Association between TNF -308G/A polymorphism and susceptibility to pulmonary tuberculosis in the Lur population of Iran

Objective: To investigate whether tumor necrosis factor-α (TNFα) -238G/A and -308G/A polymorphisms are associated with susceptibility to pulmonary tuberculosis (TB) in the Lur ethnic population of Iran. Methods: TNF polymorphisms genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism method in 100 pulmonary TB patients and 100 healthy controls from the Lur population. Results: The allelic and genotypic frequencies of TNFα -238G/A polymorphism were not significantly different between the pulmonary TB patients and the healthy controls. However, the TNFα -308G/A polymorphism showed a significantly higher frequency of genotype GG in TB subjects compared to healthy controls (94% in the patients vs. 62% in the controls, P = 0.000. 1, odds ratio = 0.104, confidence interval = 0.028-0.382). Moreover, in the TNFα -308G/A polymorphism, a significantly higher frequency of G allele was measured in the patient group compared with the control group (97% in the patient group vs. 81% in the control group, P = 0.000. 1, odds ratio = 0.132, confidence interval = 0.038-0.462). Conclusions: Our findings suggest that TNFα -308G/A polymorphism may increase the susceptibility to pulmonary TB in the Lur population of Iran. Despite TNFα polymorphisms and susceptibility to pulmonary TB, we suggest that more studies with larger sample size are needed in the future. Increasing our understanding of susceptibility risk factors may help to improve current preventive measures and treatment for TB.

Association of KIR3DS1+HLA-B Bw4[Ile80] combination with susceptibility to tuberculosis in Lur population of Iran

Natural killer [NK] cells are the effector cells of innate immunity that respond to infection and tumor. Interactions between killer cell immunoglobulin like receptors [KIR] and human leukocyte antigen [HLA] class I molecules regulate NK cells responses to eliminate infected and transformed cells. To investigate the impact of KIR genes, HLA ligand genes, and KIR-HLA combinations on susceptibility to tuberculosis [TB] in Lur population of Iran. The genomic DNA of 50 patients with TB from Lorestan province of Iran was genotyped for sixteen KIR genes and their five major HLA class I ligands were determined by a polymerase chain reaction-sequence-specific primers [PCR-SSP] assay. The results were compared with those of 200 healthy unrelated Iranian individuals. In Lur population of Iran, a significant decrease in frequency of KIR3DS1 was found in TB patients compared to control group [24% vs. 44.5%, OR=0.394, CI=0.194-0.798, p=0.013]. Also, among the three activating genes that may use HLA class I molecules as their ligands, a significant decrease was shown in frequency of KIR3DS1 with HLA-B Bw4[Ile80] ligand in TB patients compared to control group [4% vs. 23%, OR=0.14, CI=0.033-0.596, p=0.004]. These findings imply a genetic imbalance between activating and inhibitory KIR genes and KIR-HLA combinations in Lur TB patients. Low level of activating KIR3DS1 and its combination with HLA-B Bw4[Ile80] ligand might have an influence on the susceptibility to TB in Lur population of Iran

Study of KIR expression and HLA ligands in cd56+ lymphocytes of drug resistant tuberculosis patients

Analysis of receptor-ligand interactions in the context of diseases necessitates to understand how HLA-KIR genotypes function in diseases. Although CD56+ lymphocytes are derived from multiple lineages, they share a functional association with immunosurviellance and antimicrobial responses. The present study aimed to determine whether KIR phenotype in CD56 lymphocytes and corresponding HLA-class 1 ligands are associated with multidrug resistance tuberculosis [MDR-TB]. We compared the frequencies of HLA-C and HLA-BW4 genes, the expression of KIRs 2DL1/2DS1, 2DL2/2DL3, 3DL1, and 2DS4 and the combinations of HLA/KIR in 32 Nifamycin and Isoniazid-resistant TB with those in 68 drug non resistant [NR] sputum smear positive pulmonary TB patients. PCR-SSP and flow cytometry were performed for HLA and KIRs typing, respectively. We showed no significant differences between inhibitory or activating KIRs as well as HLA ligands in MDR TB patients compared with NR-TB. The combinations of inhibitory KIR-HLA ligands in MDR-TB were much more prevalent, but not statistically significant than in NR patients [p=0.07]. The frequency of MDR patients with all HLA-C and HLABW4 ligands was higher than NR-TB [p<0.009]. Conversely, the percentage of MDR patients having only one kind of HLA gene was significantly lower than NR-TB [p<0.01]. We conclude that the expression of inhibitory KIRs with corresponding HLA ligands genes, and/or co-existence of three HLA class 1 ligands for inhibitory KIRs may be associated with drug resistance in pulmonary tuberculosis

