Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination
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RESEARCH
Open Access
Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination Yiting Liu1, Katherine S. Given2, Danielle E. Harlow2, Adeline M. Matschulat1, Wendy B. Macklin2,4, Jeffrey L. Bennett1,3,4 and Gregory P. Owens1*
Abstract Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin-specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4-targeted pathology, and display seminal features of active MS lesions. Myelin-specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms. Keywords: Antibodies, Complement, Cytotoxicity, Myelin, Oligodendrocytes, Demyelination
Introduction Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) of unknown cause. Despite extensive pathological characterization of heterogeneous MS lesions, no consensus on the cellular and molecular mechanisms driving diverse lesion pathology has emerged [15, 24, 30]. The presence of persistent cerebrospinal fluid (CSF) oligoclonal immunoglobulin G (IgG) bands produced by intrathecal IgG synthesis in MS patients is one of the most striking biochemical hallmarks of disease * Correspondence: [email protected] 1 Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA Full list of author information is available at the end of the article
[21]. Deposition of IgG and activated complement products are present in the most frequently seen Type II MS lesions [15], s
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