Promoter polymorphisms of the TIM‐4 gene are correlated with disease activity in patients with systemic lupus erythematosus

Although the TIM gene family plays important roles in immune responses, little is known about TIM regulation in the development of systemic lupus erythematosus (SLE). This study aimed to investigate the association of two TIM‐4 single nucleotide polymorphisms (SNPs) rs6874202 (?1419G>A) and rs62382402 (?1609G>A) with SLE susceptibility in a Chinese Han population. The results showed no significant differences between patients with SLE and control group for rs6874202 and rs62382402 (p = .72, .53 respectively). However, the anti‐dsDNA levels in serum from SLE patients with GG genotype of TIM‐4 gene at ‐1419 site were significantly higher than those with GA and AA genotype (p = .0335), and C3 levels of SLE patients with GG and GA genotype were much lower than those with AA genotypes (p = .0187). Moreover, the apoptotic cell levels of SLE patients with AA and GG genotypes were significantly higher than those with GA genotypes in patients with SLE (p = .0393). In addition, the C3 concentration of SLE patients with the GG genotype of TIM‐4 gene at ‐1609 site was found to be significantly higher than those with the GA genotype (p = .0129). The results imply that GG genotype of the TIM‐4 gene at ‐1419 site might be associated with the disease activity of SLE.     

Genetic variation and significant association of polymorphism rs7700944 G>A of TIM-4 gene with rheumatoid arthritis susceptibility in Chinese Han and Hui populations

The T‐cell immunoglobulin and mucin domains 1 (TIM‐1) and 3 (TIM‐3) have been shown to be associated with susceptibility to rheumatoid arthritis (RA) in many ethnicities. In this study, we investigated the rs7700944 polymorphism of the intron region of TIM‐4 gene in Chinese Han and Hui populations, with and without RA in Ningxia Hui Autonomous Region of China. Our results demonstrated genetic variations of the TIM‐4 gene, along with significantly different distributions of genotypes and alleles at rs7700944 site in these two populations, with or without RA (P < 0.01). In addition, a strong association between the polymorphism with RA susceptibility was found in the studies of Chinese Han and Hui ethnic groups (P < 0.01), although the risk genotype contributed to RA susceptibility was different between the Han and Hui groups (P < 0.01). The AG was the risk genotype for RA in Han population, while GG was the risk genotype at rs7700944 site of TIM‐4 gene in Hui ethnicity. In addition to the genotype, the risk alleles of this single nucleotide polymorphism for RA in these two populations were also different, individuals with A allele was more susceptible to RA in Chinese Han [odds ratio (OR) = 1.930; 95% CI 1.412, 2.636; P < 0.01], but the risk allele in Hui was G in this study (OR = 1.823; 95% CI 1.330, 2.498; P < 0.01). These findings strongly suggest that polymorphism of rs7700944 of TIM‐4 may be a potential genetic variant among distinguished populations, as well as an important genetic factor associated with the RA susceptibility in many ethnicities.     

Interleukin‐4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus

Juvenile systemic lupus erythematosus (JSLE) is a chronic, recurrent multisystem inflammatory disease, caused by a combination of environmental events and genetic risk factors. As cytokines, including interleukin‐4 (IL‐4), seem to have a role in the pathogenesis of JSLE, the investigation was performed to evaluate the associations of specific single nucleotide polymorphisms (SNPs) of IL‐4 and IL‐4RA genes in a case–control study. Fifty‐nine patients with JSLE were recruited in this study as patients' group and compared with 140 healthy volunteers. Genotyping was performed for IL‐4 gene at positions ?1098, ?590 and ?33, as well as IL‐4 receptor α (IL‐4RA) gene at position +1902, using polymerase chain reaction with sequence‐specific primers method. Following alleles were found to be more common among patients with JSLE: C at ?590 and ?33 and T at ?1098 of IL‐4 gene (P value < 0.001; OR = 4.6, P value < 0.001; OR = 2.7 and P value < 0.001; OR = 2.1, respectively). Additionally, significant positive associations for the following genotypes were recognized in JSLE cases, compared with controls: C/C at ?33, C/C at ?590 and T/T at ?1098 of IL‐4 gene (P value < 0.001; OR = 5.3, P value < 0.001; OR = 29.5 and P value < 0.001; OR = 3.3, respectively), while following genotypes were less frequent among patients with JSLE: T/C at ?33 and ?590 and T/G at ?1098 of IL‐4 gene (P value < 0.001; OR = 0.1, P value < 0.001; OR = 0.03 and P value < 0.001; OR = 0.3, respectively). Furthermore, we noticed an astonishing negative haplotypic association for JSLE for IL‐4 (positions ?1098, ?509 and ?33) TTC, GCC and TTT haplotypes (P value < 0.001). There was also a significant relationship between TCC haplotype (IL‐4 gene at positions ?1098, ?590 and ?33) and having JSLE (P value < 0.001). On the other hand, we found no significant associations between IL‐4R polymorphisms and the susceptibility to JSLE. Cytokine gene polymorphisms may influence susceptibility to JSLE. Particular IL‐4 gene variants are associated with JSLE and might have a role in the pathophysiology of disease.     

