key: cord-285327-m0yaa1oa
authors: Vuitton, Dominique A.; Vuitton, Lucine; Seillès, Estelle; Galanaud, Pierre
title: A plea for the pathogenic role of immune complexes in severe Covid-19
date: 2020-06-08
journal: Clin Immunol
DOI: 10.1016/j.clim.2020.108493
sha: 
doc_id: 285327
cord_uid: m0yaa1oa

nan

other organs such as the kidney and the cardio-vascular or neurological systems, associated with the Cytokine Release Syndrome (CRS), commonly designated as a 'cytokine storm' [2] . The relatively low percentage of severe Covid-19 in patients with chronic inflammatory disorders treated by powerful inflammatory cytokine inhibitors [3] , as well as encouraging preliminary results with anti-IL6 agents such as tocilizumab [ . This hypothesis is justified by the delayed occurrence of the cytokine storm and patient's aggravation, pathological observations of endothelitis, association with disseminated microvascular thrombosis in the most severe cases, and location of the lesions to specific organs, including heart, brain, kidney and skin [1, 4] ; similar observations are common in experimental and clinical models of pathogenic ICs, such as serum sickness, or viral diseases with IC deposition and massive inflammatory reactions [5] . In the recent weeks, observations of intravenous immunoglobulins-(Igs-) responsive Kawasaki-like disease in children with SARS-CoV2 infection [6] and the efficacy of IL-1 receptor antagonist (anakinra) in a severely ill COVID-19 teenage patient [7] were published. Both add new arguments to the hypothesis, the former in view of the documented association of the Kawasaki syndrome with IC formation and deposition [8] and the latter because the authors showed that high inflammatory markers were associated with pathologically low levels of C3 and C4 Complement components. The first report of Covid-19 treated with the Complement C3 inhibitor AMY-101 paves the way towards a new therapeutic approach which also strongly supports our hypothesis [9] .

Historical studies on serum sickness focused on the circumstances of IC disease occurrence and stressed the triggering effect of differences in hydrostatic pressure and vasoactive changes in microvessels to enhance IC deposit, inflammatory reaction, endothelitis and microthrombosis [5] .

In SARS-CoV2 infection, the particular property of the virus to bind ACE2 [1], an enzymatic inhibitor of angiotensin II, able to modify the local microenvironment of ICs in vessels and alveoli, could be a trigger factor for IC-related endothelitis. Previous microvascular alterations, as those seen in arterial hypertension or diabetes which are well-recognized factors for Covid-19 severity [4] , may also favor pathogenic deposits of ICs with subsequent inflammation. The Historical experimental studies also demonstrated that the properties and pathogenicity of ICs are altered by antigen-antibody ratio, and occurrence of serum sickness has generally been observed in 'antigen excess' [5] . Thus, the corresponding figure may vary during the course of the infection and according to the maturity of the immune system in children or its decline in aging individuals [1]. Therapy with plasma from Covid-19 patients after recovery could, in addition to

The specific humoral and cellular immune response towards SARS-CoV2 was comprehensively analyzed in a non-severe case of the disease [11] . More recently antibody follow-up was performed in patients with mild symptoms and critically ill patients, showing differences between the two clinical forms of Covid-19 [12] . However, very few of the published reports refer to classical indicators of IC-related diseases, such as Complement components, and in the case of renal involvement [8] 

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