MOG(35-55), not NFM15-35, is the critical autoantigen for inducing demyelinating autoimmune disease.

Abstract Here we examine functional significance of CD4+ T cell cross-recognition between MOG35-55 (myelin oligodendrocyte glycoprotein) and NFM15-35 (neurofilament medium polypeptide) in demyelinating autoimmune disease. These epitopes are interesting for synergist potential in promoting autoimmunity due to identical amino acids at proposed TCR contacts while displaying variances at MHC. Surprisingly, NFM15-35 peptide is not encephalitogenic in polyclonal models and we proposed to understand why by studying how NFM15-35 effects the known encephalitogenic MOG CD4+ T cell population using peptide:MHC (pMHC) technologies. We found a NFM15-35 challenge was less potent than MOG35-55 in expanding tetramer positive, MOG38-49:I-Ab T cells. Diminished tetramer staining indicated the expanded polyclonal T cells from NFM challenge were of low affinity for MOG38-49, because tetramer enriches for T cells with high affinity for pMHC. We also found that NFM18-30 specific cells in the CNS of mice with MOG35-55 induced EAE predominantly cross-recognized MOG38-49:I-Ab using the 2-dimensional micropipette adhesion frequency assay. These data suggested MOG35-55, not NFM15-35, was the critical encephalitogenic antigen and we confirmed this by showing that demyelinating disease in NFM deficient mice exhibited identical disease course to wild type mice. Interestingly, alterations of NFM15-35 N-terminal amino acids expanded T cells that cross-recognized MOG38-49 tetramer, a phenotype concomitant with restoring encephalitogenic potential in altered NFM15-35 peptides. Overall, we support MOG35-55 as the critical autoantigen for induced demyelinating disease with the contribution of NFM15-35 being dictated by cross-recognition of MOG.