Contribution of Coronavirus-Specific Immunoglobulin G Responses to Complement Overactivation in Patients with Severe Coronavirus Disease 2019

Abstract

Background Excessive complement activation has been implicated in the pathogenesis of COVID-19, but the mechanisms leading to this response remain unclear. Methods We measured plasma levels of key complement markers, SARS-CoV-2 RNA and antibodies against SARS-CoV-2 and common cold coronaviruses (CCC) in hospitalized patients with COVID-19 of moderate (n=18) and critical severity (n=37), and healthy control subjects (n=10). Results We confirmed that complement activation is systemically increased in COVID-19 patients and is associated with a worse disease outcome. We showed that plasma levels of C1q and circulating immune complexes (CIC) were markedly increased in severe COVID-19 patients and correlated with higher IgG titers, greater complement activation and higher disease severity score. Additional analyses showed that the classical pathway was the main arm responsible for augmented complement activation in severe patients. In addition, we demonstrated that a rapid IgG response to SARS-CoV-2 and an anamnestic IgG response to the nucleoprotein of the CCC were strongly correlated with CIC levels, complement activation, and disease severity. Conclusions These findings indicate that early, non-neutralizing IgG responses may play a key role in complement overactivation in severe COVID-19. Our work underscores the urgent need to develop therapeutic strategies to modify complement overactivation in COVID-19 patients.

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

“…The alternative complement pathway can also mediate complement amplification upon the triggering of the classical or lectin pathways. However, we did not find evidence of immune complexes (18,22) or direct lectin binding (17,24) leading to complement factor turnover, given the unaltered concentrations of C4a in circulation around the time of respiratory failure.…”

“…All three complement arms were shown to be activated in COVID-19 (17)(18)(19)(20)(21)(22)(23)(24); however, their relative contributions remain ill-defined. Whereas complement was initially described as a liver-derived cascade, studies have demonstrated unexpected celland tissue-specific production and functions for the complement system (8,(25)(26)(27)(28)(29)(30).…”

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

“…Soluble C5b-9 levels were also increased and correlated with C5a, markers of inflammation and coagulation [ 12 , 33 , 36 , 68 , 70 , 71 , 78 , 120 , 125 , [129] , [130] , [131] , [132] , [133] , [134] ]. C5 was only elevated in three studies measuring C5 levels [ 66 , 135 , 136 ]. MBL levels in plasma were in general higher in COVID-19 patients compared with healthy controls [ 134 , 137 , 138 ].…”

“…Soluble levels of C5b-9 were also increased and correlated with C5a, markers of inflammation and coagulation [ 12 , 33 , 36 , 68 , 70 , 71 , 78 , 120 , 125 , [129] , [130] , [131] , [132] , 134 ]. C5 was only elevated in three observational studies investigating C5 [ 66 , 135 , 136 ].…”

“…The evidence of this review points towards a critical role of C5a in severe COVID-19. C5 was elevated in only three observational studies investigating C5 [ 66 , 135 , 136 ]. An advantage of inhibiting C5a specifically compared with upstream inhibition such as C3 or C5 inhibition, is that the formation of the MAC complex is not affected, which plays an important role in bacterial lysis [ 20 , 127 ].…”