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.

解析针对内源蛋白的自身免疫机制，对于自身免疫疾病的诊疗具有重要意义。本研究构建了一款易用的AAgAtlas门户网站（http://biokb.ncpsb.org.cn/aagatlas_portal/index.php#），支持针对1073种人类疾病检索8045个非冗余自身抗原（autoantigens，AAgs）以及47个翻译后修饰型自身抗原（post-translationally modified AAgs），所有检索结果均通过多源证据开发的认证评分进行优先级排序。借助AAgAtlas平台，本研究依据人类自身抗原的遗传特征、生物物理特性、细胞学属性、表达谱及进化特征，系统解析了其免疫原性特性。分析结果显示，人类自身抗原在蛋白质序列层面呈现进化保守性，且富集于位于蛋白质表面的三种亲水性极性氨基酸残基（K、D、E）；自身抗原还富集于参与核酸结合、转移酶催化及细胞骨架组成的蛋白质类群中。基因组、转录组与蛋白质组联合分析进一步揭示，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蛋白质表达异常密切相关。综上，本研究数据系统梳理了人类自身抗原的核心特征，可为体液自身免疫机制的解析以及人类疾病生物标志物的鉴定提供重要支撑。