Two polymorphisms in the TIM‐4 gene are associated with asthma in a Chinese Han population

The gene family of the T cell immunoglobulin and mucin domain (TIM) proteins encodes cell surface receptors that are involved in the regulation of Th1‐ and Th2‐cell‐mediated immunity. TIM‐1 gene has been found to be associated with asthma in several populations. TIM‐4, the natural ligand for TIM‐1, may influence the susceptility to asthma.To investigate the association of the TIM‐4 gene polymorphisms with asthma in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) in TIM‐4 gene, rs6882076, rs12658558 and rs4702747, were genotyped in 551 unrelated asthma patients and 549 healthy controls. We found that two SNPs of the TIM‐4 gene, rs6882076 and rs4702747, were associated with asthma susceptibility in our study population (with P‐values = 0.009 and 0.005 respectively). No association was observed between asthma and rs12658558. Our results suggest that TIM‐4 gene polymorphisms are associated with asthma in a Chinese Han population.     

Association of TIM‐1 5383‐5397ins/del and TIM‐3 ‐1541C>T polymorphisms with multiple sclerosis in Isfahan population

Multiple sclerosis (MS) is an organ‐specific autoimmune disease in central nervous system, affecting about 2.5 million people around the world. Probable involvement of two newly identified immunoregulator molecules, TIM‐1 and TIM‐3, has been reported in autoimmune diseases. In this study, for the first time, the association of TIM‐1 5383‐5397ins/del and TIM‐3 ‐1541C>T polymorphisms with MS in an Iranian population was considered. The results of our study showed that there is no significant association between TIM‐1 5383‐5397ins/del and MS (P = 0.38); however, the frequency of CT genotype of TIM‐3 ‐1541C>T in patient group was significantly higher than the control group, and there was a significant association between CT genotype and MS (P = 0.009, OR = 4.08).     

Association of group‐specific component exon 11 polymorphisms with bronchial asthma in children and adolescents

Several studies have investigated the association of Group‐specific Component (GC) gene, also known as vitamin D‐binding protein (VDBP), and various respiratory disorder susceptibility with conflicting results. In this sense, we aimed to investigate whether rs7041 and rs4588 variants confer susceptibility to bronchial asthma in a sample of an Egyptian population and to elucidate by in silico analysis the structural and functional impact of these variants. Group‐specific Component polymorphisms rs7041 and rs4588 were genotyped in 192 Egyptian children and adolescents (96 with asthma and 96 healthy controls) by TaqMan single nucleotide polymorphism genotyping assay. The rs7041 GG genotype showed a significantly elevated frequency among patients under codominant, dominant, recessive and allelic models where the patient group had greater carriage rate of G allele [OR 2.15, CI 95% (1.32‐3.50; P = 0.002)], while rs4588 CA and AA genotypes were found to be protective genotypes with controls showing a greater carriage rate of A allele [OR 0.52, CI 95% (0.30 ‐ 0.90; P = 0.02)]. Three haplotype allele combinations were identified with frequencies of GC (44.3%), TC (31.3%) and TA (24.5%) in the total study population. GC haplotype was shown to be more frequent in controls, while TC and TA haplotypes were more predominant in the patient group. Only rs7041 variant showed a significant association with family history and pubertal status. In conclusion, both study GC variants could be implicated in childhood bronchial asthma pathogenesis; rs7041 GG genotype and G allele increased asthma risk while rs4588 AA genotype and A allele conferred protection in the study population.     

