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Acquired decrease of the C3b/C4b receptor (CR1, CD35) and increased C4d deposits on erythrocytes from ICU COVID-19 patients

  • Kisserli, Aymric1, 2
  • Schneider, Nathalie3
  • Audonnet, Sandra4
  • Tabary, Thierry2, 5
  • Goury, Antoine6
  • Cousson, Joel6
  • Mahmoudi, Rachid7, 8
  • Bani-Sadr, Firouze6
  • Kanagaratnam, Lukshe8, 9
  • Jolly, Damien8, 9
  • Cohen, Jacques HM2
  • 1 Oncogeriatric Coordination Unit, Rheims University Hospital, Rheims, France
  • 2 Nanosciences Research Laboratory LRN EA 4682, University of Rheims Champagne-Ardenne, Rheims, France
  • 3 Biochemistry, Pharmacology and Toxicology Unit, Rheims University Hospital, Rheims, France
  • 4 URCACyt, Flow Cytometry Technical Platform, University of Rheims Champagne-Ardenne, Rheims, France
  • 5 Immunology Laboratory, Rheims University Hospital, Rheims, France
  • 6 Medical-Surgical ICU, Rheims University Hospital, Rheims, France
  • 7 Department of Internal Medicine and Geriatrics, Rheims University Hospital, Rheims, France
  • 8 Aging and Fragility Unit EA 3797, University of Rheims Champagne-Ardenne, Rheims, France
  • 9 Research Promotion and Support Unit, Rheims University Hospital, Rheims, France
Published Article
The Authors. Published by Elsevier GmbH.
Publication Date
May 09, 2021
DOI: 10.1016/j.imbio.2021.152093
PMID: 34022670
PMCID: PMC8106962
PubMed Central
  • Article


In order to study the mechanisms of COVID-19 damage following the complement activation phase occurring during the innate immune response to SARS-CoV-2, CR1 (the regulating complement activation factor, 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 on 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 in parallel with several parameters of clinical severity. 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, in order to down regulate complement activation and inflammation, should be considered.

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