Loss of CD4 T-cell–dependent tolerance to proteins with modified amino acids
| Autor: | Varun Gauba, Weijia Ou, Badry Bursulaya, Vanessa Gorney, Richard A. Lerner, Bernhard H. Geierstanger, Peter G. Schultz, Teresa Ramirez-Montagut, Lisa Deaton, Mingchao Kang, Christian Schmedt, Jan Grünewald |
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| Rok vydání: | 2011 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Time Factors Phenylalanine Enzyme-Linked Immunosorbent Assay Epitope Immune tolerance Epitopes Mice Epidermal growth factor Immune Tolerance Animals Amino Acids Tyrosine Autoantibodies chemistry.chemical_classification Mice Inbred BALB C Mice Inbred C3H Multidisciplinary Epidermal Growth Factor biology Tumor Necrosis Factor-alpha Autoantibody Biological Sciences Amino acid Mice Inbred C57BL Amino Acid Substitution Biochemistry chemistry Polyclonal antibodies biology.protein Electrophoresis Polyacrylamide Gel Female Immunization Mutant Proteins Antibody |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:12821-12826 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1110042108 |
| Popis: | The site-specific incorporation of the unnatural amino acid p -nitrophenylalanine (pNO 2 Phe) into autologous proteins overcomes self-tolerance and induces a long-lasting polyclonal IgG antibody response. To determine the molecular mechanism by which such simple modifications to amino acids are able to induce autoantibodies, we incorporated pNO 2 Phe, sulfotyrosine (SO 3 Tyr), and 3-nitrotyrosine (3NO 2 Tyr) at specific sites in murine TNF-α and EGF. A subset of TNF-α and EGF mutants with these nitrated or sulfated residues is highly immunogenic and induces antibodies against the unaltered native protein. Analysis of the immune response to the TNF-α mutants in different strains of mice that are congenic for the H-2 locus indicates that CD4 T-cell recognition is necessary for autoantibody production. IFN-γ ELISPOT analysis of CD4 T cells isolated from vaccinated mice demonstrates that peptides with mutated residues, but not the wild-type residues, are recognized. Immunization of these peptides revealed that a CD4 repertoire exists for the mutated peptides but is lacking for the wild-type peptides and that the mutated residues are processed, loaded, and presented on the I-A b molecule. Overall, our results illustrate that, although autoantibodies are generated against the endogenous protein, CD4 cells are activated through a neo-epitope recognition mechanism. Therefore, tolerance is maintained at a CD4 level but is broken at the level of antibody production. Finally, these results suggest that naturally occurring posttranslational modifications such as nitration may play a role in antibody-mediated autoimmune disorders. |
| Databáze: | OpenAIRE |
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