Investigating molecular mimicry by microbial peptides in the induction of experimental autoimmune encephalomyelitis

Abstract

Abstract Multiple sclerosis (MS) is an incurable neuroinflammatory autoimmune disease in which a patient’s immune system targets the myelin sheath of neurons. This impairs neuronal signaling to the periphery, manifesting as severe pain, loss of vision, and partial paralysis. Several environmental and genetic risk factors such as the DRB1*1501 haplotype have been identified, but the exact etiology of this disease remain unclear. It is thought that MS is primarily mediated by myelin-reactive CD4 +T cells, however, the autoantigen epitopes targeted are diverse and vary between patients. Furthermore, certain peptides from these autoantigens share amino acid sequence similarities with those of microbial peptides. This is the basis for a phenomenon known as “molecular mimicry”, in which these similarities are sufficient to activate autoreactive CD4 +T cells. Previous work in our lab using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), found that immunization of DRB1*1501 mice with a peptide from M. avium generates both M. avium- and myelin basic protein (MBP)-reactive CD4 +T cells, though the presence of these cells failed to induce disease. We have previously demonstrated that immunization with suboptimal amounts of multiple myelin-derived peptides, which would not induce EAE individually, result in EAE if combined. We therefore hypothesize that there is a threshold effect in which the concurrent presence of multiple microbial peptides with structural similarity to myelin can contribute to induction of EAE in transgenic DRB1*1501 mice. With the data from this study, we hope to clarify the role of microbial infection in the pathogenesis of MS. This work was supported by grant RG1602 from the National Multiple Sclerosis Society (T.G.F.), support by the Jesse H. & Mary Jones Gibbs Endowed Chair (T.G.F.), support by grant G12MD007591 from the National Institute on Minority Health and Health Disparities, and NIH/NIBIB ESTEEMED grant R25EB027605 (LS), support by NIH grant R01NS117742 (T.G.F.).