Induction of experimental autoimmune encephalomyelitis by pathogen derived peptides

Although a large body of circumstantial evidence supports the existence of crossreacting antigens between microorganisms and host, the relevance of this phenomenom as a causal factor in the development of autoimmune disease remains unclear. Experimental Autoimmune Encephalomyelitis (EAE) induced by myelin basic protein peptide (87-99) in mice is an excellent experimental system to address this issue. We screened a large number of peptides derived from different infectious agents. The peptides were chosen for their structural homology to MBP(87-99) using a computer search in which conservative substitutions were allowed. We identified three viral peptides that show a significant degree of crossreactivity in vitro with MBP(87-99), even when their sequence homology to this autoantigen is low. Repeated stimulation of T cells specific for a peptide from Human Papilloma Virus using the same viral peptide, even in very low doses, selects a population of cross reactive and potently encephalitogenic cells. Furthermore, these viral peptide-specific cells that had not been exposed to the autoantigen could be activated by a second unrelated peptide (from EBV) also leading to autoimmune disease. These results provide evidence for a causal role of crossreactivity at the level of the T cell receptor in organ-specific autoimmunity. They also suggest that multiple antigenic stimulations, either with the same or different pathogen-derived peptides, might be necessary for the induction of autoimmune disease.