Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis

The mechanisms of chronic disease and recovery from relapses in experimenta l autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis , are unknown. Deletion of myelin-specific lymphocytes by apoptosis may pla y a role in termination of the inflammatory response. One pathway of apopto sis is the passive cell death or "cell death by neglect" pathway, which is under the control of the Eel family of genes, To investigate the role of pa ssive cell death pathway in EAE, we used mice with transgenic expression of the long form of the brl-x gene (Bcl-x(L)) targeted to the T-cell Lineage. We found that mice transgenic for Bcl-x(L) have an earlier onset and a mor e chronic form of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 compared with wild-type littermate mice. This was not due to an expanded autoreactive cell repertoire. Primed peripheral lymphocytes fro m Bcl-x(L) transgenic mice showed increased proliferation and cytokine prod uction to MOG peptide in vitro compared with lymphocytes from wild-type ani mals. Immunohistologic studies demonstrated increased cellular infiltrates, immunoglobulin precipitation, and demyelination in the Bcl-x(L) transgenic central nervous system (CNS) compared with controls. There was also a decr eased number of apoptotic cells in the CNS of Bcl-x(L) transgenic mice when compared with littermates at all time points tested. This is the first rep ort of an autoimmune disease model in Bcl-x(L) transgenic mice. Our data in dicate that the passive cell death pathway is important in the pathogenesis of chronic EAE. These findings have implications for understanding the pat hogenesis of multiple sclerosis and other autoimmune diseases.