Human Neutrophil Fcγ Receptors Initiate and Play Specialized Nonredundant Roles in Antibody-Mediated Inflammatory Diseases

Abstract

Inflammation mediated by antibody-antigen complexes contributes to autoimmune diseases. Mice deficient in the common Fcgamma-chain are protected from IgG-mediated glomerulonephritis and the reverse passive Arthus (RPA) reaction and FcR-bearing macrophages, and mast cells have been assigned primary roles in these processes. Here we demonstrate that neutrophil-selective transgenic expression of the two uniquely human neutrophil Fc gamma receptors (FcgammaRs), FcgammaRIIA and FcgammaRIIIB, in Fcgamma-chain-deficient mice restored susceptibility to progressive glomerulonephritis and the cutaneous RPA reaction. FcgammaRIIIB and FcgammaRIIA mediated neutrophil accumulation, whereas FcgammaRIIA alone promoted organ injury. In a model of soluble immune complexes deposited within the vasculature, FcgammaRIIIB was responsible for neutrophil slow rolling and adhesion whereas in the cremaster RPA, induced by both vascular and tissue soluble immune complexes, FcgammaRIIA predominated. Thus, human FcgammaRs on neutrophils serve as molecular links between antibody and immunological disease, with FcgammaRIIA promoting tissue injury and FcgammaRIIIB and FcgammaRIIA displaying specialized context-dependent functions in neutrophil recruitment.

Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab

“…Activation of CD32A then cooperates with CD16B to mediate phagocytosis. 27,29,30,68 The data presented are important because they suggest that phagocytosis by PMNs may be an additional mechanism of action of CD20 antibodies in patients, and that it can be significantly enhanced by glycoengineering, particularly in physiological conditions. This is particularly significant in view of the abundance of these cells in the circulation and the facility with which they can be mobilized into the blood and tissues.…”

“…CD16B is known to be involved in PMN activation and immune complex-mediated phagocytosis by neutrophils. [26][27][28][29] Still little is known about the role of PMNs in the therapeutic activity of IgG antibodies. 30 Results about their role in vivo using murine models are still controversial.…”

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

“…15 hFc␥RIIIB has been recently reported to play specialized roles on neutrophils, different from those played by hFc␥RIIA. 2 Creating mouse models expressing multiple or, preferably, all hFcRs (with the same expression pattern as that found in humans) may be a necessity to comprehend their role in disease induction/modulation, and thereby of the cells expressing them. The recent report by Smith et al using a model of mice expressing multiple hFc␥Rs 72 opens the way to performing these analyses.…”

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

“…FcγRIIA has an immunotyrosine activating motif (ITAM) in its cytoplasmic domain, and is a mediator of destructive antibody-based inflammation in autoimmunity, while FcγRIIIB is a glycosylphosphatidylinositol-linked (GPI-linked) receptor whose physiological functions remain to be fully elucidated (8). Generation of mice expressing either of these human FcγRs selectively on neutrophils of γ -/-mice lacking their endogenous activating FcγRs allowed us to assess the role of the human FcγRs, and specifically FcγRs on neutrophils, in disease pathogenesis (9). The surface expression level of FcγRIIA on transgenic murine neutrophils and human neutrophils was comparable, while the surface expression level of FcγRIIIB on transgenic neutrophils was similar to that of FcγRIIA but lower than that on human neutrophils (9).…”

“…Generation of mice expressing either of these human FcγRs selectively on neutrophils of γ -/-mice lacking their endogenous activating FcγRs allowed us to assess the role of the human FcγRs, and specifically FcγRs on neutrophils, in disease pathogenesis (9). The surface expression level of FcγRIIA on transgenic murine neutrophils and human neutrophils was comparable, while the surface expression level of FcγRIIIB on transgenic neutrophils was similar to that of FcγRIIA but lower than that on human neutrophils (9). Neutrophil human FcγRIIA or FcγRIIIB expression restored glomerular neutrophil influx in γ -/-mice following crescentic anti-GBM-induced nephritis.…”