title: Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis.
abstract: Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments.
authors.affiliation: Institute of Immunology, Immunity and Infection, University of Glasgow, Glasgow, G12 8TA, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Elliott
authors.forename: Maren
authors.initials: M
authors.lastname: Lindner
authors.forename: Ariel
authors.initials: A
authors.lastname: Arthur
authors.forename: Kathryn
authors.initials: K
authors.lastname: Brennan
authors.forename: Sven
authors.initials: S
authors.lastname: Jarius
authors.forename: John
authors.initials: J
authors.lastname: Hussey
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.forename: Anke
authors.initials: A
authors.lastname: Stroet
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Hugh
authors.initials: H
authors.lastname: Willison
authors.forename: Susan C
authors.initials: SC
authors.lastname: Barnett
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000276:immunology* / Q000628:therapy; D009185:Myelin Proteins / Q000378:metabolism*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010951:Plasma Exchange; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D055815:Young Adult
chemical_list: D015815:Cell Adhesion Molecules; D007074:Immunoglobulin G; D009185:Myelin Proteins; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; C504594:Nfasc protein, rat; C051774:neurofilament protein H