The Role of Fc Gamma Receptors in Antibody-Mediated Rejection of Kidney Transplants

Abstract

For the past decades, complement activation and complement-mediated destruction of allograft cells were considered to play a central role in anti-HLA antibody-mediated rejection (AMR) of kidney transplants. However, also complement-independent mechanisms are relevant in the downstream immune activation induced by donor-specific antibodies, such as Fc-gamma receptor (FcγR)-mediated direct cellular activation. This article reviews the literature regarding FcγR involvement in AMR, and the potential contribution of FcγR gene polymorphisms to the risk for antibody mediated rejection of kidney transplants. There is large heterogeneity between the studies, both in the definition of the clinical phenotypes and in the technical aspects. The study populations were generally quite small, except for two larger study cohorts, which obviates drawing firm conclusions regarding the associations between AMR and specific FcγR polymorphisms. Although FcγR are central in the pathophysiology of AMR, it remains difficult to identify genetic risk factors for AMR in the recipient's genome, independent of clinical risk factors, independent of the donor-recipient genetic mismatch, and in the presence of powerful immunosuppressive agents. There is a need for larger, multi-center studies with standardised methods and endpoints to identify potentially relevant FcγR gene polymorphisms that represent an increased risk for AMR after kidney transplantation.

Keywords: AMR; FcγR; FcγR polymorphism; antibody-mediated rejection; kidney transplant; renal transplantation.

FIGURE 1

Cellular distribution and function of FcγRs [Adapted from Castro-Dopico et al. (41)]. Multiple immune cells are implicated in AMR and express FcγRs. By promoting cell-type-specific immunological mechanisms they contribute to allograft rejection. B-cells only contain the inhibitory FcγRIIB, which is why they lead to BCR inhibition and apoptosis. NK-cells only express activating FcγRs which is why they only lead to activation of immunological mechanisms such as ADCC and cytokine production. Dendritic cells, macrophages and monocytes contain both activating and inhibitory FcγRs. ADCC, antibody-dependent cellular cytotoxicity; ROS, reactive oxygen species; NET, neutrophil extracellular traps; BCR, B-cell receptor.