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Deregulated Cellular Circuits Driving Immunoglobulins and Complement Consumption Associate with the Severity of COVID-19 Patients

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Deregulated Cellular Circuits Driving Immunoglobulins and Complement Consumption Associate with the Severity of COVID-19 Patients Eur. J. Immunol. 2021. 00: 1–14 DOI: 10.1002/eji.202048858 Ana Marcos-Jiménez et al. 1 Clinical Immunity to infection Research Article Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients Ana Marcos-Jiménez∗1, Santiago Sánchez-Alonso∗1, Ana Alcaraz-Serna1, Laura Esparcia1, Celia López-Sanz1, Miguel Sampedro-Núñez2,3, Tamara Mateu-Albero1, Ildefonso Sánchez-Cerrillo1, Pedro Martínez-Fleta1, Ligia Gabrie1, Luciana del Campo Guerola1, José Miguel Rodríguez-Frade4, José M. Casasnovas4, Hugh T. Reyburn4, Mar Valés-Gómez4, Margarita López-Trascasa3, Enrique Martín-Gayo1,3, María José Calzada1,3, Santos Castañeda1, Hortensia de la Fuente1, Isidoro González-Álvaro1, Francisco Sánchez-Madrid∗∗1,3, Cecilia Muñoz-Calleja∗∗1,3 and Arantzazu Alfranca∗∗1 1 Department of Immunology, Biomedical Research Institute La Princesa Hospital (IIS-IP), Madrid, Spain 2 Department of Endocrinology, La Princesa Hospital, Madrid, Spain 3 School of Medicine, Department of Medicine, Universidad Autónoma of Madrid, Madrid, Spain 4 CSIC, Centro Nacional de Biotecnología, Madrid, Spain 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 were associated with the sever- ity and progression of COVID-19. At admission, dramatic lymphopenia of T, B, and NK cells is associated with 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, regard- less of 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 under- stand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response, and identifying new targets for therapeutic intervention. Keywords: COVID-19 r SARS-CoV-2 r immunity r complement r immunoglobulins Additional supporting information may be found online in the Supporting Information section at the end of the article. ∗ Correspondence: Cecilia Muñoz-Calleja These authors share first co-author positions. ∗∗ e-mail: [email protected] These authors share senior authorship. © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH www.eji-journal.eu This is an open access article under the terms of the Creative Commons Attribution-NonCommer- cial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 2 Ana Marcos-Jiménez et al. Eur. J. Immunol. 2021. 00: 1–14 Introduction these studies have been conducted, in most cases, with a lim- ited number of patients, and clinical parameters and disease Novel coronavirus disease (COVID-19), due to severe acute res- severity are not homogeneously recorded in all of them [11,12]. piratory coronavirus 2 (SARS-CoV-2), is either asymptomatic or Likewise, although specific antibodies and complement activation presents with mild symptoms in a majority of individuals. How- have been proposed to mediate some of the most severe com- ever, up to 20% of patients develop a severe form of the disease plications of coronavirus infections, including that of SARS-CoV-2 with pneumonia, which in some cases results in acute respiratory [2,5,13,14], solid evidence on the role of humoral immunity effec- distress syndrome (ARDS) and requires invasive mechanical ven- tor mechanisms in the pathogenesis of SARS-CoV-2-associated tilation. ARDS, together with myocardial damage, are the main ARDS is clearly needed. causes of mortality in COVID-19 [1]. A pathogenic hallmark of ARDS is the disruption of the alveolar-capillary barrier and a subsequent increase in permeabil- Results ity, which has been partially attributed to a maladaptive immune response. Thus, lung alveolar macrophages may be infected by COVID-19 patients have increased B cells and the virus and become activated, leading to a cytokine release syn- plasmablasts in peripheral blood drome, which contributes to endothelial injury with the recruit- ment and activation of innate and adaptive immune cells and Our cohort of COVID-19 patients included 276 SARS-CoV-2 the extravasation of plasma components of the humoral immu- infected individuals who were further classified according to the nity [2]. severity of their clinical signs and symptoms in mild, moderate, Humoral immunity plays a key role in the initial control of and severe, following recently described criteria [15]. The mean viral