半胱氨酸羧乙基化产生新抗原诱导 HLA 受限自身免疫。
Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.
机构信息
Department of Clinical Immunology, Xijing Hospital, and Department of Cell Biology of National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
School of Medicine, Shanghai University, Shanghai 200444, China.
出版信息
Science. 2023 Mar 17;379(6637):eabg2482. doi: 10.1126/science.abg2482.
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.
自身免疫性疾病，如强直性脊柱炎（AS），可能由破坏免疫耐受的新兴新抗原驱动。在这里，我们开发了一种用于鉴定新抗原形成过程中涉及的翻译后修饰的工作流程。通过质谱分析，我们鉴定了一组半胱氨酸残基，它们被差异羧乙基化，需要 3-羟基丙酸才能在 AS 患者中生成新抗原。整合素 αIIb [ITGA2B（CD41）]的溶酶体降解在半胱氨酸 96 处被羧乙基化（ITGA2B-ceC96），生成被 HLA-DRB1*04 呈递以刺激 CD4 T 细胞反应并诱导自身抗体产生的羧乙基化肽。用 ITGA2B-ceC96 肽免疫 HLA-DR4 转基因小鼠可促进结肠炎和椎体骨侵蚀。因此，代谢物诱导的半胱氨酸羧乙基化可产生致病性新抗原，导致自身免疫性疾病中自身反应性 CD4 T 细胞反应和自身抗体产生。
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