In Situ Tolerance within the Central Nervous System as a Mechanism for Preventing Autoimmunity

Brabb, Thea; von Dassow, Peter; Ordonez, Nadia; Schnabel, Bryan; Duke, Blythe; Goverman, Joan

In summary, our experiments suggest a model in which naive MBP-specific T cells that escape thymic or peripheral tolerance traffic at a low frequency through the CNS in normal individuals. These T cells are prevented from initiating CNS autoimmune disease by in situ tolerance when they encounter antigen within the CNS. The spontaneous autoimmune disease that occurs in some mice may be caused by a failure of tolerance at several levels. Peripheral events could activate MBP-specific T cells either by immunization, as is the common mechanism for the induction of EAE, or via molecular mimicry mediated by an infectious agent (49) (50) (51) (52) (53) . Once activated, the MBP-specific T cells are no longer susceptible to tolerance in situ and can initiate autoimmune disease. Alternatively, autoimmunity could develop because tolerance occurring within the CNS is circumvented. Potential mechanisms for overcoming tolerance in the CNS include an infection that may increase costimulation and MHC expression in situ, genetic defects in the tolerance mechanisms, or peripheral infections that may influence antigen presentation within the CNS through the release of soluble factors. These experiments reveal a new form of immunoregulation of CNS-specific T cells that must be considered in the study of the pathogenesis of CNS autoimmunity.