Abstract
The interaction of major histocompatibility complex class I chain-related protein A (MICA) and its cognate activating receptor natural killer (NK) group 2 member D (NKG2D) receptor plays a significant role in viral immune control. In the context of kidney transplantation (KTx), cytomegalovirus (CMV) frequently causes severe complications. Hypothesizing that functional polymorphisms of the MICA/NKG2D axis might affect antiviral NK and T cell responses to CMV, we explored the association of the MICA-129 Met/Val single nucleotide polymorphism (SNP) (affecting the binding affinity of MICA with the NKG2D receptor), the MICA rs2596538 G/A SNP (influencing MICA transcription), and the NKG2D rs1049174 G/C SNP (determining the cytotoxic potential of effector cells) with the clinical outcome of CMV during the first year after KTx in a cohort of 181 kidney donor-recipients pairs. Univariate analyses identified the donor MICA rs2596538 G allele status as a protective prognostic determinant for CMV disease. In addition to the well-known prognostic factors CMV high-risk sero-status of patients and the application of lymphocyte-depleting drugs, the donor MICA rs2596538 G allele carrier status was confirmed by multivariate analyses as novel-independent factor predicting the development of CMV infection/disease during the first year after KTx. The results of our study emphasize the clinical importance of the MICA/NKG2D axis in CMV control in KTx and point out that the potential MICA transcription in the donor allograft is of clinically relevant importance for CMV immune control in this allogeneic situation. Furthermore, they provide substantial evidence that the donor MICA rs2596538 G allele carrier status is a promising genetic marker predicting CMV viremia after KTx. Thus, in the kidney transplant setting, donor MICA rs2596538 G may help to allow the future development of personal CMV approaches within a genetically predisposed patient cohort.
Highlights
The major histocompatibility complex class I chain-related mole cule A (MICA), belongs to the family of non-Human leukocyte antigen (HLA) molecules and is recognized by its cognate activating natural killer (NK) group 2 member D (NKG2D) receptor, a C-type lectin-like transmembrane protein
The recipient NKG2D rs1049174 G/C allelic frequency was with 65.5% (237 out of 362) for the NKG2D rs1049174 G allele and 34.5% (119 out of 362) for NKG2D rs1049174 C allele being again similar to the corres ponding donor frequencies with 69.0% (250 out of 362) for the NKG2D rs1049174 G allele and NKG2D rs1049174 C allele 31.0% (112 out of 362)
With respect to patient CMV risk status groups, no significant differences were found in the MICA-129 Met/Val, MICA rs2596538 G/A, or NKG2D rs1049174 G/C allelic frequencies between recipients or donors
Summary
The major histocompatibility complex class I chain-related mole cule A (MICA), belongs to the family of non-HLA molecules and is recognized by its cognate activating natural killer (NK) group 2 member D (NKG2D) receptor, a C-type lectin-like transmembrane protein. The genetic variability in coding and noncoding regions of MICA and NKG2D genes affects the efficiency of the antiviral immune surveillance during CMV infections [21,22,23] According to their binding affinity to NKG2D, the 107 currently known allelic MICA variations (https://www.ebi.ac.uk/ ipd/imgt/hla/stats.html) can be stratified into two classes based on the functionally relevant single nucleotide polymorphism (SNP) rs1051792 A > G at position 454 in exon 3 of the MICA gene. We determined if and which allelic MICA and/or NKG2D variations predispose patients to increased risk of CMV replication To this end, we analyzed (i) the MICA-129 Met/Val SNP (affecting the binding affinity of MICA to the NKG2D receptor), (ii) the MICA rs2596538 A/G SNP (influencing MICA expression levels), and (iii) the NKG2D rs1049174 G/C SNP (determining the cytotoxic potential of effector cells) in 181 living-donor kidney transplant pairs and associated the allele status of donor and recipient to occurrence of CMV viremia in the first year. Two-sided p-values of 0.05 or lower were considered statistically significant
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