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How tolerance is established and may fail. Generation of immune repertoires in central lymphoid organs, thymus, and bone marrow is accompanied by deletion of self-reactive lymphocytes by apoptosis. Tolerance fails because of the interaction of a wrong environment with the wrong genes, resulting in autoimmune disease. Options for treatment will increasingly include new selective immunotherapies in place of present global immunosuppression.
Components of immune and autoimmune responses. Antigen or autoantigen engages a B-cell receptor directly and also is endocytosed by an antigen-presenting cell typically a dendritic cell, but B cells also serve in which intracellular degradation generates antigenic peptides. Binding is facilitated by CD4 interaction, as shown. Slightly different conditions apply to the activation of a CD8 T cell.
The immune system does not normally respond to self-antigens. This immunologic tolerance was postulated more than 50 years ago, but its multifactorial basis is still controversial.
A faulty central tolerance sows the seeds for autoimmune disease, and faulty peripheral tolerance leads to its eruption. Lymphocytes learn to react with antigens during lymphopoiesis in central lymphoid organs, thymus, and bone marrow. During the random rearrangements of genes that encode antigen receptors of nascent lymphocytes, the lymphocytes are exposed to antigenic signals from self-molecules. Weak interactions with low-affinity signals are stimulatory and select lymphocytes suitable for immune repertoires—positive selection.
Strong interactions with high-affinity signals are lethal, and self-reactive lymphocytes are eliminated by apoptosis—negative selection. In bone marrow, developing B lymphocytes receive stimulatory or deletional signals from self-antigens, but selection processes continue in germinal centers of peripheral lymphoid tissues as well.
Peripheral tolerance encompasses various safeguards that prevent the activation of self-reactive lymphocytes. These include ignorance, anergy, homeostatic control, and regulation. Ignorance —Autoimmune lymphocytes are kept in ignorance by sequestration of autoantigens behind cellular or vascular barriers; by the occurrence of cell death by apoptosis, which normally precludes spillage of autoantigenic intracellular constituents; and by the presence on the surface of potentially autoimmune but nonactivated T lymphocytes of signaling molecules that preclude entry of the cell into tissue parenchyma.
Anergy describes a state of unstable metabolic arrest affecting lymphocytes that can lead to apoptosis. Regulation by dedicated T cells inhibits the induction or effector functions of other classes of lymphocytes, either by the production of downregulatory cytokines or interference with receptor signaling pathways. More information is needed on markers that identify regulatory T cells 11 and their role in the development of autoimmunity. Apoptosis represents physiologic as opposed to pathologic necrotic cell death.
Deficiency or dysregulation of apoptosis results in lymphocytes becoming unresponsive to death signals essential for deletional tolerance.
Alternatively, when apoptosis is overwhelming or apoptotic fragments are not effectively removed, as can occur with deficiency of serum complement, a risk of autoimmunity exists. Two families of proteins mediate apoptosis.
The cysteine aspartate proteases caspases are activated by the binding of a cell-surface molecule fas CD95 to its ligand, fas L. The Bc12 family contains some 20 proteins, among which Bc12 itself protects against apoptosis whereas others promote apoptosis. Because apoptosis normally eliminates self-reactive lymphocytes, gene mutations that disrupt apoptosis are conducive to autoimmunity. Thus, mutations affecting fas or fas L cause autoimmune lymphoproliferative syndromes of childhood and analogous diseases in inbred mouse models.
Environmental agents can cause autoimmunity, but only the luckless few with the wrong genes will actually succumb. Experimentally, mice infected with coxsackievirus that has a tropism for either pancreatic islets 15 or heart 16 develop, despite viral clearance, an autoimmune response to breakdown products of islet cells or myocardium, resulting in chronic autoimmune inflammation.
In addition, there is the alternative, or perhaps complementary, process of molecular antigenic mimicry, whereby an antigen of a microorganism or a constituent of food that sufficiently resembles a self-molecule can induce a cross-reactive autoimmune response. The mimicry idea has an attractive logic and supporting experimental evidence, 17 but clear examples are lacking for the more common human autoimmune diseases and their animal models.
Other environmental initiators of autoimmunity that break tolerance can act like infections by causing tissue damage, such as sunlight in lupus erythematosus, or alter a host molecule sufficiently that it becomes immunogenic, as in chemical- or drug-induced autoimmune syndromes. In all these examples, a predisposing genetic background is also needed.
Antibody-dependent cellular cytotoxicity possibly in organ-specific autoimmune diseases. CD 4 cells polarized toward T H 1 responses by cytokines as in rheumatoid arthritis, multiple sclerosis, type 1 diabetes. Autoimmunity might arise entirely from within, by an intracellular self-molecule becoming in some way aberrantly expressed at the cell surface.
The internal environment is also indirectly relevant, because hormones influence female predisposition to autoimmunity, and autoimmune thyroid disease and type 1 diabetes mellitus may erupt in the postpartum period.
Less well-defined are the claimed effects of psychological stress that may act through neuroendocrine pathways. All autoimmune diseases probably have some genetic components. Susceptibility genes for autoimmunity may act along 2 tracks. One track determines tissue and disease specificity by directing the response to particular autoantigens. For example, genes that encode molecules of the major histocompatibility complex can determine which autoantigens are presented to the immune system; genes that encode the specificity of antigen receptors on T and B lymphocytes may influence which molecules are attacked; and genes may influence the susceptibility of a particular target tissue to autoimmune attack.
The other track is a general susceptibility to autoimmunity through genes that influence tolerance, apoptosis, or inflammatory responses.
These genes explain the well-known tendency for autoimmunity to run in families, with multiple and variable expressions of disease in affected individuals. The genes involved are not all wrong; some alleles of the major histocompatibility complex may confer protection against autoimmunity, and the absence of these genes causes susceptibility, as for type 1 diabetes and rheumatoid arthritis.
Genetic susceptibility to autoimmune disease is now being investigated in highly informative ways. Variant alleles and their gene products are identified by linkage analysis and positional cloning. Thus, studies of pairs of siblings in families with autoimmune disease can reveal susceptibility loci by sharing or otherwise of alleles at a known marker locus.
Selected breeding of autoimmune strains of mice such as nonobese diabetic mice or NZB lupus mice are identifying susceptibility loci for autoimmunity homologous to those identified in these human diseases. The protein products encoded by these genes will then be related to particular autoimmune syndromes.
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