Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

Abstract

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage.

Autoantibodies and SARS-CoV2 infection: The spectrum from association to clinical implication: Report of the 15th Dresden Symposium on Autoantibodies

“…COVID-19 patients suffer from a systemic inflammation with complement activation, which may be responsible for high density of β 2 GPI on the activated endothelium [ [24] , [25] , [26] , [27] ]. In this context, even low titers of aPL may become pathogenic, thus potentiating or even triggering thrombus formation, especially when anticoagulation is suspended.…”

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“…These apparently contrasting results, potentially due to the different methods for EPCs’ characterization and patient inclusion criteria, further support the need for large preclinical and laboratory studies evaluating the prognostic role of EPCs levels and function in different clinical settings. Two further studies [ 18 , 19 ] in the Special Issue focused on endothelial dysfunction in COVID-19. In particular, Macor et al [ 18 ] performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from 12 COVID-19 patients who died of acute respiratory failure.…”

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“…Furthermore, complement deposition has been reported in multiple organs of COVID-19 patients, including the lungs. Localization of C1q, C3, C4, and C5b-9 was observed in the capillaries of the interalveolar septa and on alveolar cells, highlighting the importance the complement system in inflammation and tissue damage [16].…”