Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.
basic_science · Level V
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- Record sourced from PubMed, PMID 36927018.
- Also identified by DOI 10.1126/science.abg2482.
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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<sup>+</sup> 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<sup>+</sup> T cell responses and autoantibody production in autoimmune diseases.
Medical subject headings
- Autoantibodies
- Autoimmune Diseases
- Cysteine
- HLA-DRB1 Chains
- Protein Processing, Post-Translational
- Integrin alpha2
- Spondylitis, Ankylosing