In the B cell compartment, both prolactin and estrogen are immunomodulators that affect maturation, selection and antibody secretion. Their impact may be based on their capacity to allow autoreactive B cells to escape the normal mechanisms of tolerance and to accumulate in sufficient numbers to cause clinically apparent disease. Both hormones lead to the survival and activation of autoreactive B cells, but they skew B cell maturation towards different directions, with prolactin inducing T cell-dependent autoreactive follicular B cells and estrogen eliciting T cell-independent autoreactive marginal zone B cells. Differential modulation of the cytokine milieu by hormones may also affect the development and activation of specific mature B cell subsets. This novel insight suggests that targeted manipulation of these pathways may represent a promising avenue in the treatment of lupus and other gender-biased autoimmune diseases.     

Immune recognition of influenza hemagglutinin as a viral and a neo-self-antigen

To analyze mechanisms governing tolerance and autoimmunity to self-antigens, we have generated lineages of transgenic mice that express the influenza virus PR8 hemagglutinin (HA) as a neo-selfantigen. By comparing the HA-specific T and B cell responses that can be induced in HA Tg mice with those that are induced in non-Tg (BALB/c) mice, the specificity and genetic basis with which tolerance is induced to the HA has been examined. This article summarizes studies using lineages of HA Tg mice that express different forms and amounts of the HA under the control of the SV40 promoter/enhancer. Our studies have revealed that specific subsets of HA-specific T and B cells are negatively selected from the primary repertoires of HA Tg mice. However, substantial populations of HA-specific T and B cells evade negative selection and can be activated by virus immunization. Understanding the capacity of these autoreactive lymphocytes to differentiate and participate in antigenspecific immune responses will provide important insights into mechanisms by which autoimmunity might be induced by viruses bearing structural similarities with self-antigens.     

CD4+CD25+ regulatory T cells: II. Origin, disease models and clinical aspects

Autoimmune diseases afflict approximately 5% of the population and reflect a failure in the immune system to discriminate between self and non-self resulting in the breakdown of self-tolerance. Regulatory CD4+CD25+ T cells (Treg cells) have been shown to play an important role in the maintenance of immune homeostasis and self-tolerance by counteracting the development and effector functions of potentially autoreactive T cells. We have in the previous APMIS review described the phenotype and physiology of Treg cells. The present overview deals with the thymic origin of Treg cells and their role in disease models such as autoimmune gastritis and inflammatory bowel disease. Finally, we will consider some aspects of the therapeutic potential of Treg cells.     

CD4+CD25+ regulatory T cells: I. Phenotype and physiology

The immune system protects us against foreign pathogens. However, if fine discrimination between self and non-self is not carried out properly, immunological attacks against self may be launched leading to autoimmune diseases, estimated to afflict up to 5% of the population. During the last decade it has become increasingly clear that regulatory CD4+CD25+ T cells (Treg cells) play an important role in the maintenance of immunological self-tolerance, and that this cell subset exerts its function by suppressing the proliferation or function of autoreactive T cells. Based on human and murine observations, this review presents a characterization of the phenotype and functions of the Treg cells in vitro and in vivo. An overview of the surface molecules associated with and the cytokines produced by the Treg cells is given and the origin, activation requirements and mode of action of the Treg cells are discussed. Finally, we address the possibility that Treg cells may play a central role in immune homeostasis, regulating not only autoimmune responses, but also immune responses toward foreign antigens.