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Published on: May 7, 2020
Nitration of MOG diminishes its encephalitogenicity depending on MHC haplotype
Andreas Warnecke1, Sravani Musunuri2, Marie N'diaye1
1Department of Clinical Neuroscience, Applied Immunology & Immunotherapy, Karolinska Institutet, Stockholm, Center for Molecular Medicine, Karolinska University Hospital, Solna, S-17176, Stockholm, Sweden.
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 H2b C57BL/6 mice. Furthermore, nitrated MOG displays inferior antigen-specific proliferation of 2D2 splenocytes in vitro. Conversely, H2q DBA1 mice remain fully susceptible to EAE induction using nitrated MOG as the dominant epitope of H2q mice is unaltered. Molecular modeling analysis of the MOG35-55/H2-IAb complex 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-IAb to efficiently present the altered peptide ligand of MOG35-55 because 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.
Insights
Nitration of Myelin Oligodendrocyte Glycoprotein (MOG) prevents experimental autoimmune encephalomyelitis (EAE) in certain mouse strains by altering T cell recognition. This modification
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- Post-translational modifications (PTMs) of autoantigens are suspected to influence immune responses.
- Myelin Oligodendrocyte Glycoprotein (MOG) is a key autoantigen implicated in demyelinating diseases like EAE.
- Understanding how MOG PTMs affect immunogenicity is crucial for autoimmune research.
Purpose of the Study:
- To investigate the impact of MOG tyrosine nitration on its encephalitogenicity.
- To determine the role of MHC haplotype in the response to nitrated MOG.
- To elucidate the molecular mechanisms underlying altered T cell recognition of nitrated MOG.
Main Methods:
- Induction of experimental autoimmune encephalomyelitis (EAE) in H2b C57BL/6 and H2q DBA1 mice using native or nitrated MOG.
- Assessment of antigen-specific T cell proliferation using splenocytes in vitro.
- Molecular modeling and bioinformatics analysis of MOG peptide binding to MHC class II molecules.
Main Results:
- Nitration of tyrosine 40 in MOG abrogated EAE induction in H2b mice at both protein and peptide levels.
- Nitrated MOG showed reduced antigen-specific proliferation of 2D2 T cells.
- H2q mice remained susceptible to EAE induced by nitrated MOG, indicating MHC haplotype-dependent effects.
Conclusions:
- Tyrosine nitration of MOG significantly reduces its encephalitogenic potential in an MHC haplotype-dependent manner.
- The inability of H2-IAb to present nitrated MOG35-55 due to altered binding explains the lack of T cell reactivity.
- Nitration is a critical PTM influencing T cell recognition of autoantigens, with implications for autoimmune disease pathogenesis.
