Association of HLA-A and Non-Classical HLA Class I Alleles.

Antony Nicodemus Antoniou,Federico Carlini,Christophe Picard,Virginia Ferreira,Julie Di Cristofaro,Jean-François Eliaou,Céline René,Audrey Tous,Stéphane Buhler,Jacques Chiaroni

doi:10.1371/journal.pone.0163570

Abstract

The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region.

Highlights

A complete Human Leukocyte Antigen (HLA) match is associated with better long term survival in transplant patients, the effects of HLA-A, -B and -DRB1 matching are unequal and depend upon the organ being transplanted
The HLA-A molecule displays specific features compared to HLA-B that could account for its particular role: HLA-A and HLA-B alleles carry an unpaired cysteine at different positions of the cytoplasmic tail domain, which is reported to be involved in recycling, targeting for degradation and influencing recognition by Natural Killer cells (NK) receptors as well as in the formation of fully folded Major Histocompatibility Complex (MHC) class I dimers in exosomes [7]
A new HLA-H allele (HÃ02:04new) was identified at a frequency of 8.7% in this study, defined by a silent G>A substitution at position 368 compared to the IMGT Genomic DNA (gDNA) reference for HÃ02:04

Summary

Introduction

A complete Human Leukocyte Antigen (HLA) match is associated with better long term survival in transplant patients, the effects of HLA-A, -B and -DRB1 matching are unequal and depend upon the organ being transplanted. HLA-A mismatches were found to have less influence on kidney allografts than HLA-B mismatches [1] This difference could reflect the higher number of HLA-B alleles compared to HLA-A and/or the cytotoxic T-cell allo-repertoire for HLA-A and -B antigens, as lower frequencies of Cytotoxic T-Lymphocyte precursor (CTLp) are found for HLA-A mismatches than for HLA-B mismatches [2, 3]. In Lung Transplantation (LTx), the risk of Bronchiolitis Obliterans Syndrome only increased in the presence of two HLA-A mismatches, not for 0 or 1 mismatch or for HLA-B or -DR mismatches [6] These data support the hypothesis that HLA-A mismatching leads to a particular immunological situation in organ transplantation compared to other loci. The HLA-A locus on chromosome 6 is surrounded by HLA class Ib (non-classical) genes: HLA-E (at the centromeric end), HLA-G, -H and HLA-F (at the telomeric end)

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