GENETICALLY-DETERMINED FAILURE OF ACTIVATION-INDUCED APOPTOSIS OF AUTOREACTIVE T-CELLS AS A CAUSE OF MULTIPLE-SCLEROSIS

I postulate that multiple sclerosis is an autoimmune disease that invo lves genetically determined failure of activation-induced apoptosis of autoreactive T cells in the central nervous system. Activation of cen tral-nervous-system-reactive T cells in peripheral lymphoid organs by exposure to crossreacting antigens or superantigens derived from commo n infectious agents may trigger attacks of multiple sclerosis. In norm al individuals these activated T cells are deleted by activation-induc ed apoptosis, but in individuals predisposed to multiple sclerosis the y survive, proliferate, and damage the central nervous system. The cli nical course of multiple sclerosis may vary according to the antigens in the central nervous system being targeted: targeting of myelin anti gens leads to a relapsing-remitting course of clinical recovery due to remyelination or other mechanisms; targeting of axonal antigens leads to a progressive course from onset because axonal regeneration is lim ited in the central nervous system. This hypothesis can account for ma ny characteristics of multiple sclerosis and has predictions that can be tested.