title: Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype.
abstract: Post-translational modifications of autoantigens are hypothesized to affect their immunogenicity. We here report that nitration of tyrosine 40 in Myelin Oligodendrocyte Glycoprotein (MOG) abrogates its encephalitogenicity both at protein and peptide levels in the experimental autoimmune encephalomyelitis (EAE) model in H2bC57BL/6 mice. Furthermore, nitrated MOG displays inferior antigen-specific proliferation of 2D2 splenocytes in vitro. Conversely, H2qDBA1 mice remain fully susceptible to EAE induction using nitrated MOG as the dominant epitope of H2qmice is unaltered. Molecular modeling analysis of the MOG35-55/H2-IAbcomplex and bioinformatics peptide binding predictions indicate that the lack of T cell reactivity towards nitrated MOG can be attributed to the inability of murine H2-IAbto efficiently present the altered peptide ligand of MOG35-55because the nitrated tyrosine 40 cannot be accommodated in the p1 anchor pocket. In conclusion we demonstrate nitration as a relevant determinant affecting T cell recognition of carrier antigen depending on MHC haplotype. Our data have implications for understanding the role of post-translationally modified antigen in autoimmunity.
authors.affiliation: Department of Clinical Neuroscience, Applied Immunology & Immunotherapy, Karolinska Institutet, Stockholm, Center for Molecular Medicine, Karolinska University Hospital, Solna, S-17176, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Warnecke
authors.affiliation: Department of Chemistry-BMC, Analytical Chemistry and Science for Life Laboratory, Uppsala University, Box 599, 751 24 Uppsala, Sweden.
authors.forename: Sravani
authors.initials: S
authors.lastname: Musunuri
authors.affiliation: Department of Clinical Neuroscience, Applied Immunology & Immunotherapy, Karolinska Institutet, Stockholm, Center for Molecular Medicine, Karolinska University Hospital, Solna, S-17176, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: N'diaye
authors.affiliation: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Stockholm, Sweden.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sandalova
authors.affiliation: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Department of Infectious Diseases, Karolinska University Hospital, Solna, SE-17176, Stockholm, Sweden.
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.affiliation: Department of Chemistry-BMC, Analytical Chemistry and Science for Life Laboratory, Uppsala University, Box 599, 751 24 Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.affiliation: Department of Clinical Neuroscience, Applied Immunology & Immunotherapy, Karolinska Institutet, Stockholm, Center for Molecular Medicine, Karolinska University Hospital, Solna, S-17176, Stockholm, Sweden. Electronic address: Robert.Harris@ki.se.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
mesh_terms: D000818:Animals; D001483:Base Sequence; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009566:Nitrates / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D063308:Myelin-Oligodendrocyte Glycoprotein; D009566:Nitrates
keywords: 3-Nitrotyrosine; Antigen presentation; Autoimmunity; Epitope spreading; Experimental autoimmune encephalomyelitis; Major histocompatibility complex; Myelin oligodendrocyte glycoprotein; Oxidative stress; Post-translational modification