How can cryptic epitopes trigger autoimmunity?

T cell tolerance depends on the presentation of selfproteins to T cells and therefore can only be established to those self-determinants which, under steady-state conditions, are generated in sufficient amounts to be recognized by T cells undergoing deletion in thymus or anergy in the periphery. Thus, there is large number of self-determinants that are cryptic because they are not generated at all or are generated at subthreshold levels. T cells specific for these cryptic epitopes are present in the normal repertoire and might become activated and autoaggressive if the epitopes are presented at higher concentrations. This concept, which had been originally proposed by Sercarz and colleagues, represents today the major hypothesis for the pathogenesis of autoimmune diseases (1). The fundamental question is how epitopes that are normally cryptic may become visible to the immune system and elicit a sustained pathogenetic response. Two reports in this issue of The Journal of Experimental Medicine describe two novel mechanisms that may be responsible for revealing cryptic determinants. It is tempting to put this new information together with previous reports to try to delineate how different mechanisms may synergize for the induction, development, and maintenance of an autoimmune response.