Autoimmune diseases require the presence of autoreactive T cells and, in the case of immunoglobulin mediated diseases, of autoreactive B cells. In view of the potent and large number of regulatory mechanisms that protect against autoimmune disease, activation of autoreactive T and B cells is thought to require a series of destabilizing events. One important aspect is the activation and reactivation of potentially autoreactive T cells (Rocken et al. 1992). However, induction of autoreative T cells or B cells alone does not induce or predispose for autoimmune diseases. For example, in individuals, which are genetically predisposed of developing autoimmune diabetes, the relative risk of becoming diabetes increases significantly if their T cells respond vigorously against endogenous antigens from pancreatic islet cells. In sharp contrast, individuals from the same population are largely protected against autoimmune diabetes, when they exert high immunoglobulin titers but weak T cell responses against the same antigens (Harrison et al. 1993). This further underlines that 'reactivity' does not equal autoimmune disease.
One of the fundamental questions that are still unanswered yields with the primary event leading to the induction of autoreactivity. Some data suggest that, in the presence of an appropriate genetic background, minimal events such as normal tissue necrosis may be sufficient for the induction of, perhaps even potentially harmful, autoreactivity (Albert et al. 1998; Matzinger and Anderson 2001).
Most data suggest that a series of tolerance inducing mechanisms normally inhibits T and B cells to react against many autoantigens (Naucler et al. 1996). Therefore, stimuli that induce reactivity against these autoantigens have to overcome the diverse tolerance inducing barriers. Epidemiologic data suggest that the realization of autoimmune diseases is often preceded by infectious diseases and attention was given to the events by which infections may abolish the status of tolerance (Sinha et al. 1990; Matzinger 1994). At least three mechanisms are thought to contribute to this phenomenon: reactivation of tolerant T and B cells, induction of autoreactive T cells by molecular mimicry and modification of the cytokine pattern during the course of infectious diseases.
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