Pathogenic myelin-specific antibodies in multiple sclerosis target conformational proteolipid protein 1–anchored membrane domains

125 words) B cell clonal expansion and cerebrospinal fluid (CSF) oligoclonal IgG bands are established features of the immune response in multiple sclerosis (MS).Clone-specific IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF plasmablasts bound to conformational proteolipid protein 1 (PLP1) membrane complexes and, when injected into mouse brain with human complement, recapitulated histologic features of MS pathology: oligodendrocyte cell loss, complement deposition, and CD68 + phagocyte infiltration.Conformational PLP1 membrane epitopes were complex and governed by the local cholesterol and glycolipid microenvironment.Antibodies against conformational PLP1 membrane complexes targeted multiple surface epitopes, were enriched within the CSF compartment, and were detected in most MS patients but not in inflammatory and non-inflammatory neurologic controls.CSF PLP1 complex antibodies provide a pathogenic autoantibody biomarker specific for MS.