To reiterate a point made at the outset of this chapter, one route to escape from negative selection involves the avoidance of regulatory influences at any of several points. One of these is in the thymus, where the AIRE gene regulates the transcription of many autoantigens (see Subheading 3.6.). In the periphery, there are many sites at which regulation can fail and any one of these may abrogate control of otherwise forbidden clones. Three other examples will follow, one describing how failure to process a regulatory determinant leads to arthritis, another showing how the lack of control over determinant spreading can lead to an autoimmune disease state, and a third describing effects arising from the frequency of regulatory components. In a mouse strain such as the nonobese diabetic mouse, where there appear to be several general failures in overall regulation (for example, in the appropriate timing and extent of apoptosis [21,22]), there is an overall susceptibility, traceable to 20 different genetic loci, which leads to a variety of autoimmune conditions in different organs (23). In this case, the closely related nonobese resistant strain, with several non-MHC gene differences, overrides one or a few of these regulatory failures and re-establishes a state of disease resistance.
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