S100 beta protein is a calcium binding protein that is not only expressed by astrocytes in the CNS, but also in many other tissues including the eye, thymus, spleen and lymph nodes. Despite this tissue distribution, which was expected to induce a firm state of self-tolerance to S100 beta, the Lewis rat mounts a strong T cell response to this autoantigen. The pathogenicity of this T cell response was demonstrated by the adoptive transfer of S100 beta-specific T cells which induced an inflammatory response in the CNS and eye of naive syngeneic recipients. The distribution of lesions in this novel model of EAE resembles that seen in some patients with MS, suggesting that the initial autoimmune insult in MS may be directed against a non-myelin antigen co-expressed in the CNS and extra-neural tissues.