C-Reactive Protein Enhances IgG-Mediated Cellular Destruction Through IgG-Fc Receptors in vitro

Abstract

Antibody-mediated blood disorders ensue after auto- or alloimmunization against blood cell antigens, resulting in cytopenia. Although the mechanisms of cell destruction are the same as in immunotherapies targeting tumor cells, many factors are still unknown. Antibody titers, for example, often do not strictly correlate with clinical outcome. Previously, we found C-reactive protein (CRP) levels to be elevated in thrombocytopenic patients, correlating with thrombocyte counts, and bleeding severity. Functionally, CRP amplified antibody-mediated phagocytosis of thrombocytes by phagocytes. To investigate whether CRP is a general enhancer of IgG-mediated target cell destruction, we extensively studied the effect of CRP on in vitro IgG-Fc receptor (FcγR)-mediated cell destruction: through respiratory burst, phagocytosis, and cellular cytotoxicity by a variety of effector cells. We now demonstrate that CRP also enhances IgG-mediated effector functions toward opsonized erythrocytes, in particular by activated neutrophils. We performed a first-of-a-kind profiling of CRP binding to all human FcγRs and IgA-Fc receptor I (FcαRI) using a surface plasmon resonance array. CRP bound these receptors with relative affinities of FcγRIa = FcγRIIa/b = FcγRIIIa > FcγRIIIb = FcαRI. Furthermore, FcγR blocking (in particular FcγRIa) abrogated CRP's ability to amplify IgG-mediated neutrophil effector functions toward opsonized erythrocytes. Finally, we observed that CRP also amplified killing of breast-cancer tumor cell line SKBR3 by neutrophils through anti-Her2 (trastuzumab). Altogether, we provide for the first time evidence for the involvement of specific CRP-FcγR interactions in the exacerbation of in vitro IgG-mediated cellular destruction; a trait that should be further evaluated as potential therapeutic target e.g., for tumor eradication.

A Report on the First 7 Sequential Patients Treated Within the C-Reactive Protein Apheresis in COVID (CACOV) Registry

“…These secondary autoimmune reactions may be causally linked to CRP. CRP, by activating complement and macrophages via Fcγ-receptors [ 2 – 4 , 21 ] and through its direct cytotoxic effects [ 22 , 23 ], can cause an excessive autoimmune reaction of ancient innate immunity and may thus be the central effector molecule in severe SARS-CoV-2-induced pneumonia and subsequent multiple organ failure. Based on this hypothesis, selective extracorporeal CRP apheresis may indeed be the therapy of choice to avoid severe courses of COVID-19 [ 16 , 18 – 19 ].…”

Immunoassay for quantification of antigen-specific IgG fucosylation

“…C-terminally biotinylated human FcγRIIIa-V158 was produced using the genetic sequence encoding for the extracellular domain of the receptor with the addition of a C-terminal tail containing polyhistidine (10xHis)-tag and an Avi-Tag (GLNDIFEAQKIEWHE). The DNA sequence was codon-optimized using GeneArt Tools (Invitrogen) as described by Temming et al 43 and cloned in the pcDNA3.1 mammalian expression vector. The receptor was produced in HEK293 Freestyle cells as described previously.…”

Neuronal C-Reactive Protein Mediates Neuropathic Pain by Activating Nociceptive FcγRI-Coupled Signaling

“…CRP is a member of the pentraxin family, a ligand for Fc receptors on phagocytes and a major acute phase protein in tissue damage and inflammation 23,42,43 . CRP is unanimously regarded as an inflammatory biomarker associated with depression, schizophrenia, posttraumatic stress disorder and autism [44][45][46][47][48] .…”