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.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) of unknown cause
MS04-2 #30 (MS#30) reactivity was primarily located in discrete surface domains external to MAG on myelinated axons or along oligodendroglial processes projecting to axons with little to no surface staining of oligodendrocyte cell bodies (Fig. 1i; arrows and arrow heads; Online Resource, Additional file 1: Video S1)
MS#30 causes loss of mature oligodendrocytes in the presence of human complement We examined the effects of MS#30 on ex vivo cerebellar slices
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) of unknown cause. 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 [21]. Deposition of IgG and activated complement products are present in the most frequently seen Type II MS lesions [15], suggesting a possible role of intrathecal IgG in CNS tissue injury. We have constructed recombinant monoclonal IgG1 antibodies (rAbs) from expanded CSF plasmablast clones isolated from MS patients [22] and demonstrated their differential patterns of binding to antigens expressed by astrocytes and neurons or to myelin-enriched antigens [3, 13].
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