Wang Julia Y, Roehrl Michael W, Roehrl Victor B, Roehrl Michael H
Curandis, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
J Transl Autoimmun. 2022;5:100147. doi: 10.1016/j.jtauto.2022.100147. Epub 2022 Feb 25.
Chronic and debilitating autoimmune sequelae pose a grave concern for the post-COVID-19 pandemic era. Based on our discovery that the glycosaminoglycan dermatan sulfate (DS) displays peculiar affinity to apoptotic cells and autoantigens (autoAgs) and that DS-autoAg complexes cooperatively stimulate autoreactive B1 cell responses, we compiled a database of 751 candidate autoAgs from six human cell types. At least 657 of these have been found to be affected by SARS-CoV-2 infection based on currently available multi-omic COVID data, and at least 400 are confirmed targets of autoantibodies in a wide array of autoimmune diseases and cancer. The autoantigen-ome is significantly associated with various processes in viral infections, such as translation, protein processing, and vesicle transport. Interestingly, the coding genes of autoAgs predominantly contain multiple exons with many possible alternative splicing variants, short transcripts, and short UTR lengths. These observations and the finding that numerous autoAgs involved in RNA-splicing showed altered expression in viral infections suggest that viruses exploit alternative splicing to reprogram host cell machinery to ensure viral replication and survival. While each cell type gives rise to a unique pool of autoAgs, 39 common autoAgs associated with cell stress and apoptosis were identified from all six cell types, with several being known markers of systemic autoimmune diseases. In particular, the common autoAg UBA1 that catalyzes the first step in ubiquitination is encoded by an X-chromosome escape gene. Given its essential function in apoptotic cell clearance and that X-inactivation escape tends to increase with aging, UBA1 dysfunction can therefore predispose aging women to autoimmune disorders. In summary, we propose a model of how viral infections lead to extensive molecular alterations and host cell death, autoimmune responses facilitated by autoAg-DS complexes, and ultimately autoimmune diseases. Overall, this master autoantigen-ome provides a molecular guide for investigating the myriad of autoimmune sequalae to COVID-19 and clues to the rare adverse effects of the currently available mRNA and viral vector-based COVID vaccines.
慢性和使人衰弱的自身免疫后遗症是新冠疫情后时代令人严重担忧的问题。基于我们的发现，即糖胺聚糖硫酸皮肤素（DS）对凋亡细胞和自身抗原（自身抗原）具有特殊亲和力，且DS-自身抗原复合物协同刺激自身反应性B1细胞反应，我们从六种人类细胞类型中汇编了一个包含751种候选自身抗原的数据库。根据目前可用的多组学新冠数据，其中至少657种已被发现受新冠病毒感染影响，并且至少400种是多种自身免疫性疾病和癌症中自身抗体的确认靶点。自身抗原组与病毒感染中的各种过程显著相关，如翻译、蛋白质加工和囊泡运输。有趣的是，自身抗原的编码基因主要包含多个外显子，具有许多可能的可变剪接变体、短转录本和短UTR长度。这些观察结果以及众多参与RNA剪接的自身抗原在病毒感染中表达发生改变的发现表明，病毒利用可变剪接对宿主细胞机制进行重新编程，以确保病毒复制和存活。虽然每种细胞类型都会产生独特的自身抗原库，但从所有六种细胞类型中鉴定出了39种与细胞应激和凋亡相关的常见自身抗原，其中几种是系统性自身免疫性疾病的已知标志物。特别是，催化泛素化第一步的常见自身抗原UBA1由一个X染色体逃避基因编码。鉴于其在凋亡细胞清除中的重要功能，且X染色体失活逃避往往随年龄增长而增加，因此UBA1功能障碍可能使老年女性易患自身免疫性疾病。总之，我们提出了一个模型，说明病毒感染如何导致广泛的分子改变和宿主细胞死亡、自身抗原-DS复合物促进的自身免疫反应，以及最终导致自身免疫性疾病。总体而言，这个主要的自身抗原组为研究新冠病毒感染引发的众多自身免疫后遗症提供了分子指南，并为目前可用的基于mRNA和病毒载体的新冠疫苗的罕见不良反应提供了线索。
