An autoantigen-ome from HS-Sultan B-Lymphoblasts offers a molecular map for investigating autoimmune sequelae of COVID-19

Abstract

To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID autoantigens (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. 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. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs) of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. 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. Furthermore, B-cell-specific IgM-associated endoplasmic reticulum (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 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. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design.

An autoantigen profile from Jurkat T-Lymphoblasts provides a molecular guide for investigating autoimmune sequelae of COVID-19

“…Because different tissues or cells may give rise to distinct pools of autoAgs, we have been profiling autoAgs from multiple human tissues and cell types, including human lung fibroblast HFL1 cells, human lung epithelial-like A549 cells, and B-lymphoblast HS-Sultan cells. [1][2][3] In this study, we report an autoantigen-ome identified from human Jurkat T-lymphoblast cells.…”

“…Proteins eluted with 1.0 M NaCl possess the strongest DSaffinity and, strikingly, 10/11 (90.9%) are known autoAgs (Table 1), indicating that increasing affinity to DS increases the propensity of a protein to be an autoAg, consistent with our prior findings. [1][2][3][4][5][7][8][9] These include histones (H4, H2B Histone autoAbs are nearly always present in drug-induced systemic lupus erythematosus, and ribosomal P autoAbs are tested for to aid in the differential diagnosis of lupus patients with neuropsychiatric symptoms. C1QBP has been repeatedly identified as a putative autoAg in several of our prior studies, [1,2,7,8] and was recently confirmed as an autoAg in the neurodegenerative disorder primary openangle glaucoma.…”

“…[4,6] Based on autoAg-DS affinity, we have identified several hundred autoAgs from various cells and tissues. [1][2][3][7][8][9] A variety of autoAbs have been identified in COVID-19 patients. [10][11][12][13][14][15][16][17][18][19][20] Children infected with SARS-CoV-2 who develop the rare multisystem inflammatory syndrome show multiple autoAbs, including classical antinuclear antigen (ANA) autoAbs and specific autoAbs recognizing endothelial, gastrointestinal, or immune cell autoAgs.…”

“…As revealed by our prior studies, SARS-CoV-2 infection may induce numerous molecular changes in the host and transform naturally non-antigenic self-molecules to antigenic autoAgs. [1][2][3] In order to better understand the possible extent of autoimmune disorders caused by SARS-CoV-2, we are building a comprehensive catalog of all possible intrinsic autoAgs across cell and tissue types related to the viral infection. Herein, we report a profile of autoAgs identified from human Jurkat T-cells using our DS-affinity enrichment approach, which will provide valuable molecular targets for understanding the diverse autoimmune sequelae of COVID-19.…”