ABSTRACTIn order to study the mechanisms of COVID-19 damage following the complement activation phase occurring during the innate immune response to SARS-CoV-2, the CR1, receptor regulating complement activation factor, CR1 (CD35, the C3b/C4b receptor), C4d deposits on Erythrocytes (E), and the products of complement activation C3b/C3bi were assessed in 52 COVID-19 patients undergoing O2 therapy or assisted ventilation in ICU units in Rheims France.An acquired decrease of CR1 density of E from COVID-19 patients was observed (Mean 418, SD 162, N=52) versus healthy individuals (Mean = 592, SD = 287, N= 400), Student’s t-test p<10−6, particularly among fatal cases, and paralleling several clinical severity parameters.Large deposits of C4d on E in patients were well above values observed in normal individuals, mostly without concomitant C3 deposits, in more than 80% of the patients. This finding is reminiscent of the increased C4d deposits on E previously observed to correlate with sub endothelial pericapillary deposits in organ transplant rejection, and with clinical SLE flares. Conversely, significant C3 deposits on E were only observed among ¼ of the patients.The decrease of CR1/E density, deposits of C4 fragments on E and previously reported detection of virus spikes or C3 on E among COVID-19 patients, suggest that the handling and clearance of immune complex or complement fragment coated cell debris may play an important role in the pathophysiology of SARS-CoV-2. Measurement of C4d deposits on E might represent a surrogate marker for assessing inflammation and complement activation occurring in organ capillaries and CR1/E decrease might represent a cumulative index of complement activation in COVID-19 patients.Taken together, these original findings highlight the participation of complement regulatory proteins and indicate that E are important in immune pathophysiology of COVID-19 patients. Besides a potential role for monitoring the course of disease, these observations suggest that novel therapies such as the use of CR1, or CR1-like molecules with the aim of down regulating complement activation and inflammation for therapy should be considered.HIGHLIGHTSAcquired decrease of CR1 density on E in COVID-19 patients correlated with clinical severity and mortality.Large C4d deposits were found on E in most patients, reminiscent of those observed on E of patients undergoing organ transplant rejection that were associated with peri-capillary deposits, as well as on E from patients undergoing SLE flares.C4d deposits on E may be useful as a surrogate marker for inflammation and complement activation in organ capillaries.Decreased CR1/E may be useful as a cumulative index of complement activation in COVID-19 patients.The use of CR1 or CR1-like molecules for down-regulating complement activation for therapy should also be considered.These original findings indicate the participation of complement regulatory proteins in COVID-19 and on the role of E in immune mechanisms of the disease.
Hemopexin Modulates Expression of Complement Regulatory Proteins in Rat Glomeruli