infections and cell-to-cell spread. It is mediated by the com- duration of symptoms before admission was 7.36 ± 5.2 days. plement system and the immunoglobulins (Ig) [3, 4]. Different Table 1 shows the main demographic and laboratory character- SARS-CoV-2 components such as pathogen-associated molecular istics. The median (percentile 25 and 75) age was 63 (53.25–75) patterns (PAMPs) and N protein, together with C reactive pro- and 163 (59.05%) were men. tein (CRP) from plasma, may activate either the alternative or the We conducted an initial analysis following the COVID-19 lectin pathways of the complement cascade early during infection admission protocol, which comprised the quantification of the [5]. Furthermore, early IgM isotype antibodies efficiently trigger main peripheral blood lymphocyte subsets, including T, B, and the classical complement cascade. Secreted IgA antibodies neu- NK lymphocytes as well as plasmablasts, by multiparametric flow tralize viruses within the mucosa of the respiratory and gastroin- cytometry (Fig. 1A, Suppl. Fig. S1). The proportion of T lympho- testinal tracts. Finally, in a more advanced stage of the disease, cytes (either CD4+ or CD8+) and NK cells was similar in all the virus-specific IgG antibodies opsonize viral particles. This may patients and healthy volunteers, with the exception of CD8+ T lead to the formation of immune complexes that contribute to cells, which decreased in severe patients (Fig. 1B). Conversely, the activation of the classical complement pathway. Furthermore, the percentage of B cells was higher in COVID-19 patients and opsonized viral particles can attach to Fc receptors on phago- increased with disease severity, raising from a mean of 9.15% cytes and NK cells. The latter constitute major innate immunity in healthy donors to 20.49% in severely ill patients. In accor- mediators during antiviral responses, since they kill infected cells dance, plasmablasts were remarkably higher in patients, both in through different mechanisms, including antibody-dependent cell relative and absolute values (mean 1.51% vs 17.98%; and 2.83 cytotoxicity (ADCC), which is mediated by the FcγRIIIA (CD16) cells/μl vs 27.37 cells/μl, respectively), and regardless of sever- binding to clustered IgG displayed on the cell surface of virally ity degree (Fig. 1B). This increase in absolute plasmablasts num- infected cells [6]. Isotype switching and affinity antibody matura- ber is of special relevance, given the lymphopenia present in tion, as well as the generation of memory B cells and long-lived COVID-19 patients (Table 1), and the diminished absolute num- plasma cells, are B cell responses driven by helper T cells, in par- ber of other lymphocyte subsets (Fig. 1B). The elevated num- ticular follicular helper T cells (Tfh). ber of plasmablasts suggested a redistribution of the main mat- However, the deregulated humoral immune response can uration stages of the B lineage, including naïve, transitional, damage host tissues. Complement-mediated tissue injury is unswitched memory, IgM-only memory, and class-switched mem- elicited by an intense inflammatory loop secondary to C3a- ory B-cells, which were identified in a subgroup of 84 patients and C5a-mediated recruitment and activation of neutrophils, from our initial cohort, with the gating strategy shown in Sup- monocytes, macrophages, lymphocytes, and platelets. Phagocytes porting Information Fig. S2. In COVID-19 patients, the propor- in turn generate ROS and proteases, and neutrophils release tion of IgM-only memory B-cells increased, while unswitched neutrophil extracellular traps (NETs), which exacerbate tissue memory cells decreased (Fig. 1C). This redistribution was more damage [7–10]. marked in mild patients and progressively diminished in moder- Several studies on SARS-CoV-2 infection have attempted to ate and severe patients. Nevertheless, differences among patients elucidate phenotypic features of immune cell subsets either asso- with different severity degree were not statistically significant ciated with severity or predictive of disease outcome. However, (Suppl. Fig. S3). © 2021 The Authors. European Journal of Immunology published by www.eji-journal.eu Wiley-VCH GmbH Eur. J. Immunol. 2021. 00: 1–14 Immunity to infection 3 Table 1. Demographic and laboratory characteristics of the study population classified by severity degree. All variables
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