Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis

Abstract

Summary Beyond their prominent role in hemostasis and thrombosis, platelets are increasingly recognized as having immunologic functions. Supporting this, human platelets express FcγRIIA (CD32a), a low‐affinity Fc receptor (FcR) for the constant region of IgG that recognizes immune complexes (ICs) and IgG‐opsonized cells with high avidity. In leukocytes, FcγRIIA engagement initiates strong effector functions that are key for immune and inflammatory responses, including cytokine release, antibody‐dependent cell‐mediated killing of pathogens, and internalization of ICs. However, the physiologic relevance of platelet‐expressed FcγRIIA has received little attention in previous reviews on FcRs. This article summarizes and discusses the available information on human platelet FcγRIIA. The importance of this receptor in heparin‐induced thrombocytopenia, a prothrombotic adverse drug effect, is well documented. However, studies demonstrating platelet activation by IgG‐opsonized bacteria point to the physiologic relevance of platelet FcγRIIA in immunity. In this context, platelet activation and secretion may facilitate both a direct antimicrobial function of platelets and crosstalk with other immune cells. Additionally, a role for platelet FcγRIIA in IgG‐independent hemostasis and physiologic thrombosis, by means of amplifying integrin αIIbβ3 outside‐in signaling, has also been proposed. Nonetheless, the thrombotic complications found in some infective and autoimmune diseases may result from unbalanced FcγRIIA‐mediated platelet aggregation. Moreover, FcγRIIA is not expressed in mice, and thrombocytopenia and/or thrombotic events found after drug administration can only be recapitulated by the use of human FcγRIIA‐transgenic mice. Altogether, the available data support a functional role for platelet FcγRIIA in health and disease, and emphasize the need for further investigation of this receptor.

TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice

“…Bacteria can induce platelet activation and immune responses via FcγRIIA and integrins. 6,7 The question of whether TULA-2 mediates platelet-bacteria interaction necessitates further exploration. TULA-2 might prevent overactivation of platelets and amplification of inflammatory response in the presence of bacteria as seen in sepsis given its role in quenching FcγRIIA overstimulation.…”

“…Among platelet-activating receptors, Fc receptor for IgG IIA (FcγRIIA; CD32a), an Fc receptor for the constant region of immunoglobulin G on platelets, is implicated in immune-mediated thrombocytopenia and thrombosis disorders, [1][2][3] internalization of immune complexes, 4 platelet spreading, 5 and inflammatory response and host defense against bacteria. 6,7 The FCGR2A gene, which encodes FcγRIIA in humans, is absent in mice. 1 The FcγRIIA pathway has been demonstrated as a crucial mediator of the heparin-induced thrombocytopenia (HIT), which is a severe adverse effect of heparin treatment.…”

Human platelet activation by Escherichia coli: roles for FcγRIIA and integrin αIIbβ3

“…These mechanisms are diverse and include activation by whole bacteria or their released products [1, 6]. Despite multiple bacterial-strain specific molecular interactions, human platelet FcγRIIA is required for activation by a number of different Gram-positive species [7–15] and might contribute to the thrombotic complications found in infective diseases [15]. FcγRIIA is a low-affinity receptor for the constant region of IgGs that recognizes IgG-coated bacteria or their products through avidity.…”

CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice

“…Similarly, our findings do not explain IV.3-induced passive cutaneous anaphylaxis because the mice used to demonstrate passive cutaneous anaphylaxis possessed mast cells having CD32a as the sole FcgR. 6 Clearly, however, the presence of CD32a on platelets, the immunobiology of which was recently reviewed, 31 fundamentally alters the biology of pathologic reactions to IgG antibodies. Nowhere is this more apparent than in the context of therapeutic mAbs, many of which For personal use only.…”