Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic

Abstract Multiple sclerosis is clinically characterized by relapses and remissions (relapsing-remitting multiple sclerosis) that over time may evolve to a progressive course (secondary progressive multiple sclerosis) or as having a progressive course from disease onset (primary progressive multiple sclerosis). At present, it is not definitively known whether these clinical entities constitute a single pathological disease or whether these manifestations represent two distinct disease entities sharing inflammatory demyelination as a pathological feature. Here we show using a novel mouse model that CSF of primary progressive multiple sclerosis patients is unique in its capacity to induce motor disability and spinal cord pathology including demyelination, impaired remyelination, reactive astrogliosis and axonal damage. Notably, removal of immunoglobulin G from primary progressive multiple sclerosis CSF via filtration or immunodepletion attenuates its pathogenic capacity. Furthermore, injection of recombinant antibodies derived from primary progressive multiple sclerosis CSF recapitulates the pathology. Our findings suggest that the clinical and pathological features of primary progressive multiple sclerosis are antibody-mediated and pathogenically distinct from relapsing-remitting and secondary progressive multiple sclerosis. Our study has potentially important implications for the development of specific therapies for patients with primary progressive multiple sclerosis. Wong et al. show that a single intrathecal injection of CSF from patients with primary progressive—but not relapsing–remitting or secondary progressive—multiple sclerosis is able to induce motor deficits, demyelination and axonal damage in mice. Antibody depletion reduces the pathogenic capacity of primary progressive multiple sclerosis CSF. See Guo and Lennon (https://doi.org/10.1093/brain/awad107) for a scientific commentary on this article.