1. Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.
- Author
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Zhai Y, Chen L, Zhao Q, Zheng ZH, Chen ZN, Bian H, Yang X, Lu HY, Lin P, Chen X, Chen R, Sun HY, Fan LN, Zhang K, Wang B, Sun XX, Feng Z, Zhu YM, Zhou JS, Chen SR, Zhang T, Chen SY, Chen JJ, Zhang K, Wang Y, Chang Y, Zhang R, Zhang B, Wang LJ, Li XM, He Q, Yang XM, Nan G, Xie RH, Yang L, Yang JH, and Zhu P more...
- Subjects
- Animals, Mice, Autoimmunity genetics, Autoimmunity immunology, Mice, Transgenic, Gastrointestinal Microbiome, Humans, Autoantibodies metabolism, Autoimmune Diseases genetics, Autoimmune Diseases metabolism, Cysteine metabolism, HLA-DRB1 Chains genetics, HLA-DRB1 Chains metabolism, Protein Processing, Post-Translational, Integrin alpha2 metabolism, Spondylitis, Ankylosing genetics, Spondylitis, Ankylosing metabolism
- Abstract
Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4
+ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4+ T cell responses and autoantibody production in autoimmune diseases. more...- Published
- 2023
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