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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

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SARS-CoV-2 Proteins
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    Autoantibodies against Progranulin HGNC and IL-1 receptor antagonist HGNC in critically ill COVID-19 MESHD

    Authors: Lorenz Thurner; Natalie Fadle; Moritz Bewarder; Igor Kos; Evi Regitz; Onur Cetin; Bernhard Thurner; Yvan Fischer; Torben Rixecker; Klaus-Dieter Preuss; Claudia Schormann; Frank Neumann; Sylvia Hartmann; Theresa Bock; Dominic Kaddu-Mulindwa; Birgit Bette; Joerg Thomas Bittenbring; Konstantinos Christofyllakis; Angelika Bick; Vadim Lesan; Zanir Abdi; Sebastian Mang; Andre Becker; Carlos Metz; Frederik Seiler; Johannes Lehmann; Philipp Agne; Thomas Adams; Andreas Link; Christian Werner; Angela Thiel-Bodenstaff; Matthias Reichert; Guy Danziger; Cihan Papan; Jan Pilch; Thorsten Pfuhl; Patrick Wuchter; Christian Herr; Stefan Lohse; Hubert Schrezenmeier; Michael Boehm; Frank Langer; Gereon Gaebelein; Bettina Friesenhahn-Ochs; Robert Bals; Frank Lammert; Sixten Koerper; Juergen Rissland; Christian Lensch; Stephan Stilgenbauer; Soeren L. Becker; Sigrun Smola; Marcin Krawczyk; Philipp Lepper

    doi:10.1101/2021.04.23.441188 Date: 2021-04-26 Source: bioRxiv

    INTRODUCTION: Hyperinflammation is frequently observed in patients with severe COVID-19 MESHD. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far. RATIONALE: In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 MESHD was screened by ELISA for antibodies against PGRN HGNC, IL-10 HGNC, IL-18BP HGNC, IL-22BP HGNC and IL-1-RA HGNC. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. RESULTS: PGRN HGNC-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL 1 HGNC-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19 MESHD. In a validation cohort of 41 patients with critical COVID-19 MESHD high-titered PGRN HGNC-Abs were detected in 12 (29.3%) and IL-1-RA HGNC-Abs in 19 of 41 patients (46.2%). PGRN HGNC-Abs and IL-1-RA HGNC-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19 MESHD, PGRN HGNC-Abs and IL-1-RA HGNC-Abs were detected significantly less frequently and at low titers. Neither PGRN HGNC- nor IL-1-RA HGNC-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN HGNC-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA HGNC. Plasma levels of both free PGRN HGNC PGRN MESHD and IL-1-RA HGNC were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN HGNC-Abs from patients reduced PGRN HGNC-dependent inhibition of TNF HGNC- signaling in vitro. The pSer81 hyperphosphorylated PGRN HGNC isoform was exclusively detected in patients with high-titer PGRN HGNC-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA HGNC isoform was only found in patients with high-titer IL-1-RA HGNC-Abs. No autoantibodies against IL-10 HGNC, IL-18BP HGNC or IL-22BP HGNC were found. CONCLUSION: To conclude, neutralizing autoantibodies to IL-1-RA HGNC and PGRN HGNC occur in a significant proportion of patients with critical COVID-19 MESHD, with a concomitant decrease in circulating PGRN HGNC and IL-1-RA HGNC, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection MESHD itself, or are preexisting and predispose for a critical course.

    Targeting of the NLRP3 HGNC Inflammasome for early COVID-19 MESHD

    Authors: Carlo Marchetti; Kara Mould; Isak W. Tengesdal; William J. Janssen; Charles A. Dinarello

    doi:10.1101/2021.02.24.432734 Date: 2021-02-24 Source: bioRxiv

    Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus MESHD 2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1 HGNC are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1{beta}, triggering both local as well as systemic inflammation MESHD. This cascade of inflammatory cytokines in patients with COVID-19 MESHD is termed Cytokine Release Syndrome ( CRS MESHD), and is associated with poor outcomes and death MESHD. Many studies reveal that blocking IL-1{beta HGNC} activities in COVID-19 MESHD patients reduces disease severity and deaths MESHD. Here we report highly significant circulating levels of IL-1{beta HGNC}, IL-1 Receptor antagonist HGNC, IL-6 HGNC, TNF HGNC, IL-10 HGNC and soluble urokinase plasminogen activator receptor HGNC in COVID-19 MESHD patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 ( NLRP3 HGNC) early in the infection. We observed increased NLRP3 HGNC gene expression in myeloid cells correlated with IL-1{beta HGNC} gene expression and also with elevated circulating IL-1{beta HGNC} levels. We conclude that early in SARS-CoV-2 infection MESHD, NLRP3 HGNC activation takes place and initiates the CRS. Thus, NLRP3 HGNC is a target to reduce the organ damage of inflammatory cytokines of the CRS.

    Increased Interleukin-6 HGNC and Macrophage Chemoattractant Protein-1 are associated with Respiratory Failure in COVID-19 MESHD 

    Authors: Marthe Jørgensen; Jan Cato Holter; Erik Egeland Christensen; Camilla Schjalm; Kristian Tonby; Søren Erik Pischke; Synne Jenum; Linda G Skeie; Sarah Nur; Andreas Lind; Hanne Opsand; Tone Burvald Enersen; Ragnhild Grøndahl; Anne Hermann; Susanne Dudman; Fredrik Müller; Thor Ueland; Tom Eirik Mollnes; Pål Aukrust; Lars Heggelund; Aleksander Rygh Holten; Anne Ma Dyrhol-Riise

    doi:10.21203/rs.3.rs-39162/v1 Date: 2020-06-30 Source: ResearchSquare

    Background: In SARS-CoV-2 infection MESHD ARS-CoV-2 infection MESHDthere is an urgent need to identify patients that will progress to severe COVID-19 MESHD and may benefit from targeted treatment.Objectives: Analyze plasma cytokines in COVID-19 MESHD patients and investigate their association with r espiratory failure MESHD(R F) MESHD and treatment in Intensive Care Unit (ICU). Method: Hospitalized patients (n=34) with confirmed COVID-19 MESHD were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. R F MESHDwas defined as PaO2/FiO2 ratio (P/F) <40kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. Measurements and Results:  COVID-19 MESHD patients with R F MESHDand/or treated in ICU showed overall increased systemic cytokine levels. Plasma I L-6, HGNC I L-8, HGNC G -CSF, HGNC M CP-1, HGNC M IP-1α HGNClevels were negatively correlated with P/F, whereas combinations of I L-6, HGNC I P-10, HGNC I L-1ra HGNCand M CP-1 HGNCshowed the best association with R F MESHDin ROC analysis (AUC 0.79-0.80, p<0.05). During hospitalization the decline was most significant for I P-10 HGNC(P<0.001). Conclusion: Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19 MESHD. I L-6 HGNCand M CP-1 HGNCwere inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe R F MESHDand as targets for improved treatment strategies. 

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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