








key: cord-339934-g6ufz29l
authors: Yu, Hai-qiong; Sun, Bao-qing; Fang, Zhang-fu; Zhao, Jin-cun; Liu, Xiao-yu; Li, Yi-min; Sun, Xi-zhuo; Liang, Hong-feng; Zhong, Bei; Huang, Zhi-feng; Zheng, Pei-yan; Tian, Li-feng; Qu, Hui-Qi; Liu, De-chen; Wang, Er-yi; Xiao, Xiao-jun; Li, Shi-yue; Ye, Feng; Guan, Li; Hu, Dong-sheng; Hakonarson, Hakon; Liu, Zhi-gang; Zhong, Nan-shan
title: Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients
date: 2020-05-13
journal: Eur Respir J
DOI: 10.1183/13993003.01526-2020
sha: 
doc_id: 339934
cord_uid: g6ufz29l

Humoral immune response to SARS-CoV-2 showed an early response of IgA, instead of IgM, in COVID-19 patients. As highlighted by our study, enhanced IgA responses observed in severe COVID-19 might confer damaging effects in severe COVID-19.

To the Editor:

In comparison to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 appears to be more contagious [1] , and Coronavirus Disease 2019 patients demonstrate varied clinical manifestations distinct from those seen in patients with SARS-CoV and middle east respiratory syndrome coronavirus (MERS-CoV) infections [2] .

Collective results from the clinical and epidemiological observations suggest a distinct viralhost interaction in COVID-19 patients. Profiling of the antibody response during SARS-CoV-2 infection may help improve our understanding of the viral-host interaction and the immunopathological mechanisms of the disease.

Studies on humoral responses to infections have been mainly geared toward the production of high-affinity IgG antibodies that efficiently resolve an infection. It has been well recognized, however, that humoral immune response to infection can be a double-edged sword that either serves as a protective mechanism to resolve the infection or aggravates the tissue injury, e.g. IgG response causes fatal acute lung injury by skewing inflammationresolving response in SARS [3] . In the case of respiratory infection, while IgM and IgG isotypes have been the primary emphasis in characterizing immunity, mucosal and systemic IgA responses that may play a critical role in the disease pathogenesis, have received much less attention.

This study was designed to better understand the timing and patterns of humoral The present study showed that the levels of specific IgM antibody were significantly lower than those of IgA in both severe and non-severe patents. This pattern of humoral immune response is different in case of SARS-CoV infection, in which IgM and IgA showed similar chronological profiles in terms of both seroconversion time and antibody titres [5] , in line with the knowledge that viremia is common in SARS.

As a mucosal targeted virus, SARS-CoV-2 would be expected to generate secretory IgA (sIgA) and induce strong mucosal immunity. Indeed, the mucosal anti-viral immunity has been shown to result in part from the IgA-mediated interactions with the pathogenic microorganisms to prevent pathogens from adhering to the cell surface [6] . However, recent studies also found that sIgA is able to induce interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and granulocyte-macrophage colony stimulating factor (GM-CSF) production by normal human lung fibroblasts (NHLFs) [7] . It is also proposed that sIgA may have synergistic effects with IgG in promoting antibody-dependent cellular cytotoxicity (ADCC) [8] . In contrast to mucosal IgA, the role of serum IgA have been relatively unexplored. Previous studies have shown that IgA mediates either pro-or antiinflammatory effects in innate immune cells and suggested a plausible role of IgA as a driver of autoimmune diseases and regulator of immune hyperactivation [9] . Monomeric binding of serum IgA to the Fc alpha receptor (FcαRI) has been suggested to mediate inhibitory function via the receptor inhibitory signals in a variety of myeloid cells [10] . In contrast, crosslinking of the FcαRI by IgA and pathogen is able to transmit activating signals leading to phagocytosis, respiratory burst, ADCC, increased antigen presentation, degranulation, and cytokine release [11] . Cytokines including transforming growth factor beta (TGF-β) and IL-10 can induce antibody isotype switching [12] . Upregulated IgA production may be the result of increased levels of TGF-β and IL-10 that promote antibody switching in SARS-CoV-2 infection.

Considering the roles of mucosal and systemic IgA in COVID-19, inducing IgA production, e.g. using Lactoferrin to activate canonical TGF-β signaling [13] , or retinoic acid to enhance lactoferrin-induced IgA responses [14] , has been proposed as novel therapies for severe COVID-19. However, as highlighted by our study, enhanced IgA responses observed in severe COVID-19 might confer damaging effects in severe COVID-19. As a result, we hypothesize that severe COVID-19 might be at least in part an IgA-mediated disease (related to IgA deposition and vasculitis), which helps to explain common organ injuries in COVID-19, e.g. acute pulmonary embolism, kidney injury, etc. [15] We acknowledge the limitations of this study, including no measurement of local IgA, and limited number of patients. 

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Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

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Chronological evolution of IgM, IgA, IgG and neutralisation antibodies after infection with SARS-associated coronavirus

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Secretory immunoglobulin A induces human lung fibroblasts to produce inflammatory cytokines and undergo activation

Secretory IgA antibodies synergize with IgG in promoting ADCC by human polymorphonuclear cells, monocytes, and lymphocytes

Immunomodulatory properties of human serum immunoglobulin A: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cells

Monomeric and polymeric IgA show a similar association with the myeloid FcαRI/CD89

The unexplored roles of human serum IgA

AT celldependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts

Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGFβ signaling

Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression

Acute pulmonary embolism and COVID-19 pneumonia: a random association?



