研究人员开发了一个工作流程，对参与新抗原形成的翻译后修饰进行分析。通过质谱分析，研究人员确定了一组半胱氨酸残基被羧乙基化不同程度地修饰，这需要3-羟基丙酸来产生强直性脊柱炎（AS）患者的新抗原。在Cys96处羧乙基化的整合素αIIb[ITGA2B(CD41)]的溶酶体降解（ITGA2B-ceC96）产生了羧乙基化的肽，由HLA-DRB1*04呈递，然后刺激CD4+T细胞反应并诱导自身抗体产生。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，从而导致自身免疫性疾病中的自体反应性CD4+T细胞反应和自身抗体的产生。
据介绍，自身免疫性疾病，如AS可由新出现的新抗原驱动，进而破坏免疫耐受。
附：英文原文
Title: Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
Author: Yue Zhai, Liang Chen, Qian Zhao, Zhao-Hui Zheng, Zhi-Nan Chen, Huijie Bian, Xu Yang, Huan-Yu Lu, Peng Lin, Xi Chen, Ruo Chen, Hao-Yang Sun, Lin-Ni Fan, Kun Zhang, Bin Wang, Xiu-Xuan Sun, Zhuan Feng, Yu-Meng Zhu, Jian-Sheng Zhou, Shi-Rui Chen, Tao Zhang, Si-Yu Chen, Jun-Jie Chen, Kui Zhang, Yan Wang, Yang Chang, Rui Zhang, Bei Zhang, Li-Juan Wang, Xiao-Min Li, Qian He, Xiang-Min Yang, Gang Nan, Rong-Hua Xie, Liu Yang, Jing-Hua Yang, Ping Zhu
Issue&Volume: 2023-03-17
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.
DOI: abg2482
Source: https://www.science.org/doi/10.1126/science.abg2482