T-CELLS SPECIFIC FOR THE MYELIN OLIGODENDROCYTE GLYCOPROTEIN MEDIATE AN UNUSUAL AUTOIMMUNE INFLAMMATORY RESPONSE IN THE CENTRAL-NERVOUS-SYSTEM

Myelin oligodendrocyte glycoprotein (MOG)-specific T cells mediate an autoimmune inflammatory response in the central nervous system (CNS) t hat differs radically from conventional models of T cell-mediated expe rimental allergic encephalomyelitis (EAE). Using synthetic peptides an encephalitogenic T cell epitope of MOG for the Lewis rat was identifi ed within the extracellular IgG V-like domain of the protein, amino ac ids 44-53 (FSRVVHLYRN).The adoptive transfer of CD4+ T cells specific for this epitope induce an intense, dose-dependent inflammatory respon se in the CNS of naive syngeneic recipients. However, unlike the infla mmatory response induced by myelin basic protein (MBP)-specific T cell lines, inflammation mediated by the MOG peptide-specific T cells fail ed to induce a gross neurological deficit. This unexpected observation was not due to a reduction in the overall inflammatory response in th e CNS, but was specifically associated with a decrease in the extent o f parenchymal (as opposed to perivascular) inflammation, a selective d ecrease in the number of ED1+ macrophages infiltrating the CNS, and a total lack of peripheral nerve inflammation. The decreased recruitment of macrophages into the CNS could not be ascribed to deficiences in t he synthesis of interferon-gamma, tumor necrosis factor-a, interleukin (IL)-6 or IL-2 by the T cell line. Moreover, this sub-clinical inflam matory response induced severe blood-brain barrier dysfunction as demo nstrated by the induction of severe clinical disease following intrave nous injection of a demyelinating MOG-specific monoclonal antibody. Th e neurological deficit in EAE thus exhibits an unexpected dependence o n the identity of the target autoantigen, which determines the extent and nature of the local inflammatory response and ultimately the exten t of the neurological deficit.