Antibodies against Myelin Proteolipid Protein (PLP) drive inflammation and demyelination in multiple sclerosis 4560

Description Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS), in which aberrantly activated B and T cells attack the myelin sheath. B cell depletion is an effective therapy for MS, but specific B and T cell autoantigens have not yet been identified. We sequenced the single-cell B cell repertoire in the cerebro-spinal fluid (CSF) of MS patients, tested individual B cell receptors (BCRs) for their reactivity to myelin, and identified BCRs that bind with high affinity to protein proteolipid protein (PLP). PLP is a highly conserved complex membrane protein with extraordinarily high expression in CNS myelin. Our patient-derived anti-PLP antibodies aggravate mouse models of MS within hours of injection, by attracting innate immune cells to the CNS. In addition, incubation of live primary rat oligodendrocytes with anti-PLP antibodies induced apoptosis independent of CDC and ADCC, a potentially important pathomechanism in progressive MS. Native protein conformations are necessary to facilitate antibody binding, and we developed tools, including PLP-expressing virus-like particles (VLP), to identify and sort anti-PLP B cells from MS patients. We describe the anti-PLP BCR repertoire and we show that unmutated germline sequences lack reactivity to PLP, leading us to search for potential pathogens that trigger anti-PLP B cell responses. In summary we present evidence for a pathogenic anti-PLP B cell response in MS and characterize it mechanistically.