Interleukin-17A rs2275913, Interleukin-17F rs763780 and rs2397084 gene polymorphisms as possible risk factors in Juvenile lupus and lupus related nephritis

There are no reports about the association of interleukin (IL)-17A and IL-17F gene polymorphism and susceptibility to pediatric systemic lupus erythematosus (pSLE). Objective: To examine the possible role of IL-17A rs2275913, IL-17F rs763780 and rs2397084 polymorphisms as risk factors for pSLE in a cohort of Egyptian children and to investigate their association with the clinico-pathological features including lupus nephritis (LN). Methods: Typing of IL-17A and IL-17F polymorphisms was done using restriction fragment length polymorphism for 115 children with SLE and 259 age- and sex-matched healthy controls. Results: No significant differences were found between pSLE patients and healthy controls for the allele and genotype frequencies of IL-17A rs2275913, IL-17F rs763780 and rs2397084 (p?>?0.05). However, the combined genotype GGAGAA and the haplotype GGA had significant association with pSLE (p_c?=?0.042 and <0.001, respectively). The AA genotype of IL-17F rs763780 is more frequent in female patients (p?=?0.002) and the AA genotype of IL-17F rs2397084 is more associated with positivity of ds-DNA (p?=?0.007). No more associations were found for the demographic and clinical data of pSLE patients including risk of LN development, risk of non-remission, overall survival, activity and chronicity indices. Conclusion: The GGAGAA combined genotype and the GGA haplotype of IL-17A rs2275913, IL-17F rs763780 and rs2397084 can be considered risk factors for the development of SLE in Egyptian children. IL-17A rs2275913, IL-17F rs763780 and rs2397084 are not related to the LN development, SLE disease activity or overall survival.     

Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils

Nitric oxide synthase (NOS) catalyses the production of nitric oxide (NO) from L‐Arginine, which participates in diverse biological processes including inflammation and apoptosis. Macrophages, chondrocytes, osteoblasts and osteoclasts express inducible NOS (iNOS) at the site of synovial inflammation. NO produced at the inflamed joint may contribute to peri‐articular bone loss, mediate apoptosis and regulate Th1/Th2 balance in rheumatoid arthritis (RA). Variations in the promoter region of NOS gene regulate the nitric oxide synthase expression and iNOS (NOS2) polymorphisms have been associated with susceptibility to autoimmune disorders. Hence, this study was conducted to identify the possible contributions of NOS2 ‐1659G/A, ‐1026C/A, ‐277A/G promoter polymorphisms towards development of RA in South Indian Tamils. A total of 242 (219 females, 23 males) patients with RA (mean age 41.2 ± 10.9 years, disease duration 8.5 ± 4.3 years) and 279 age‐ and sex‐matched healthy individuals of South Indian Tamil ethnicity were genotyped for NOS2 ‐1659C/T, ‐1026G/T and ‐277A/G promoter polymorphisms by TaqMan chemistry. Nature of disease (erosive or nonerosive), the presence of extra‐articular manifestations, seropositivity for rheumatoid factor and anticyclic citrullinated peptide, serum C‐reactive protein (CRP) level and response to therapy were assessed for all patients. The three single nucleotide polymorphisms (SNPs) were in Hardy–Weinberg equilibrium. The frequency of GG genotype and G allele of NOS2‐277 was higher in patients (pc = 5.7 × 10^?9, OR = 6.09, 95% CI = 3.09–12.8 and pc = 4 × 10^?13, OR = 2.37, 95% CI = 2.06–3.62, respectively) compared to controls. Similarly, the frequency of NOS2‐1026 (rs2779249) GT genotype and the T allele was higher in patients with RA (pc = .01, OR = 1.61, 95% CI = 1.09–2.36, and pc = .04, OR = 1.40, 95% CI = 1.02–1.91, respectively). However, no significant difference in frequency of NOS2‐1659C/T polymorphism was observed between patients and controls. None of the studied SNPs were associated with erosive disease, seropositivity or extra‐articular manifestations. The ‐277A/G and ‐1026 G/T promoter polymorphisms in iNOS may confer susceptibility to RA in South Indian Tamils.     

