The acute phase of COVID-19 is accompanied by various autoimmune responses, and autoimmune diseases, which tend to be chronic and debilitating, are major concerns of COVID-19 sequelae. It is yet unknown how long the COVID aftereffects will persist, and more importantly, what the underlying causative mechanisms of long COVID syndrome are. A significant proportion of patients who have recovered from the acute viral infection of COVID-19 continue to suffer from lingering health problems, so called “long COVID” syndrome. The novel coronavirus SARS-CoV-2 has caused the worldwide COVID-19 pandemic with hundreds of millions infected and high morbidity and mortality. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. Furthermore, B-cell-specific IgM-associated ER complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. Numerous nuclear autoAgs were identified, including both classical ANAs and ENAs of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs.
Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs.
To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID-autoantigens (autoAgs).