An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19

Wang, Julia Y.; Zhang, W; Mw, Roehrl; Vb, Roehrl; Mh, Roehrl

doi:10.1101/2021.01.24.427965

Cited by 13 publications

(21 citation statements)

References 269 publications

(64 reference statements)

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“…The entire "autoantigenome" of SARS-CoV-2-positive patients has been mapped [52]. This has provided valuable links of autoimmunity with thrombosis, fibrosis, and smooth muscle dysfunction in COVID-19.…”

Section: Antinuclear Antibodies In Covid-19mentioning

confidence: 99%

COVID-19 and the clinical course of rheumatic manifestations

2021

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The manifestations of COVID-19 have been evolving over time. Various post-COVID-19 syndromes are being recognised. Various viruses have been implicated in the pathogenesis of autoimmune diseases, and we expect a similar outcome with the severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 virus penetrates various tissues and organs and has a predisposition to lead to endotheliitis that may cause vascular manifestations including thrombosis. SARS-CoV-2 has been shown to activate Toll-like receptors and the complement system. It perpetuates NETosis and leads to autoantibody formation. These predispose to systemic autoimmunity. Both reactive arthritis and connective tissue disorders such as lupus and inflammatory myositis have been reported after COVID-19. Other reported autoimmune disorders include haemolytic anaemia, immune thrombocytopenia, cutaneous vasculitis, and Guillain Barré-like acute demyelinating disorders. The multisystem inflammatory syndrome in children and its adult counterpart are another post-COVID-19 entity that presents as an admixture of Kawasaki disease and staphylococcal toxic shock syndrome. Patients with preexisting rheumatic diseases may flare during the SARS-CoV-2 infection. They may develop novel autoimmune features also. The immune-suppressants used during the acute COVID-19 illness may confound the outcomes whereas comorbidities present in patients with rheumatic diseases may mask them. There is an urgent need to follow-up patients recovering from COVID and monitor autoantibody production in the context of rheumatic manifestations. Key Points • COVID-19 is associated with both innate and acquired immune reactions and production of various autoantibodies. • Various immune-mediated manifestations such as arthritis, myositis, haemolytic anaemia, thrombocytopenia, and acute demyelination may develop after COVID-19. • Longitudinal cohort data are warranted to describe, predict, and test prevent various rheumatic manifestations in post-COVID-19 subjects.

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Section: Antinuclear Antibodies In Covid-19mentioning

confidence: 99%

COVID-19 and the clinical course of rheumatic manifestations

2021

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“…This vast number of perturbed autoAgs demonstrates that COVID-19 could lead to a wide variety of autoimmune diseases. For example, 42 autoAgs are associated with the myelin sheath and many are associated with other components of the nervous system, as we have described previously, which may help explain a myriad of neurological symptoms caused by COVID-19 [1]. As another example, 11 autoAgs are related to stress fibers (contractile actin filament bundles consisting of short actin filaments with alternating polarity) and 25 proteins are associated with myofibrils (contractile elements of skeletal and cardiac muscle), which may explain various muscular and cardiomuscular sequelae of COVID-19.…”

Section: Resultsmentioning

confidence: 93%

“…Potential autoAgs were identified by DS-affinity from protein extracts from six human cell lines as previously described, including HFL1 fetal lung fibroblasts [1], A549 lung epithelial cells [2], HS-Sultan B-lymphoblasts [4], Wil2-NS B-lymphoblasts [7], Jurkat T-lymphoblasts [5], and HEp-2 fibroblasts [11].…”

Section: Methodsmentioning

confidence: 99%

“…We have discovered previously that DS possesses peculiar affinity for apoptotic cells and their released autoAgs [6–9]. DS, a major component of the extracellular matrix and connective tissue, is increasingly expressed during tissue injury and accumulates in wound areas [1, 10]. Because of their affinity, DS and autoAgs form macromolecular complexes which cooperatively activate autoreactive B1 cells.…”

Section: Introductionmentioning

confidence: 99%

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A Master Autoantigen-ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases

Wang¹,

Roehrl²,

Roehrl

2021

Preprint

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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 but reported adverse effects of the currently available COVID vaccines.

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“…We then tested clinical autoantibody standard sera and sera from patients with autoimmune diseases such as lupus and Sjögren syndrome and demonstrated that DS affinity enabled the identification of many more autoAgs than current clinical tests are able to (2). Based on our DS•autoAg affinity hypothesis, we have thus far identified over 200 potential protein autoAgs from cells lines and murine liver and kidney tissues (2,(4)(5)(6) and autoAgs related to autoimmunity in COVID-19 (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Dermatan Sulfate Is a Potential Regulator of IgH via Interactions With Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts

Lee

Rho²,

Roehrl

et al. 2021

Front. Immunol.

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Dermatan sulfate (DS) and autoantigen (autoAg) complexes are capable of stimulating autoreactive CD5+ B1 cells. We examined the activity of DS on CD5+ pre-B lymphoblast NFS-25 cells. CD19, CD5, CD72, PI3K, and Fas possess varying degrees of DS affinity. The three pre-BCR components, Ig heavy chain mu (IgH), VpreB, and lambda 5, display differential DS affinities, with IgH having the strongest affinity. DS attaches to NFS-25 cells, gradually accumulates in the ER, and eventually localizes to the nucleus. DS and IgH co-localize on the cell surface and in the ER. DS associates strongly with 17 ER proteins (e.g., BiP/Grp78, Grp94, Hsp90ab1, Ganab, Vcp, Canx, Kpnb1, Prkcsh, Pdia3), which points to an IgH-associated multiprotein complex in the ER. In addition, DS interacts with nuclear proteins (Ncl, Xrcc6, Prmt5, Eftud2, Supt16h) and Lck. We also discovered that DS binds GTF2I, a required gene transcription factor at the IgH locus. These findings support DS as a potential regulator of IgH in pre-B cells at protein and gene levels. We propose a (DS•autoAg)-autoBCR dual signal model in which an autoBCR is engaged by both autoAg and DS, and, once internalized, DS recruits a cascade of molecules that may help avert apoptosis and steer autoreactive B cell fate. Through its affinity with autoAgs and its control of IgH, DS emerges as a potential key player in the development of autoreactive B cells and autoimmunity.

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An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19

Cited by 13 publications

References 269 publications

COVID-19 and the clinical course of rheumatic manifestations

COVID-19 and the clinical course of rheumatic manifestations

A Master Autoantigen-ome Links Alternative Splicing, Female Predilection, and COVID-19 to Autoimmune Diseases

Dermatan Sulfate Is a Potential Regulator of IgH via Interactions With Pre-BCR, GTF2I, and BiP ER Complex in Pre-B Lymphoblasts

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