title: Pathogenic T cells in MOBP-induced murine EAE are predominantly focused to recognition of MOBP21F and MOBP27P epitopic residues.
abstract: Myelin-associated oligodendrocytic basic protein (MOBP) is a central nervous system (CNS)-specific myelin constituent important in stabilizing the unique multi-layered structure of the CNS-myelin sheath. Although autoimmunity against MOBP has been associated with multiple sclerosis pathogenesis, anti-MOBP pathogenic T cells have been poorly investigated as compared to T cells against other encephalitogenic myelin proteins. We have recently determined MOBP15-36 as the major encephalitogenic epitope of MOBP for SJL/J mice. In this study, epitope-specificity was dissected to the level of residues crucial for activation/control of MOBP-specific encephalitogenic T cells. Structural bioinformatic analysis of MOBP15-36/I-A(s) interaction and experimental data have determined MOBP21F and MOBP27P of I-A(s)-binding nonameric core epitope (MOBP20-28) as TCR-contact residues critical for functional activation of encephalitogenic MOBP-specific T cells. Accordingly, the non-encephalitogenic/nonstimulatory pMOBP16-21A27A-33 inhibited encephalitogenic MOBP-reactive T cells, shifted their cytokine secretion profile, and effectively suppressed pMOBP15-36-induced EAE. Moreover, pMOBP16-21A27A-33 fully reversed ongoing clinical EAE induced by whole MOBP as well as by pMOBP15-36. Data show that encephalitogenic MOBP-reactive T cells are predominantly focused to recognition of MOBP21F and MOBP27P, and suggest that both their selection and control are governed by MOBP21F and MOBP27P epitopic residues. Such focused epitopic recognition may affect profoundly on peripheral self-tolerance to MOBP and on potential altered peptide ligand-mediated therapy of MOBP-related autoimmune pathogenesis.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nathali
authors.initials: N
authors.lastname: Kaushansky
authors.forename: Rina
authors.initials: R
authors.lastname: Zilkha-Falb
authors.forename: Reut
authors.initials: R
authors.lastname: Hemo
authors.forename: Hans
authors.initials: H
authors.lastname: Lassman
authors.forename: Miriam
authors.initials: M
authors.lastname: Eisenstein
authors.forename: Aldema
authors.initials: A
authors.lastname: Sas
authors.forename: Avraham
authors.initials: A
authors.lastname: Ben-Nun
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C560487:MOBP protein, human; C571326:MOG protein, human; C560488:Mobp protein, mouse; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010455:Peptides; D011994:Recombinant Proteins