title: Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination.
abstract: Myelin/oligodendrocyte glycoprotein (MOG) is a target antigen for myelin-destructive Abs in autoimmune central nervous system demyelinating disorders. Little is known about the molecular and structural basis of these pathogenic Ab responses. Here, we have characterized anti-MOG Ab specificities in the marmoset model of experimental allergic encephalomyelitis, by means of a combinatorial IgG-Fab library. We found that a diverse population of Ig genes encodes for auto-Abs that exclusively recognize conformation-dependent antigenic targets on MOG. These antigenic domains correspond to exposed epitopes in vivo, as the Fab fragments recognize native MOG in situ in marmoset brain tissue. The Ab fragments described here represent Ab specificities that are common constituents of the humoral immune repertoire against MOG in outbred populations, as demonstrated by their ability to displace native anti-MOG Abs present in sera from MOG-immune marmosets and patients with multiple sclerosis. Furthermore, neuropathological analysis and characterization of Ab epitope specificities in animals immunized with MOG or MOG-derived peptides revealed that only conformation-dependent Abs are associated with demyelinating activity, suggesting that epitope recognition is an important factor for Ab pathogenicity. Our findings provide novel and unexpected knowledge on the diversity of anti-MOG Ab responses in nonhuman primates and humans, and will permit the dissection of pathogenic auto-Ab properties in multiple sclerosis.
authors.affiliation: Department of Neurology, University of California San Francisco, Box 0114, 505 Parnassus Avenue, San Francisco, CA 94143-0114, USA.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: von Büdingen
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Antje
authors.initials: A
authors.lastname: Fuhrmann
authors.forename: Cameron B
authors.initials: CB
authors.lastname: Nabavi
authors.forename: Joy I
authors.initials: JI
authors.lastname: Lee
authors.forename: Claude P
authors.initials: CP
authors.lastname: Genain
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D002144:Callithrix; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D007114:Immunization; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000276:immunology; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000276:immunology*; D009836:Oligodendroglia / Q000276:immunology*
chemical_list: D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007145:Immunoglobulin kappa-Chains