Human Autoantigen Atlas: Searching for the Hallmarks of Autoantigens

Understanding autoimmunity to endogenous proteins is crucial in diagnosing and treating autoimmune diseases. In this work, we developed a user-friendly AAgAtlas portal (http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#), which can be used to search for 8045 non-redundant autoantigens (AAgs) and 47 post-translationally modified AAgs against 1073 human diseases that are prioritized by a credential score developed by multisource evidence. Using AAgAtlas, the immunogenic properties of human AAgs was systematically elucidated according to their genetic, biophysical, cytological, expression profile, and evolutionary characteristics. The results indicated that human AAgs are evolutionally conserved in protein sequence and enriched in three hydrophilic and polar amino acid residues (K, D, and E) that are located at the protein surface. AAgs are enriched in proteins that are involved in nucleic acid binding, transferase, and the cytoskeleton. Genome, transcriptome, and proteome analyses further indicated that AAb production is associated with gene variance and abnormal protein expression related to the pathological activities of different tumors. Collectively, our data outlines the hallmarks of human AAgs that facilitate the understanding of humoral autoimmunity and the identification of biomarkers of human diseases.阐明机体针对内源性蛋白质的自身免疫机制，对于自身免疫疾病的诊断与治疗至关重要。本研究构建了一款操作简便的AAgAtlas门户（http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#），该平台可检索针对1073种人类疾病的8045种非冗余自身抗原（autoantigens, AAgs）及47种翻译后修饰型自身抗原，所有抗原均通过多源证据构建的可信度评分（credential score）进行优先级排序。依托AAgAtlas平台，研究人员可基于人类自身抗原的遗传、生物物理、细胞学、表达谱及进化特征，系统阐明其免疫原性特征。研究结果显示，人类自身抗原在蛋白质序列层面呈现进化保守性，且富含位于蛋白质表面的三种亲水极性氨基酸残基（K、D、E）。自身抗原富集于参与核酸结合、转移酶功能及细胞骨架构成的蛋白质中。基因组、转录组（transcriptome）及蛋白质组（proteome）分析进一步表明，自身抗体（autoantibody, AAb）的产生与不同肿瘤病理活动相关的基因变异及异常蛋白表达密切相关。综上，本研究数据明确了人类自身抗原的核心特征，可为体液自身免疫的研究以及人类疾病生物标志物的鉴定提供重要助力。