Increased CD16 expression on NK cells is indicative of antibody-dependent cell-mediated cytotoxicity in chronic-active antibody-mediated rejection

Sablik, Kasia A.; Litjens, Nicolle H.R.; Klepper, Mariska; Betjes, M.

doi:10.1016/j.trim.2019.02.005

Cited by 29 publications

(19 citation statements)

References 44 publications

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“…Interactions between endothelial‐bound HLA IgG antibodies and myeloid and NK cell FcγRs can facilitate tethering and adhesion of leukocytes. Endothelial cells exposed to HLA antibodies produce cytokines and growth factors that can signal in an autocrine and paracrine manner and promote inflammation 58,59 . Data from in vitro experimental assays indicate that FCGR2A polymorphisms on monocytes govern interactions with distinct HLA IgG subclasses 60 .…”

Section: Attributes Of Hla Antibodiesmentioning

confidence: 99%

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Tambur

Campbell

Chong

et al. 2020

American Journal of Transplantation

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Section: Attributes Of Hla Antibodiesmentioning

confidence: 99%

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Tambur

Campbell

Chong

et al. 2020

American Journal of Transplantation

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“…Together with enrichment of other NK-associated transcripts this supported the role of antibody-dependent cellular cytotoxicity (ADCC) in chronic rejecting renal allografts [8][9][10] . In addition, increased expression of the FCGR3A (known as CD16) was noted on circulating NK cells of kidney transplant recipients with a diagnosis of c-aABMR 11 and markers that re ect CD16-dependent activation of circulating NK cells may identify heart transplant recipients at risk for developing cardiac allograft vasculopathy 12 .…”

Section: Introductionmentioning

confidence: 99%

The FCGR3A 158 V/V-Genotype is Associated With Decreased Survival of Renal Allografts With Chronic Active Antibody-Mediated Rejection

Litjens

Peeters

Gestel

et al. 2021

Preprint

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Natural killer (NK) cells express the Fc-receptor CD16 (FCGR3A) and could therefore mediate renal endothelial cell damage in cases of chronic-active antibody mediated rejection (c-aABMR). The V/V-genotype of the FCGR3A 158 F/V polymorphism is associated with increased CD16 expression and cytotoxicity by NK cells. This study evaluated whether this genotype is associated with the diagnosis of c-aABMR and renal allograft loss.The distribution of the FGCR3A 158 F/V-genotypes was not different for c-aABMR cases (N=133) compared to control kidney transplant recipients (N=116, p=0.65). The V-allele was associated with increased median fluorescence intensity (MFI) of CD16 by NK cells (MFI 3.5x104 versus 1.3x104 for V/V and F/F-genotype, P<0.001). Increased expression of CD16 correlated with CD16-dependent degranulation of NK cells (R=0.4; P=0.02). Moreover, the V/V-genotype was significantly associated with a higher glomerulitis score and an independent risk factor (HR 1.98; P=0.04) for decreased allograft survival. Death-censored graft survival in c-aABMR cases at 3 years follow-up was 33% for the FCGR3A 158 V/V-genotype versus 62% for the F/F-genotype. In conclusion, the FCGR3A V/V-genotype increases CD16-mediated NK cell cytotoxicity and is associated with a higher glomerulitis score and decreased graft survival in cases with c-aABMR.

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“…The intensity of host antibody dependent cell cytotoxicity (ADCC) is known to be conditioned by the capacity of NK effector cells to form conjugates with antibody-coated allogeneic cells, which is in part influenced by the FCGR3A [158V/F] genotype (45–47). We and others have recently shown that polymorphic variation in the FCGR3A genes is also likely to affect the pathogenic effects of IgG alloantibodies by controlling the level of the CD16 dependent recipient's immunological cytotoxic responses to allogeneic donor cells exposed to chronic alloantibody threat (35, 48–51).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Increased CD16 expression on NK cells is indicative of antibody-dependent cell-mediated cytotoxicity in chronic-active antibody-mediated rejection

Cited by 29 publications

References 44 publications

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

The FCGR3A 158 V/V-Genotype is Associated With Decreased Survival of Renal Allografts With Chronic Active Antibody-Mediated Rejection

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

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