Fcγ Receptors in Solid Organ Transplantation

Abstract

In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (FcγRs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by FcγRs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.

Keywords: Antibodies; Antibody-mediated rejection; Fcγ receptors; IgG; Infection; Single nucleotide polymorphisms.

Fig. 1

Human Fcγ receptors. a FcγRs in antibody-mediated rejection. DSA deposition within allografts can stimulate numerous pro-inflammatory mechanisms, including the direct activation of graft endothelium (i), complement activation via the classical pathway (ii), and the activation of FcγR-expressing immune cells. b Human FcγRs family members differ in IgG affinity, cellular distribution and signalling mechanisms. There are five activating FcγRs that signal via immunoreceptor tyrosine-based activation motifs (ITAM), four with low IgG affinity (FcγRIIA, FcγRIIC, FcγRIIIA and FcγRIIIB) and one with high affinity (FcγRI), capable of binding monomeric IgG. There is a single inhibitory receptor, FcγRIIB, with an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM). c Cellular distribution and function of FcγRs—FcγRs are expressed across numerous immune cells implicated in ABMR, and promote cell type-specific immunological mechanisms that could contribute to allograft rejection, including endothelial adhesion, ADCC, pro-inflammatory cytokine production and ROS production

Fig. 2

Variation in activating and inhibitory FcγR expression and IgG binding affinity alters inflammation, responses to infection and antibody production. SNPs in human FCGR genes that lead to higher affinity of activating FcγR for IgG (FcγRIIA-131H, FcγRIIIA-158V) or reduced inhibitory receptor function (FcγRIIB-232T) result in an increased A/I ratio. In the presence of deposited alloantibody, this can drive allograft inflammation through ADCC, cytokine release, and immune cell adhesion, as well as by lowering the threshold for B cell activation and survival in the periphery. However, a high A/I ratio may also promote DSA clearance by mononuclear phagocytes, contributing to the resolution of inflammation and enhance resistance to secondary complications, such as infection and malignancy