Association analysis of −416 G>C polymorphism of T‐cell immunoglobulin and mucin domain‐1 gene with asthma in Iran

TIM (T‐cell immunoglobulin (Ig) and mucin domain)‐1, one of the members of TIM family, expresses on Th2 cells and promotes the production of Th2 signature cytokines. This can increase a series of responses in these cells which could be one of the causes of asthma or asthma‐related phenotypes. The aim of this study was to investigate whether a TIM‐1 promoter single nucleotide polymorphism (SNP), ?416 G>C, is associated with asthma in Iranian population. In this case–control study, existence of the ?416 G>C polymorphism was assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in 300 patients with asthma (97 atopic, 203 nonatopic) and 309 healthy volunteers. Additionally, the relationship between these polymorphism genotypes and total serum IgE levels in this Iranian population was evaluated. We discovered a significant association between the ?416 G>C polymorphism and atopic asthma susceptibility in the population, but this SNP showed no connection with nonatopic asthma (P < 0.05). However, our results showed significant relation between this polymorphism and serum IgE level (P < 0.05). Our results suggest that ?416 G>C polymorphism in TIM‐1 gene could be a predisposing factor for atopic asthma in Iranian population, and CC genotype of this SNP can be associated with increased level of IgE in patients with asthma in the same population.     

Effects of MASP2 haplotypes and MASP‐2 levels in hepatitis C‐infected patients

Mannan‐binding lectin (MBL) and MBL‐associated serine protease 2 (MASP‐2) are components of the lectin pathway, which activate the complement system after binding to the HCV structural proteins E1 and E2. We haplotyped 11 MASP2 polymorphisms in 103 HCV patients and 205 controls and measured MASP‐2 levels in 67 HCV patients and 77 controls to better understand the role of MASP‐2 in hepatitis C susceptibility and disease severity according to viral genotype and fibrosis levels. The haplotype block MASP2*ARDP was associated with protection against HCV infection (OR = 0.49, p = .044) and lower MASP‐2 levels in controls (p = .021), while haplotype block AGTDVRC was significantly increased in patients (OR = 7.58, p = .003). MASP‐2 levels were lower in patients than in controls (p < .001) and in patients with viral genotype 1 or 4 (poor responders to treatment) than genotype 3 (p = .022) and correlated inversely with the levels of alkaline phosphatase, especially in individuals with fibrosis 3 or 4 (R = ?.7, p = .005). MASP2 gene polymorphisms modulate basal gene expression, which may influence the quality of complement response against HCV. MASP‐2 levels decrease during chronic disease, independently of MASP2 genotypes, most probably due to consumption and attenuation mechanisms of viral origin and by the reduced liver function, the site of MASP‐2 production.     

Association of Genes in the NF‐κB Pathway with Antibody‐Positive Primary Sjögren's Syndrome

Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF‐κB in primary SS. NF‐κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF‐κB and of IKBKE (IKKε), which is an NF‐κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti‐SSA and/or anti‐SSB antibodies (n = 868), case–control meta‐analysis found an association between antibody‐positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10^?5, OR = 1.33, 95%CI: 1.16–1.52 for rs3792783 and P = 1.3 × 10^?3, OR = 1.21, 95%CI: 1.08–1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody‐positive primary SS (P = 5.7 × 10^?3, OR = 1.47, 95%CI: 1.12–1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta‐analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody‐positive primary SS.     

The -1541 C>T and +4259 G>T of TIM-3 polymorphisms are associated with rheumatoid arthritis susceptibility in a Chinese Hui population

The T‐cell immunoglobulin and mucin domain 3 (TIM‐3) has been shown to be associated with susceptibility to rheumatoid arthritis (RA). In this study, we investigated the association of four single‐nucleotide polymorphisms (SNPs) of the TIM‐3 gene with RA susceptibility in Chinese Hui and Han groups. Using restriction fragment length or sequence‐specific primer–polymerase chain reaction (PCR), patients with RA and nonarthritis control individuals from these two ethnicities were analysed for SNPs of ?1541 C>T, ?882 T>C, ?574 T>G and +4259 G>T, in the TIM‐3 gene. Our results demonstrated that the polymorphisms of +4259 G>T SNP of TIM‐3 gene was associated with the RA susceptibility in both the Hui (P < 0.01) and Han populations (P < 0.05). However, the ?1541 C>T and ?574 T>G SNPs were distinctly associated with RA for the Hui and Han populations, respectively. In addition, haplotype analysis found no statistically differences in the distribution of nine detected haplotype frequency between patients with RA and controls in this study (P > 0.05). These findings suggest that polymorphism of +4259 G>T in TIM‐3 gene may be one of the most important genetic factors associated with the RA susceptibility among different populations, and genetic variations of TIM‐3 gene contribute to RA susceptibility among different populations.     

