Tolerance and autoimmunity

Central tolerance

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, such that self reactive lymphocytes are eliminated by apoptosis—negative selection.4

In bone marrow, developing B lymphocytes receive stimulatory or deletional signals from self antigens, but selection processes continue in germinal centres of peripheral lymphoid tissues as well.5 Exactly how these selection processes operate is uncertain, but important influences include the extent of representation and level of exposure to tolerogenic self molecules and, in the thymus, the HLA constitution of the individual.6 In any event, not all self antigens are available for efficient negative selection, so that central tolerance is “leaky” and results in export to the periphery of self reactive lymphocytes that require control throughout life.

Peripheral tolerance

Peripheral tolerance encompasses various safeguards that prevent activation of self reactive lymphocytes. These include ignorance, anergy, homoeostatic 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 non-activated) T lymphocytes of signalling molecules that preclude entry of the cell into tissue parenchyma.7

Anergy describes a state of unstable metabolic arrest affecting lymphocytes that can lead to apoptosis.8 It occurs when a lymphocyte receives an antigenic signal without the normally necessary costimulatory second signal (see fig 2).9 Anergy is a protective (tolerogenic) outcome after interaction between an autoimmune T cell and a self peptide on a parenchymal cell that is not competent to deliver a costimulatory signal.10

Homoeostatic control occurs by expression of cytotoxic T lymphocyte antigen 4 (CTLA-4, CD152) on activated T lymphocytes as an alternative to the CD28 ligand. When CD80/86 on the antigen presenting cell interacts with CTLA-4 the T cell is switched off.

Regulation by dedicated T cells inhibits the induction or effector functions of other classes of lymphocytes, either by production of down regulatory cytokines or interference with receptor signalling pathways. More information is needed on markers that identify regulatory T cells11 and their role in the development of autoimmunity.

Environmental risk factors

Environmental agents can cause autoimmunity, but only the luckless few with the wrong genes will actually succumb. Infection is strongly implicated because it can readily disrupt peripheral tolerance in ways that include exposure of self to the immune system through breakdown of vascular or cellular barriers; the occurrence of cell death by necrosis rather than apoptosis; “bystander” activation of macrophages and T lymphocytes, which can then provide costimulatory signals; and superantigen effects of bacterial products. Experimentally, mice infected with coxsackievirus with a tropism for either pancreatic islets15 or heart16 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 micro-organism 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 can act like infections by causing tissue damage, such as sunlight in lupus erythematosus, or alter a host molecule sufficiently for it to become immunogenic, as in chemical or drug induced autoimmune syndromes. Again, a permissive genetic background is also needed.

Autoimmunity might arise entirely from within, by an intracellular self molecule becoming in some way aberrantly expressed at the cell surface. The “internal” environment accounts for paraneoplastic autoimmune associations of cancers of the ovary, lung, and breast in which an antigen associated with the tumour provokes remarkable autoimmune responses that damage structures such as cerebellar, motor, or sensory neurones; nerve terminals, as in the Lambert-Eaton myasthenic syndrome; or retinal cells.18 These syndromes reflect a misguided immune defence against the cancer since they usually precede overt expression of the cancer and even limit dissemination.

The internal environment is also indirectly relevant, since hormones influence female predisposition to autoimmunity, and autoimmune thyroid disease and type 1 diabetes may erupt in the postpartum period. Less well defined are the claimed effects of psychological stress that may act via neuroendocrine pathways.

Genetic risk factors

All autoimmune diseases probably have some genetic components. Susceptibility genes for autoimmunity may act along two 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 via genes that influence tolerance, apoptosis, or inflammatory responses. These genes explain the tendency for autoimmunity to run in families, with 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.19 Procedures include genome-wide scanning of individuals from affected families, using DNA microarrays to identify specific genetic elements. Variant alleles and their gene products are identified by linkage analysis and positional cloning. Thus studies on pairs of siblings of 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 is identifying susceptibility loci for autoimmunity homologous to those identified in these human diseases.20 Comparison of results from genome-wide scanning of autoimmune humans and mice, and use of the database of the human genome project, should provide a “blueprint” in the next few years for the estimated 20 (or perhaps more) genetic determinants for autoimmune disease. This newly acquired genetic data can then be used by clinicians to analyse complex autoimmune syndromes like rheumatoid arthritis, multiple sclerosis, and type 1 diabetes to understand their heterogeneity of expression.