In vivo effector functions of high-affinity mouse IgG receptor FcγRI in disease and therapy models

Abstract

Two activating mouse IgG receptors (FcγRs) have the ability to bind monomeric IgG, the high-affinity mouse FcγRI and FcγRIV. Despite high circulating levels of IgG, reports using FcγRI or FcγRIV mice or FcγRIV-blocking antibodies implicate these receptors in IgG-induced disease severity or therapeutic Ab efficacy. From these studies, however, one cannot conclude on the effector capabilities of a given receptor, because different activating FcγRs possess redundant properties in vivo, and cooperation between FcγRs may occur, or priming phenomena. To help resolve these uncertainties, we used mice expressing only FcγRI to determine its intrinsic properties in vivo. FcγRI mice were sensitive to IgG-induced autoimmune thrombocytopenia and anti-CD20 and anti-tumour immunotherapy, but resistant to IgG-induced autoimmune arthritis, anaphylaxis and airway inflammation. Our results show that the in vivo roles of FcγRI are more restricted than initially reported using FcγRI mice, but confirm effector capabilities for this high-affinity IgG receptor in vivo.

Tissue-specific expression of IgG receptors by human macrophages ex vivo

“…Since the IgG concentration in alveoli is much lower than in plasma, we hypothesize that FcγRI is partially unoccupied, making it a true high-affinity receptor for IgG-opsonized microbial agents. This is in line with recent publications that show that FcγRI is not fully saturated by IgG, neither in mice [32] nor in humans [33], making it readily available for immune complexes.…”

Natural-Killer-like B Cells Display the Phenotypic and Functional Characteristics of Conventional B Cells

“…This suggested that the binding of the anti- NK1.1 and anti-NKp46 mAbs was not mediated by FcγRIIB on B cells. This conclusion was corroborated with the use of FcγRIIB-deficient mice and FcγR-deficient mice lacking FcγRI, FcγRIIB, FcγRIII, and FcγRIV (Gillis et al, 2017). The frequencies of CD19 + cells that co-stained with anti-NK1.1 (CD19 + NK1.1 + C57BL/6 mice: 0.045 ± 0.002; FcγRIIB-deficient mice: 0.06 ± 0.003; FcγR-deficient mice: 0.06 ± 0.002; mean ± SEM) or anti-NKp46 (data not shown) were similar between the mutant strains and the wild-type strain.…”

IL-4 controls activated neutrophil FcγR2b expression and migration into inflamed joints

“…Inflammation triggered by autoantibodies depends on several processes, which are initiated by the formation of antibody-antigen ICs (41). In the K/BxN serum transfer model, IgG IC-mediated cross-linking of activating FcγRs on neutrophils is essential for the development of joint inflammation (8,10,42), which in turn can be suppressed by the inhibitory FcγR2b (43,44). Mouse neutrophils have a clear basal expression of activating FcγR3 (CD16) and FcγR4 (CD16-2) (SI Appendix, Fig.…”