Susceptibility to pulmonary tuberculosis in Iranian individuals is not affected by compound KIR/HLA genotype.

Natural killer (NK) cells have distinctive functional capacities that are likely to contribute both to innate and adaptive immunity to Mycobacterium tuberculosis. Killer cell immunoglobulin-like receptors (KIR) and their ligands, i.e. human leukocyte antigen (HLA) class I molecules contribute partly in regulation of NK cell activity. In this study, the impact of compound KIR/HLA genotype on susceptibility to pulmonary tuberculosis (TB) has been evaluated in Iranian individuals. A total of 107 TB patients and 100 matched healthy controls were genotyped for 17 KIR genes and their three major HLA class I ligand groups (-C1, -C2 and -Bw4: -B Bw4(Ile80) , -B Bw4(Thr80) and -A Bw4) by a polymerase chain reaction-sequence-specific primers assay. Various analyses including distribution of KIR and HLA ligand genes and genotypes, frequency of inhibitory and activating KIR+HLA combinations and compound genotype status regarding balance of inhibitory and activating components showed no significant difference between patient and control groups. These findings may suggest that compound KIR/HLA genotype has no major impact on limiting Mycobacterium tuberculosis infection.

KIR3DL1+HLA-B Bw4Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population.

Contribution of killer cell immunoglobulin-like receptors (KIR) and their human leucocyte antigen (HLA) class I ligands in the pathogenesis of autoimmune diseases has been shown in several studies. In this study, the possible association of KIR genes, their known HLA ligands and compound KIR/HLA genotypes with ankylosing spondylitis (AS) was assessed. Combined KIR/HLA ligand genotyping was performed by a polymerase chain reaction-sequence-specific primers assay in 35 Iranian patients with AS, and genotypes were compared to those in 200 healthy individuals. The frequencies of telomeric cluster genes KIR2DL5A, KIR2DS1 and KIR3DS1 were significantly increased in AS patient group (P(c) = 0.0082, P(c) = 0.0195 and P(c) = 0.0328, respectively). Conversely, HLA-Bw4 ligand (the presence of one or more -B Bw4(Ile80) , -B Bw4(Thr80) and -A Bw4 epitopes) (P(c) = 0.0004) and HLA-B Bw4(Ile80) (P(c) = 0.053) were less frequent in these patients. Meanwhile, compound KIR/HLA genotype analyses revealed lower frequency of KIR3DL1+HLA-B Bw4(Ile80) (P(c) = 0.0343) and higher frequency of KIR2DS1+HLA-C2 (P(c) = 0.0308) combinations in patients with AS than in controls. In addition, the genotypes iKIR+HLA > aKIR+HLA (P(c) = .0308) and iKIR+HLA > aKIR (P(c) = 0.0258) were statistically less common, and genotypes iKIR+HLA = aKIR+HLA (P(c) = 0.0081) and iKIR+HLA < aKIR (P(c) = 0.077) were more common in patient group. Our findings suggest a role for excessive or inappropriate NK cell activation through 'KIR/HLA' system in AS disease.

Compound KIR-HLA genotype analyses in the Iranian population by a novel PCR-SSP assay.

Natural killer (NK) cells eliminate infected and transformed cells while still are self-tolerant. Interactions of the independently segregating Killer cell immunoglobulin-like receptors (KIR) and human leucocyte antigens (HLA) loci play a critical role in NK cell regulation. Different compound KIR-HLA genotypes can impart different thresholds of activation to the NK-cell repertoire and such genotypic variation has been found to confer altered risk in a number of human diseases including viral infections, autoimmune disorders, reproduction abnormalities and cancers. In this study, we presented a novel combined KIR-HLA polymerase chain reaction-sequence-specific primers genotyping assay for simultaneous determination of KIR genes and their three major HLA class I ligand groups (C1, C2, and Bw4). Moreover, known inhibitory and activating KIR + HLA (iKIR + HLA: 2DL2/3 + C1, 2DL1 + C2, 3DL1 + Bw4; and aKIR + HLA: 2DS2 + C1, 2DS1 + C2, 3DS1 + Bw4) combinations as well as co-inheritance of aKIR genes and iKIR + HLA pairs were analysed in a total of 200 unrelated healthy Iranian individuals. All tested subjects had at least one of the three iKIR + HLA pairs and the frequencies of various inhibitory combinations in the study group were: 31.5%, three iKIR + HLA pairs, 53.5%, two iKIR + HLA pairs, and 15%, 0ne iKIR + HLA pair. Furthermore, we revealed that majority of Iranians (69%) carry compound genotypes with greater number of inhibitory pairings than activating combinations (iKIR + HLA > aKIR + HLA). Conversely, iKIR + HLA < aKIR (45%) was dominant genotype in the study group. We conclude that selective evolutionary pressure has propensity to maintain KIR-HLA genotypes with more inhibitory combinations to guarantee self-tolerance. In contrast, existence of activating KIR genes without normal endogenous ligands, potentially arms the NK population for competent immunosurveillance and stronger defense against infections.

Distribution of KIR genes in the Iranian population.

Killer-cell immunoglobulin-like receptors (KIR) are a family of inhibitory and activating receptors that are expressed mainly by natural killer cells. The KIR gene family is highly polymorphic, and its genomic diversity is achieved through differences in gene content as well as allelic polymorphism. The number of KIR loci has been reported to be various among individuals and therefore resulting in different KIR haplotypes. This study represents the first report on the distribution of 17 presently defined KIR genes and pseudogenes in the Iranian population. In our study, 200 unrelated healthy individuals were KIR typed by a novel polymerase chain reaction-sequence-specific primers genotyping assay, and Iranian KIR genes distribution was compared with other ethnic groups. Over all, twenty-six different genotype profiles were found in our population and all KIR genes were observed. The most frequent non-framework KIR genes detected in our population were KIR2DL1 (96.5%), KIR3DL1 (91.5%), KIR2DS4 (91.5%) and the pseudogene KIR2DP1 (96.5%). The most commonly observed KIR genotype in Iranian population with a frequency of 27.5% consisted of KIR2DL1, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3 and KIR2DS4 genes and the pseudogenes KIR2DP1 and KIR3DP1, which was compatible with a homozygote group-A haplotype. In addition, we found a new genotype (KIR2DL2, KIR2DL4, KIR2DL5, KIR3DL2, KIR3DL3, KIR2DS2, KIR2DS3, KIR2DS5, KIR3DS1 and KIR3DP1) in our samples. The results show that distribution of KIR genes in the Iranian population has common general features with the Caucasian populations studied before but still with unique, decreased or increased frequencies of several loci.