Inhibitory killer cell immunoglobulin-like KIR3DL1 in combination with HLA-B Bw4[iso] protect against ankylosing spondylitis

The HLA class I molecules serve as ligands for both T cell receptors and killer cell immunoglobulin-like receptors [KIRs]. We investigated the HLA-C and HLA-Bw4 alleles as well as KIRs expression on CD56 positive lymphocytes to evaluate whether these genes and molecules could influence Ankylosing spondylitis [AS] susceptibility, alone or in combination. We typed 40 AS patients and 40 normal controls for HLA-C asn[80] [group 1] and HLA-C lys[80] [group 2], HLA-B Bw4[thero], HLA-B Bw4[iso] and HLA-A Bw4 alleles by PCR-SSP method. We also assessed the expression of KIR2DL1/2DS1, KIR2DL2/2DL3, KIR3DLI and KIR2DS4 by flow cytometry. The Pearson chi-square or Fisher exact test was performed for statistical analysis. The frequency of HLA-B Bw4[iso] but not HLA-B Bw4[thero] and HLA-A Bw4, ligand for the inhibitory KIR3DL1, was significant reduced in AS patients as compared with controls [p<0.01]. No significant differences were observed in gene carrier frequencies of HLA-C group 1 and 2 between AS and controls. Although no differences were found in the expression of KIR receptors between AS and normal was reduced in patients with AS compared to healthy controls [p<0.009]. We conclude that HLA-B Bw4[iso], the ligand of inhibitory KIR3DL1, with and without the expression of KIR3DL1 might be involved in protection against AS. Our results suggest that besides the HLA and KIR genotype, expression levels of KIRs may be involved in the pathogenesis of AS disease

KIR2DS3 is associated with protection against acute myeloid leukemia

Interaction between killer cell immunoglobulin-like receptors [KIR] and human leukocyte antigen [HLA] class I molecules is important for regulation of natural killer [NK] cell function. The aim of this study was to investigate the impact of compound KIR-HLA genotype on susceptibility to acute leukemia. Cohorts of Iranian patients with acute myeloid leukemia [AML; n=40] and acute lymphoid leukemia [ALL; n=38] were genotyped for seventeen KIR genes and their three major HLA class I ligand groups [C1, C2, Bw4] by a combined polymerase chain reaction-sequence-specific primers [PCR-SSP] assay. The results were compared with those of 200 healthy control individuals. We found a significantly decreased frequency of KIR2DS3 in AML patients compared to control group [12.5% vs. 38%, odds ratio=0.23, p=0.0018]. Also, the KIR3DS1 was less common in AML group than controls [27.5% vs. 44.5%, p=0.0465, not significant after correction]. Other analyses including KIR genotypes, distribution and balance of inhibitory and activating KIR+HLA combinations, and co-inheritance of activating KIR genes with inhibitory KIR+HLA pairs were not significantly different between leukemia patients and the control group. However, in AML patients a trend toward less activating and more inhibitory KIR-HLA state was observed. Interestingly, this situation was not found in ALL patients and inhibition enhancement through increase of HLA ligands and inhibitory combinations was the main feature in this group. Our findings may suggest a mechanism for escape of leukemic cells from NK cell immunity