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

Marcos-Jimenez, A.; Sanchez-Alonso, S.; Alcaraz-Serna, A.; Esparcia, L.; Lopez-Sanz, C.; Sampedro-Nunez, M.; Mateu-Albero, T.; Sanchez-Cerrillo, I.; Martinez-Fleta, P.; Gabrie, L.; Del Campo, L.; Lopez-Trascasa, M.; Martin-Gayo, E.; Calzada, M.; Castaneda, S.; de la Fuente, H.; Gonzalez-Alvaro, I.; Sanchez-Madrid, F.; Munoz-Calleja, C.; Alfranca, A.

Background: SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the pathogenesis and outcome of COVID-19. We aimed to investigate which specific responses from either cellular or humoral immunity associate to severity and progression of COVID-19. Methods: A cohort of 276 patients classified in mild, moderate and severe, was studied. Peripheral blood lymphocyte subpopulations were quantified by flow cytometry, and immunoglobulins and complement proteins by nephelometry. Results: At admission, dramatic lymphopenia of T, B and NK cells associated to severity. However, only the proportion of B cells increased, while T and NK cells appeared unaffected. Accordingly, the number of plasma cells and circulating follicular helper T cells (cTfh) increased, but levels of IgM, IgA and IgG were unaffected. When degrees of severity were considered, IgG was lower in severe patients, suggesting an IgG consumption by complement activation or antibody-dependent cellular cytotoxicity (ADCC). Activated CD56-CD16+ NK-cells, which mediate ADCC, were increased. Regarding complement, C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, compared to healthy donors. Moreover, IgG 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. Conclusion: Our study provides important clues to understand the immune response observed in COVID-19 patients, which is probably related to viral clearance, but also underlies its pathogenesis and severity. This study associates for the first time COVID-19 severity with an imbalanced humoral immune response characterized by excessive consumption of IgG and C4, identifying new targets for therapeutic intervention.