An Autoantigen Profile from Jurkat T-Lymphoblasts Provides a Molecular Guide for Investigating Autoimmune Sequelae of COVID-19

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

doi:10.1101/2021.07.05.451199

Cited by 3 publications

(4 citation statements)

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“…Meanwhile, proteomics has also made significant contributions to understanding SARS-CoV-2 and COVID-19, including “long COVID”, with persistent cough, fatigue, muscle and joint pain, memory loss, brain fog, or depression. Several papers show a striking relationship to human autoimmunity; − an analysis of human lung cells showed that a large number of COVID-dysregulated proteins during acute infection are known human autoantigens …”

Section: Highlights From the Pathology Resource Pillarmentioning

confidence: 99%

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

et al. 2022

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The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 407 (93.2%) of the 19 750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, "A Function for Each Protein".

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Section: Highlights From the Pathology Resource Pillarmentioning

confidence: 99%

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

et al. 2022

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“…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%

“…To gain a better understanding of autoimmune sequelae due to COVID-19, we present a master autoantigen atlas of over 750 potential autoAgs identified from six human cell types [1, 2, 4, 5, 7, 11]. These autoAgs show significant correlation with pathways and processes that are crucial in viral infection and mRNA vaccine action, reveal common autoAgs associated with apoptosis and cell stress which may serve as markers for systemic autoimmune diseases, and provide a detailed molecular map for understanding and for investigating diverse autoimmune sequalae of COVID-19 and potential rare side-effects to viral vector- and mRNA-based vaccines.…”

Section: Introductionmentioning

confidence: 99%

“…Autoimmune disorders are an important feature of the disease manifestations of COVID-19 and long- COVID syndromes. Based on the insights we gained from numerous COVID-related autoantigens (autoAgs) and their associated cellular process and pathways [1–5], we propose a model to explain how viral infections in general and SARS-CoV-2 in particular can lead to a wide array of autoimmune diseases (Figure 1). We illustrate how viral infections lead to extensive molecular alterations in the host cell, host cell death and tissue injury, autoimmune reactions, and the eventual development of autoimmune diseases.…”

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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NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

2022

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Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.

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An Autoantigen Profile from Jurkat T-Lymphoblasts Provides a Molecular Guide for Investigating Autoimmune Sequelae of COVID-19

Cited by 3 publications

References 123 publications

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

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

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

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