title: High immunogenicity of intracellular myelin oligodendrocyte glycoprotein epitopes.
abstract: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS with associated axonal loss. There is strong evidence for an autoimmune pathogenesis driven by myelin-specific T cells. Myelin oligodendrocyte glycoprotein (MOG) induces a type of experimental autoimmune encephalomyelitis in animals which is very MS-like since there are demyelinating CNS lesions and axonal loss. This underscores the potential role of MOG in MS pathogenesis. We performed a T cell reactivity pattern analysis of MS patients at the onset of relapse or progression of neurological deficits and controls that were stratified for the genetic risk factor HLA-DRB1*1501. For the first time, we show that there is an HLA-DR-restricted promiscuous dominant epitope for CD4(+) T cells within the transmembrane/intracellular part of MOG comprising aa 146-154 (FLCLQYRLR). Surprisingly, controls had broader T cell reactivity patterns toward MOG peptides compared with MS patients, and the transmembrane and intracellular parts of MOG were much more immunogenic compared with the extracellular part. Measurements of in vitro binding affinities revealed that HLA-DRB1*1501 molecules bound MOG 146-154 with intermediate and HLA-DRB1*0401 molecules with weak affinities. The binding of MOG 146-154 was comparable or better than myelin basic protein 85-99, which is the dominant myelin basic protein epitope in context with HLA-DRB1*1501 molecules in MS patients. This is the first study in which the data underscore the need to investigate the pathogenic or regulatory role of the transmembrane and intracellular part of MOG for MS in more detail.
authors.affiliation: Department of Neurology, University of Tübingen, Tübingen, Germany. robert.weissert@uni-tuebingen.de
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Jens
authors.initials: J
authors.lastname: Kuhle
authors.forename: Katrien L
authors.initials: KL
authors.lastname: de Graaf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wienhold
authors.forename: Martin M
authors.initials: MM
authors.lastname: Herrmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Müller
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Forsthuber
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiesmüller
authors.forename: Arthur
authors.initials: A
authors.lastname: Melms
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005110:Extracellular Space / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000302:isolation & purification / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D016130:Immunophenotyping; D009980:Influenza A virus / Q000276:immunology; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology* / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016056:Immunodominant Epitopes; C571326:MOG protein, human; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D014764:Viral Proteins