FCGR3A and FCGR2A Genotypes Differentially Impact Allograft Rejection and Patients' Survival After Lung Transplant

Abstract

Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37–9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08–3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.

NK cells in antibody‐mediated rejection – Key effector cells in microvascular graft damage

“…Thus, kidney‐transplant patients expressing FcgR3A V158 high‐affinity genotypes demonstrate more robust ABMR responses. Similar clinical effects have also been described in heart transplantation where patients with high‐affinity FcgR3A more commonly progressed to chronic allograft vasculopathy (Paul et al., 2018), and in lung transplants where high‐affinity FcgR3A conveyed a higher risk for acute rejection (Paul et al., 2019). These studies suggest that NK cells with an enhanced ability to bind to anti‐HLA increase the intensity of the ABMR process irrespective of organ type.…”

The FCGR3A 158 V/V-genotype is associated with decreased survival of renal allografts with chronic active antibody-mediated rejection

“…In accordance with these findings we previously showed increased CD16 expression by circulating NK cells in cases with c-aABMR 11 . This FCGR3A polymorphism was also found to stratify patients at risk for acute rejection in the first 3 months after transplantation, in a cohort of lung transplant recipients 39 . They also observed the V/V-genotype to behave different from F/V-genotype, i.e.…”

Deep Learning Reveals Key Immunosuppression Genes and Distinct Immunotypes in Periodontitis

“…Previous studies have reported single-nucleotide polymorphisms (SNPs) of FCGR3A (rs396991 and rs4455090) were correlated with periodontitis and might impact susceptibility to periodontitis (Kobayashi et al, 2001;Chai et al, 2010). Besides, FCGR3A polymorphism and the allele rs396991 was identified as an independent susceptibility marker of allograft rejection in patients after organ transplants, highly responsive to natural killer (NK) cells (Paul et al, 2019). FOS was also identified as a significant TF in the study.…”