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.

Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

“…In AE patients, it is not understood whether intrathecal B cells and ASCs divide or affinity mature in the CNS. Meningeal tertiary lymphoid structures (TLS) represent a proposed site of CNS B cell maturation in multiple sclerosis, another CNS autoimmune disease in which pathogenic B cells and autoantibodies are reported ( 21 – 23 ). In multiple sclerosis, and in several tumors, these TLS may act as ectopic germinal centers (GCs), classical sites where BCR somatic hypermutation, affinity maturation, and immunoglobulin class-switch recombination occur, typically with T cell help ( 23 – 26 ).…”