title: Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis.
abstract: Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demyelination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these auto Abs. Compared with healthy controls, native MOG-specific IgGs were most frequently found in serum of clinically isolated syndromes (P < 0.001) and relapsing-remitting MS (P < 0.01), only marginally in secondary progressive MS (P < 0.05), and not at all in primary progressive MS. We demonstrate that epitopes exposed in this cell-based assay are different from those exposed on the refolded, extracellular domain of human recombinant MOG tested by solid-phase ELISA. In marmoset monkeys induced to develop MS-like CNS inflammatory demyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other myelin constituents. We conclude that (i) epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs; (ii) these Abs, which are not detected in solid-phase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and (iii) the cell-based assay provides a practical serologic marker for early detection of CNS autoimmune demyelination including its preclinical stage at least in the primate MS model.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143, USA.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
authors.forename: Til
authors.initials: T
authors.lastname: Menge
authors.forename: Cecile
authors.initials: C
authors.lastname: Delarasse
authors.forename: Bruno
authors.initials: B
authors.lastname: Della Gaspera
authors.forename: Danielle
authors.initials: D
authors.lastname: Pham-Dinh
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
authors.forename: H-C
authors.initials: HC
authors.lastname: von Büdingen
authors.forename: Claude P
authors.initials: CP
authors.lastname: Genain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000906:Antibodies / Q000097:blood; D001681:Biological Assay; D015415:Biomarkers / Q000097:blood; D016466:CHO Cells; D002144:Callithrix; D006224:Cricetinae; D003412:Cricetulus; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D007249:Inflammation / Q000175:diagnosis / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein
chemical_list: D000906:Antibodies; D015415:Biomarkers; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; C571326:MOG protein, human; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein