Immune cells of the adaptive immune response are specifically activated, but the hallmark of autoimmunity is the dysregulation of the immune system, especially T and B cells recognizing self-antigens as foreign. Activation of an autoimmune response could be enhanced by a variety of other, albeit, non-mutually exclusive non-specific mechanisms including bystander activation and superantigens. The difference between other non-specific mechanisms that initiate autoimmunity and molecular mimicry is that microbial mimics specifically direct the immune response towards a tissue and/or organ. Originally, T cell recognition was postulated to be highly specific and cross-reactivity was thought to be a rare phenomenon. However, the structural requirements for peptide binding by MHC class II molecules that are presented to T cells were found to be based on amino Linear sequence matches in amino acid motifs is not the only criteria for mimicry [32] . It has been hypothesized that self-reactive immune cells are primed by molecular mimicry and bystander activation, thereby sensitizing the immune cells and leading to a "fertile field" but no apparent disease. Subsequent environmental insults could induce these sensitized autoreactive cells to cause an autoimmune disease. Work from our laboratory demonstrated that recombinant viruses having molecular mimicry with self-CNS antigens were unable to initiate an autoimmune disease individually [38] . However, infected mice that were subsequently challenged, after viral clearance, with a non-specific immunologic insult developed disease [38] . Further, subsequent experiments showed that conventional inflammatory responses to specific pathogens were able to induce disease in animals primed with a molecular mimic to a CNS antigen [39]. Therefore, not only is the priming of the immune system necessary for an autoimmune disease but the milieu to which the primed immune cells are exposed is an important factor in initiating an autoimmune disease. Animal models of various autoimmune diseases have explored the role of molecular mimicry as a contributing factor ( Table 2) .