Is activation of autoreactive lymphocytes always detrimental? Viral infections and regulatory circuits in autoimmunity.

Viral infections are implicated in the pathogenesis of autoimmune disorders through several mechanisms [1–12]. Many of these rely on the fact that potentially autoreactive but resting lymphocytes, which ‘escaped’ thymic negative selection, are present in the periphery of most individuals [13–16]. There are multiple ‘built-in’ safety mechanisms to prevent the activation of these cells under normal circumstances. However, an external inflammatory insult such as a viral infection leading to immune activation could disturb the carefully established equilibrium of self-tolerance [6, 17, 18]. Various virus-induced mechanisms that break ‘tolerance’ or ‘unresponsiveness’ to self are discussed in this chapter. However, direct evidence for viral infections causing autoimmune diseases has been difficult to obtain in humans. One reason is that humans are exposed to a multitude of infections during lifetime and therefore a direct causal association between a particular virus and a disease is hard to establish. The second reason is that viruses have the ability to mutate frequently and one strain can contain multiple different sequences (‘quasi-species’) that can differ in their diabetogenicity. Last, some viral infections disrupt autoimmune processes and provide, at least in experimental models, a cure from disease. Several animal models have been generated to create conditions under which viruses induce or dampen autoimmunity and to analyze the principles by which this can occur [19, 20]. These models serve as valuable tools for understanding