PERSISTENT INFECTION WITH THEILERS VIRUS LEADS TO CNS AUTOIMMUNITY VIA EPITOPE SPREADING

Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease(1), which may be initiated by a virus infection(2). Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4(+) T cell-mediated demyelinat ing disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mic e is initiated by a mononuclear inflammatory response mediated by viru s-specific CD4(+) T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an or dered progression and may play a pathologic role in chronic disease. K inetic and functional studies show that T-cell responses to the immuno dominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry)(7,8), but because of de novo priming of self-reacti ve T cells to sequestered autoantigens released secondary to virus-spe cific T cell-mediated demyelination (that is, epitope spreading)(9,10) . Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.