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J Autoimmun. 2008 Feb-Mar;30(1-2):5-11. doi: 10.1016/j.jaut.2007.11.009.

Cell damage and autoimmunity: a critical appraisal.

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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.


In April 2007, an international Colloquium bridging scientific and clinical disciplines was held to discuss the role of cellular and tissue damage in the initiation, development and persistence of autoimmune disease. Five potential etiologic and pathophysiologic processes fundamental to autoimmune disease (i.e. inflammation, infection, apoptosis, environmental exposure and genetics) were the focus of the presentations and integrative discussions at the Colloquium. The information presented on these topics is condensed in this review. Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Further application of well-designed, long-term epidemiologic and population-based studies is urgently needed to relate antecedent exposures with later occurring stigmata of autoimmunity with a goal of discerning potentially susceptible individuals or subpopulations. Suspect infections requiring closer interrogation include EB virus (SLE and other diseases), HCV (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis) and Helicobacter pylori (autoimmune gastritis) among others. And even if a micro-organism was to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Plausible mechanisms include potentiation and diversion of innate immunity; exposure or spillage of intracellular autoantigens; or provision of autoantigenic mimics. Integrity of apoptosis as a critical safeguard against autoimmunity was discussed in the contexts of over-reactivity causing autoantigens to gain enhanced exposure to the immune system, or under-reactivity producing insufficient elimination of autoreactive clones of lymphocytes. Although environmental agents are widely believed to serve as necessary "triggers" of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified and their mechanism of action defined. Finally an essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. They may be predictive of future or impending disease.

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