Abstract
Aim Chronic lung allograft dysfunction (CLAD) is a major obstacle in the long-term success of lung transplantation. Recipient natural killer (NK) cells substantially influence the immune response to the allografts. NK cells can respond to allograft via three distinct mechanisms: missing-self, induced-self, and antibody dependent cell cytotoxicity (ADCC). NK cell ADCC is regulated by CD16 (FcRIIIa), a low-affinity cell-surface receptor for the Fc portion of IgG antibodies. CD16 is encoded byFCGR3A, which carries a functional single nucleotide polymorphism that substitutes phenylalanine (F) for valine (V) at residue 158. Despite identical levels of CD16 expression, 158V homozygotes have higher binding affinity for IgG compared with 158F homozygotes. We hypothesized that the recipients carrying high binding FCGR3A-158V variants would have worse outcome compared to the weakly binding FCGR3A-158F carriers. Methods We developed a melting curve based q-PCR method to analyze FCGR3A-V158F variants in a cohort of 252 lung transplant recipients. CLAD was determined by date of FEV1 or FVC drop to Results Numbers of recipients with FCGR3A-158 FF, VV, and VF genotypes are 107 (42%), 30 (12%) and 115 (46%), respectively. CLAD-free survival was shorter in the 158VV group (3.0 median years) than the 158FF group (6.0 median years, HR 1.6, 95% CI 1.0-2.7, P = 0.05) and VF group (5.3 median years, ns) (Figure). Conclusions We observed an association between theFCGR3A-158 VV genotype and worse CLAD-free survival. Recipients with this genotype would presumably have more NK cell-mediated ADCC activity and could be at increased risk of graft dysfunction in the context of donor-specific antibodies. Mechanistic studies and validation in other cohorts will be needed to determine the significance of this finding to lung transplant outcomes. Download : Download high-res image (64KB) Download : Download full-size image
Published Version
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