Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination.
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.
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Yiting
Y
Liu
Department of Cell and Developmental Biology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Katherine S
KS
Given
Department of Cell and Developmental Biology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Danielle E
DE
Harlow
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Adeline M
AM
Matschulat
Department of Cell and Developmental Biology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.|Program in Neuroscience, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Wendy B
WB
Macklin
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.|Department of Ophthalmology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.|Program in Neuroscience, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA.
Jeffrey L
JL
Bennett
Department of Neurology, University of Colorado, School of Medicine, 12700 E. 19th Ave, Aurora, CO, USA. greg.owens@ucdenver.edu.
Gregory P
GP
Owens
D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D016923:Cell Death; D002531:Cerebellum / Q000276:immunology / Q000473:pathology; D003165:Complement System Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009185:Myelin Proteins / Q000276:immunology*; D009474:Neurons / Q000276:immunology / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology* / Q000473:pathology*; D009902:Optic Neuritis / Q000276:immunology / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D046509:Tissue Culture Techniques
D007074:Immunoglobulin G; D009185:Myelin Proteins; D011994:Recombinant Proteins; D003165:Complement System Proteins
Antibodies; Complement; Cytotoxicity; Demyelination; Myelin; Oligodendrocytes