Proinflammatory IgG Fc structures in patients with severe COVID-19
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause Coronavirus Disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that severe COVID-19 patients produced a unique serologic signature, including increased IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating FcγR, FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including IL-6 and TNF. These results show that disease severity in COVID-19 correlates with the presence of afucosylated IgG1, a pro-inflammatory IgG Fc modification.
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SciScore for 10.1101/2020.05.15.20103341: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Characterization of these samples was performed under a protocol approved by the Institutional Review Board of Stanford University (protocol #55718).
Consent: Written informed consent was obtained from all study participants.Randomization 50 samples were obtained from a Ugandan cohort of women and children enrolled in PROMOTE (NCT 02163447), a randomized clinical trial of novel antimalarial chemoprevention regimens in Eastern Uganda 26. Blinding Investigators were blinded to study subjects diagnoses during screening; COVID-19 patients and children were not known by investigators at the time of ELISA screening for RBD reactivity of serum or by investigators … SciScore for 10.1101/2020.05.15.20103341: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Characterization of these samples was performed under a protocol approved by the Institutional Review Board of Stanford University (protocol #55718).
Consent: Written informed consent was obtained from all study participants.Randomization 50 samples were obtained from a Ugandan cohort of women and children enrolled in PROMOTE (NCT 02163447), a randomized clinical trial of novel antimalarial chemoprevention regimens in Eastern Uganda 26. Blinding Investigators were blinded to study subjects diagnoses during screening; COVID-19 patients and children were not known by investigators at the time of ELISA screening for RBD reactivity of serum or by investigators involved in relative quantitation of Fc glycoforms and IgG subclasses by mass spectrometry. Power Analysis not detected. Sex as a biological variable 50 samples were obtained from a Ugandan cohort of women and children enrolled in PROMOTE (NCT 02163447), a randomized clinical trial of novel antimalarial chemoprevention regimens in Eastern Uganda 26. Table 2: Resources
Antibodies Sentences Resources The various secondary antibodies used for isotyping were 1:5000 dilutions of HRP-conjugated Goat Anti-Human IgG Fc (Southern Biotech) Anti-Human IgGsuggested: NoneThe following morning, cell culture media was replaced with complete RPMI containing anti-CD107a antibody (BioLegend; clone H4A3). anti-CD107asuggested: NoneSoftware and Algorithms Sentences Resources All other data were analyzed with GraphPad Prism 8.0 software. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:A limitation of the present study is the absence of in vivo experimental data to define this due to the current lack of a humanized FcγR animal model for COVID-19 that would enable such mechanistic studies. In vivo models with well characterized FcγR-IgG interactions and signaling outcomes will be essential for defining the role of antibodies in SARS-CoV-2 immunity and disease. Interestingly, prior studies have found high levels of afucosylated IgG1 in patients with severe dengue virus infections and elevated maternal anti-dengue afucosylation predicted risk for dengue disease in their infants10, 12. Mechanistic studies have shown that afucosylated anti-dengue immune complexes and the associated enhancement in FcγRIIIa ITAM signaling can modulate diverse aspects of dengue virus-host interactions10, 12. These studies show that production of pro-inflammatory IgG antibodies was more common in severe cases of COVID-19. Future longitudinal studies including analysis of pre- and post-infection samples will be needed to determine whether these Fc structures can be used as a pre-infection biomarker for risk of progression to severe COVID-19.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04331899 Active, not recruiting Single-Blind Study of a Single Dose of Peginterferon Lambda-… NCT01967238 Active, not recruiting An Open Label Study of IgG Fc Glycan Composition in Human Im… NCT02163447 Completed Reducing the Burden of Malaria in HIV-uninfected Pregnant Wo… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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