Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID‐19 patients

Abstract

SARS‐CoV‐2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID‐19. We investigated whether the specific immune responses in the peripheral blood of 276 patients associated to severity and progression of COVID‐19. At admission, dramatic lymphopenia of T, B and NK cells associated to severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56‐CD16+ NK‐cells increased. Regarding humoral immunity, levels of IgM, IgA and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID‐19 patients, associating severity with an imbalanced humoral response and identifying new targets for therapeutic intervention. This article is protected by copyright. All rights reserved

Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

“…After a full-text review of the remaining 21 articles, two were excluded because they did not meet the inclusion criteria. Thus, 19 studies were included in the meta-analysis (Figure 1) (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). These studies enrolled 3,764 COVID-19 patients, 2,643 (48% males, mean age 54 years) with low disease severity or survivor status and 1,121 (58% males, mean age 65 years) with high severity or non-survivor status during follow up.…”

“…One study was conducted in Turkey ( 23), one in Spain (33), and the remaining 17 in China (22,(24)(25)(26)(27)(28)(29)(30)(31)(32)(34)(35)(36)(37)(38)(39)(40). Of the 17 studies conducted in China, 10 were from the Renmin Hospital, Wuhan (24-29, 35, 38-40) (Supplementary Table ).…”

MASPs at the crossroad between the complement and the coagulation cascades - the case for COVID-19

“…C3a, C5a and MAC have been found at high levels in COVID-19 patients, increasing with severity of the disease, together with immunoglobulin IgG and C4 consumption (Gao et al, 2020b;Marcos-Jimenez et al, 2020;Skendros et al, 2020). C5a is a product of C5 cleavage and has a potent chemotactic response, inducing the migration of the neutrophils (Ehrengruber et al, 1994), and the formation of NETs (reviewed by Bont et al, 2019).…”

SARS-CoV-2 associated Complement genetic variants possibly deregulate the activation of the Alternative pathway affecting the severity of infection

“…Several studies attempting to dissect the molecular and cellular aspects of the SARS-CoV-2 virus pathophysiology have investigated the host immune responses and the roles of complement in viral sensing and the inflammation dynamics during infection ( Yuki et al, 2020 )( Kaneko et al, 2020 )( Wilk, 2020 )( Yu et al, 2020 )( Java et al, 2020 ). Aspects of the pandemic COVID-19 pathology resemble, from moderate to severe cases, clinical features traditionally associated with complementopathies ( Marcos-Jiménez et al, 2021 )( Joseph et al, 2020 )( Baines and Brodsky, 2017 ). Some of these are associated with disease phenotypes characterised by the deregulated activation of the Alternative pathway resulting in complement C3 consumption and deprivation of the downstream activation processes ( Fig.…”

“…The activation of the Alternative pathway by the spike glycoprotein S has been of particular interest as it promotes entry of the virus into cells and is a major antigenic target for B cell responses ( Walls et al, 2020 ). Furthermore, the potential exploitation of the activation of the Alternative pathway via the amplification loop by SARS-CoV-2 is of even greater particular interest, because it can explain to a considerable extent the gradual diminishment of complement responses during the systemic establishment of the virus ( Marcos-Jiménez et al, 2021 )( Kulkarni and Atkinson, 2020 ).…”