Association study of MICA gene polymorphisms with rheumatoid arthritis susceptibility in south Tunisian population.

The aim of this study was to investigate the role of major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, important in natural killer (NK) cell function, in patients with rheumatoid arthritis (RA). A transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6 and A9 in the MICA gene, and single-nucleotide polymorphisms (SNPs): the Met129Val polymorphism (rs1051792) and the nonsynonymously coding SNP (rs1051794) were genotyped in 142 patients with RA and 123 unrelated healthy individuals using, respectively, PCR fluorescent method, nested PCR-RFLP and allele specific PCR (ASP). Association was assessed based on the χ2 test, genotype relative risk (GRR) and odds ratio (OR) with 95% confidence intervals (CIs). Our results show a trend of association of the different MICA genotypes G/G, G/A and A/A (P = 0.029) which did not attain the significance after Bonferroni's correction (pc = 0.08). Although, we revealed a significant association of the genotype A/A of MICA-250 in patients with RA compared to healthy controls (pc = 0.033). In contrast, no significant differences between alleles and genotypes frequencies were found either with MICA-TM or MICA met129 val (P > 0.05) in our sample. Moreover, stratification of patients with RA according to clinical and immunological data for the different polymorphisms studied shows a significant association of both MICA-250 G allele (pc = 0.0075) and MICA-250 GG genotype (pc = 0.008) and both allelic (val) (pc = 0.021) and genotypic (val/val) distribution (pc = 0.0095) for MICA met129 val in the RF-positive subgroup compared to RF-negative patients with RA. In contrast, we found a strong association of the MICA-TM A9 allele in RF-negative patients with RA (pc = 0.0003). This study indicates the involvement of the MICA-250 polymorphism in the genetic susceptibility and severity to RA and suggests that variations in MICA-TM and MICA met129 val may have an effect on RA severity in our south Tunisian sample.

Identification of a disulfide isomerase protein of Leishmania major as a putative virulence factor.

Several approaches have been previously used to elucidate the genetic basis of Leishmania virulence. In general, they were based on laboratory Leishmania clones genetically modified or grown in the presence of selecting agents. In a previous study, we demonstrated that Leishmania major freshly isolated from human cutaneous lesions showed significant differences in the severity of the experimental disease induced in BALB/c mice. Here, using the mRNA differential display technique, we analyzed gene expression in L. major promastigotes showing different levels of virulence. We have identified a novel Leishmania gene encoding a 477-amino-acid protein exhibiting two distinct regions that are identical to the putative active-site sequence (CGHC) of the eukaryotic protein disulfide isomerase (PDI). The recombinant protein displayed a specific PDI enzymatic activity. This L. major disulfide isomerase protein (LmPDI) is predominantly expressed, at both the mRNA and protein levels, in highly virulent strains. Specific PDI inhibitors abolished the enzymatic activity of the recombinant protein and profoundly affected parasite growth. These findings suggest that LmPDI may play an important role in Leishmania natural pathogenicity and may constitute a new target for anti-Leishmania chemotherapy.