Cutting Edge: The Murine High-Affinity IgG Receptor FcγRIV Is Sufficient for Autoantibody-Induced Arthritis

Abstract

K/BxN serum-induced passive arthritis was reported to depend on the activation of mast cells, triggered by the activating IgG receptor FcγRIIIA, when engaged by IgG1 autoantibodies present in K/BxN serum. This view is challenged by the fact that FcγRIIIA-deficient mice still develop K/BxN arthritis and because FcγRIIIA is the only activating IgG receptor expressed by mast cells. We investigated the contribution of IgG receptors, IgG subclasses, and cells in K/BxN arthritis. We found that the activating IgG2 receptor FcγRIV, expressed only by monocytes/macrophages and neutrophils, was sufficient to induce disease. K/BxN arthritis occurred not only in mast cell-deficient Wsh mice, but also in mice whose mast cells express no activating IgG receptors. We propose that at least two autoantibody isotypes, IgG1 and IgG2, and two activating IgG receptors, FcγRIIIA and FcγRIV, contribute to K/BxN arthritis, which requires at least two cell types other than mast cells, monocytes/macrophages, and neutrophils.

Properties of mouse and human IgG receptors and their contribution to disease models

“…Using "Fc␥RIV-only" mice we reported that Fc␥RIV induced arthritic inflammation in the passive K/BxN model of arthritis 66 in the presence of IgG2-immune complexes. 41 These results are in agreement with those obtained when inducing collagen-induced arthritis in 3KO mice. 65 "Fc␥RIV-only" mice also developed lung inflammation after activation of alveolar macrophages in the presence of IgE-immune complexes, 26 and experimental thrombocytopenia induced by antiplatelet mouse IgG2a mAbs.…”

“…38 Notably, human FcRn has no affinity for mouse IgG1, but its low affinity for mouse IgG2a and IgG2b 39 is sufficient to restore a mouse IgG2-dependent autoimmune arthritis in a transgenic mouse model (mice deficient for FcRn and transgenic for hFcRn). 40,41 Major differences between human Fc␥R expression patterns and that of their mouse homolog also exist: (1) the expression of mouse, but not human, Fc␥RI is restricted to monocyte-derived DCs; (2) the expression of human, but not mouse, Fc␥RIIB is mainly restricted to B cells and basophils; (3) the expression of human Fc␥RIIIA, but not mouse Fc␥RIII, is restricted to NK cells and monocytes/ macrophages; (4) Fc␥RIV exist in mice but not in humans 24,25 ; and (5) Fc␥RIIA, Fc␥RIIC, and Fc␥RIIIB exist in humans but not in mice. 12 Fc␥R homologs between humans and mice may thus be defined based on expression and ligand binding, rather than on amino acid similarity.…”

“…38 Furthermore, using Fc␥RI/IIB/III Fc⑀RI/II FcRnsextuple knockout (6KO) mice, we have reported that Fc␥RIV-dependent induction of K/BxN arthritis requires FcRn, probably to transport pathogenic IgG2 antibodies to the joints and to protect these antibodies from degradation. 41 These analyses using "Fc␥RIV-only" mice, have not yet been performed using "Fc␥RI-only" or "Fc␥RIII-only" mice to evaluate their contribution to the induction of inflammatory models. "Fc␥RIII-only" mice may not be particularly worthy to generate because Fc␥RIII is the only activating IgG receptor that binds IgG1.…”

Mouse and human neutrophils induce anaphylaxis

“…A nonlethal PSA could also be observed in Rag2 -/-5KO mice injected with IC made of GPI and K/BxN serum (GPI/anti-GPIinduced PSA) ( Figure 3E), which contains polyclonal IgG1 and IgG2 anti-GPI antibodies (25,26). Neutrophil depletion abolished this GPI/anti-GPI-induced PSA in Rag2 -/-5KO mice ( Figure 3F).…”

Cutting Edge: FcγRIII (CD16) and FcγRI (CD64) Are Responsible for Anti-Glycoprotein 75 Monoclonal Antibody TA99 Therapy for Experimental Metastatic B16 Melanoma

“…Various FcgRIV-dependent disease models were abolished using the same dose of the same batch of anti-FcgRIV mAbs (data not shown and Refs. 8,14), indicating that FcgRIV was efficiently and systemically blocked in vivo. Notably, this mAb does not, by itself, induce FcgRIV-mediated cell activation in vitro (9).…”