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

https://doi.org/10.1016/j.imbio.2021.152093Get rights and content
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Highlights

  • Acquired decrease of CR1 density on E in COVID-19 patients correlated with severity.

  • C4d deposits were found on E, as in transplant rejection with peri-capillary deposits.

  • C4d deposits on E, a surrogate marker for complement activation in organ capillaries.

  • Decreased CR1/E as a cumulative index of complement activation in COVID-19 patients.

  • CR1-like molecules for down-regulating complement activation should also be considered.

  • These findings indicate on the role of E in immune mechanisms in COVID-19.

Abstract

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.

Abbreviations

CR1
complement receptor type 1
CR1/E
complement receptor type 1 per erythrocyte
CR1/E%
complement receptor type 1 per erythrocyte as percentage of the CR1/E density expected from the CR1 density polymorphism genotype of the patient
C3
complement fragment 3
C4
complement fragment 4
C1q
complement component 1q
C1r
complement component 1r
C1s
complement component 1s
C3a
complement component 3a
C3b
complement component 3b
C4a
complement component 4a
C4d
complement component 4d
C5a
complement component 5a
DAT
direct antiglobulin test
E
erythrocytes
FITC
fluorescein iso-thio-cyanate
HbA1c
glycosylated hemoglobin type A
ICU
intensive care unit
IgG
immunoglobulin G
IgM
immunoglobulin M
MBL
mannan binding lectin
MASP1
mannan binding lectin serine protease1
PE
phyco-erythrin
RFLP
restriction fragment length polymorphism
Sa02
oxygen saturation
SCR
short consensus repeat
SLE
systemic lupus erythematosus

Keywords

COVID-19
Complement
CR1
CD35
C3
C4
Erythrocytes

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