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Autoimmunity. 2008 Mar;41(2):123-32. doi: 10.1080/08916930801929021.

Molecular mechanisms of autoimmunity.

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  • 1Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.


Autoimmunity is mediated by a variety of mechanisms, molecular and cellular events, and responses. Predisposition to a given autoimmune response requires the requisite allele(s) that controls antigen presentation by antigen-presenting cells for T cell recognition. Some autoimmune responses emerge following infection by a pathogen, whose protein(s) possess structural similarities in some of its epitopes to regions on proteins of the host. Thus, antibodies evoked against a pathogen might cross-react with a self-protein and act as autoantibodies, and the involved autoantigen then provides a source for persistent stimulation. Proteins to which the immune system is ordinarily self-tolerant might, if altered, elicit autoimmune responses. Ways in which self-proteins can be altered include mutations and altered expression, posttranslational modification, covalent modifications, denaturation, native disorder or misfolding. Sequestered proteins normally sheltered from immune recognition become immunogenic and targets of immune effector functions, once exposed to the immune system. Other alterations can occur because of disruption in the levels or activity of regulatory proteins. These include certain alleles of the cytotoxic T lymphocyte-associated antigen-4 gene (possibly a nonspecific exacerbating molecule of disease risk in several autoimmune diseases), the lymphoid protein tyrosine phosphatase nonreceptor type 22 gene (associated with type 1 diabetes and other autoimmune diseases), TNF-alpha (involved in chronic inflammation, autoimmunity and malignancies) and the FOXP3 gene (expressed by CD4+C25+ regulatory T cells), whose mutations can cause immune dysregulation, polyendocrinopathy and X-linked inheritance syndromes of systemic autoimmunity. An autoimmune response can also arise from natural antibodies or autoantibodies that occur independently of known immunization and are able to bind to microbial antigens, altered proteins as well as self-antigens. Natural autoantibodies possess in general a low intrinsic affinity for antigen, but can function as templates for the generation of pathogenic autoantibodies, that emerge through a process of clonal selection entailing somatic hypermutation and class switch DNA recombination, as driven by antigen.

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