Human natural killer (NK) cells are essential for controlling infection, cancer and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B and -C genes, we show that the Chinese Southern Han are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the Chinese Southern Han KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B specific receptors. In all these characteristics, the Chinese Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity and effector strength, likely augmenting resistance to endemic viral infections.
BackgroundEnd-Stage Renal Disease (ESRD) is a worldwide public health problem. Currently, many genome-wide association studies have suggested a potential association between human leukocyte antigen (HLA) and ESRD by uncovering a causal relationship between HLA and glomerulonephritis. However, previous studies, which investigated the HLA polymorphism and its association with ESRD, were performed with the modest data sets and thus might be limited. On the other hand, few researches were conducted to tackle the Chinese population with ESRD. Therefore, this study aims to detect the susceptibilities of HLA polymorphism to ESRD within the Cantonese community, a representative southern population of China.MethodsFrom the same region, 4541 ESRD patients who were waiting for kidney transplantation and 3744 healthy volunteer bone marrow donors (controls) were randomly chosen for this study. Polymerase chain reaction-sequence specific primer method was used to analyze the HLA polymorphisms (including HLA-A, HLA-B and HLA-DRB1 loci) in both ESRD patients and controls. The frequencies of alleles at these loci and haplotypes were compared between ESRD patients and controls.ResultsA total of 88 distinct HLA alleles and 1361 HLA A-B-DRB1 haplotypes were detected. The frequencies of five alleles, HLA-A*24, HLA-B*55, HLA-B*54, HLA-B*40(60), HLA-DRB1*04, and one haplotype (HLA-A*11-B*27-DRB1*04) in ESRD patients are significantly higher than those in the controls, respectively.ConclusionsFive HLA alleles and one haplotype at the HLA-A, HLA-B and HLA-DRB1 loci appear to be associated with ESRD within the Cantonese population.
Interactions of human natural killer (NK) cell inhibitory receptors with polymorphic HLA-A, -B and -C molecules educate NK cells for immune surveillance against tumor cells. The
KIR A
haplotype encodes a distinctive set of HLA-specific NK cell inhibiting receptors having strong influence on immunity. We observed higher frequency of
KIR A
homozygosity among 745 healthy Chinese Southern Han than 836 adult patients representing three types of leukemia: ALL (OR = 0.68, 95% CI = 0.52–0.89,
p
= 0.004), AML (OR = 0.76, 95% CI = 0.59–0.98,
p
= 0.034), and CML (OR = 0.72 95% CI = 0.51–1.0, ns). We observed the same trend for NHL (OR = 0.47 95% CI = 0.26–0.88
p
= 0.017). For ALL, the protective effect of the
KIR AA
genotype was greater in the presence of KIR ligands C1 (Pc = 0.01) and Bw4 (Pc = 0.001), which are tightly linked in East Asians. By contrast, the C2 ligand strengthened protection from CML (Pc = 0.004). NK cells isolated from
KIR AA
individuals were significantly more cytotoxic toward leukemic cells than those from other
KIR
genotypes (
p
< 0.0001). These data suggest KIR allotypes encoded by East Asian
KIR A
haplotypes are strongly inhibitory, arming NK cells to respond to leukemogenic cells having altered HLA expression. Thus, the study of populations with distinct
KIR
and
HLA
distributions enlightens understanding of immune mechanisms that significantly impact leukemia pathogenesis.
Two novel HLA-A alleles differing from their closest related alleles by nucleotide exchanges in introns, A*29:02:01:02 and A*68:01:01:02, were identified.
This study used long-range polymerase chain reaction to sequence 4.5 or 4.3 kb of genomic DNA covering human leukocyte antigen C (HLA-C) and its flanks in 45 Chinese Han subjects to better characterize variation in the gene in a single population. Sequences of 35 HLA-C alleles were obtained from the population, including major alleles of 13 lineages of HLA-C. Four novel alleles, C*03:04:01:02, C*04:01:01:03, C*08:22, and C*17:01:01:02, were identified, and complete full-length sequences of 18 HLA-C alleles were obtained for the first time. All sequences herein reported also represent extensions through the promoter region and the 3'-untranslated region. Fourteen 5'-nucleotide sequences and 14 3'-nucleotide sequences were detected outside the coding region. In total, 316 single-nucleotide polymorphisms unequally distributed in HLA-C subregions were observed. In addition to exons 2 and 3, nucleotide variability was found to be particularly high in exon 5, which encodes the transmembrane region. The differentiation of the C*07 and C*17 lineages in this region accounts for the high variability. The congruence of phylogeny across most regions of the gene suggests that gene conversion or recombination has not markedly influenced divergence between lineages in the evolution of HLA-C.
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