GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

Although it is well established that autoreactive lymphocytes induce demyelination in multiple sclerosis, the exact antigenic targets that initiate disease are undefined. Planas et al. studied CD4+ T cells from the cerebrospinal fluid of patients with multiple sclerosis. One CD4+ T cell clone was reactive to the human enzyme GDP-L-fucose synthase; T cells from other patients were then identified, as well as myelin-reactive cells. Intriguingly, some of the GDP-L-fucose synthase–reactive cells could also be stimulated by a bacterial version of the enzyme. These tantalizing results identify a new autoantigen and suggest that one possible trigger of disease could be cross-reactivity to microbiota-derived peptides.

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood.

By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–L-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-L-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide.

These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.

10 Oct 2018

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