Association of polymorphisms in interleukin (IL)‐12A and ‐B genes with rheumatoid arthritis in a Chinese population

Rheumatoid arthritis (RA) is characterized by synovial infiltrates and progressive cell‐mediated destruction of the joints, which results in significant disability and early mortality. Genetic factors may play an important role in the development of RA. The aim of this study was to investigate the association of common polymorphisms in interleukin (IL)‐12A and IL‐12B genes with RA in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) in IL‐12 genes were genotyped in 412 patients with RA and 279 control subjects using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Our data showed that IL‐12B gene SNPs rs3212227 and rs6887695 were observed as a risk factor of RA. The minor allele (C) frequency of IL‐12B gene rs3212227 and rs6887695 increased the risk of RA. Individuals carrying the rs3212227/rs6887695 C/C haplotype were associated with a significantly increased risk of RA. RA patients with the C allele of IL‐12B gene rs6887695 was a protective factor to erosive arthropathy. Carriers of the C allele of IL‐12B gene rs3212227 were significantly more likely to be RF‐positive. No significant association was observed between rs2243115 in IL‐12A and RA, due probably to the limited power. These results suggest that common variants in IL‐12B may contribute to the development of RA in the Chinese population.     

IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL‐1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence‐specific primers (PCR‐SSP). IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 were evaluated for SNP study. The frequency of the IL‐1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385–0.886; P‐value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176–2.111; P‐value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047–0.484; P‐value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL‐1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.     

Polymorphisms in the TNF‐α, TNFR1 gene and risk of rheumatoid arthritis in Chinese Han population

Recent advances have highlighted a major genetic contribution to the pathogenesis of rheumatoid arthritis (RA).The aim of this study was to investigate whether polymorphisms of TNF‐α (rs1800630, rs1800629) and TNFR1 (rs767455) were associated with susceptibility to and clinical outcome of RA in Chinese Han population. The target gene polymorphisms were genotyped in 256 patients with RA and 331 healthy controls using a high resolution melting (HRM) method. ESR, CRP, RF anti‐CCP and anti‐GPI level were also assayed and compared in genotypes of each polymorphism. Significant difference was observed in the genotype distributions and allele frequencies of TNF‐α rs1800629 (P = 0.001, P < 0.001, respectively) between patients with RA and controls. There is no evidence to suggest an association between genotypes of the 3 SNPs according to age, gender, disease duration, DAS28 and serum level of autoantibodies. This study identifies a potentially important role for TNF‐α rs1800629 polymorphisms in the susceptibility to RA.However, further studies in larger cohorts are required.     

IL‐12B and IL‐10 gene polymorphisms in the development of Hashimoto's thyroiditis

Functional genetic polymorphisms that altered gene expression of cytokines are candidate genetic factors that could modulate the development and progression of Hashimoto's thyroiditis (HT). IL‐12B gene encoded the IL‐12p40 subunit, which is included in the pro‐inflammatory heterodimeric cytokines IL‐12p70 and IL‐23. IL‐10 is an important Treg cytokine suppressing inflammatory cytokine production and autoimmunity. This study was designed to compare ?1082A/GIL‐10 and +1188A/C3′UTRIL‐12B genotype distribution in 130 patients with HT to a group of 157 healthy controls in attempts to determine an association with HT development. Genotyping for the 3′UTRA/C IL‐12B polymorphism was performed using RFLP‐PCR and genotyping for ?1082A/G IL‐10 by ARMS‐PCR assay. Patients with HT were divided into euthyroid and hypothyroid stages. There were no significant differences in the genotype and allele frequencies of the IL‐12B polymorphism between patients with HT and controls. We observed higher euthyroid HT risk for individuals with CC genotype, unlike to develop hypothyroidism with OR = 1.68. Regarding the polymorphism rs1800896, it was shown the significantly higher frequency of homozygous genotype GG in cases vs controls (OR = 2.19; P = 0.024). Moreover, the combination of genotype AA of 3′UTRIL‐12B with GG of ?1082IL‐10 was associated with a threefold increasing risk (OR = 3.188; P = 0.022) of developing HT compared to individuals with the presence of 3′UTR allele C (AC+CC) simultaneously with AA genotype of ?1082IL‐10. Our data raise the possibility that the combined effect of polymorphisms from proinflammatory and anti‐inflammatory cytokines may be more decisive to HT development.     

Enhanced suppressor function of TIM‐3+FoxP3+ regulatory T cells

T‐cell immunoglobulin and mucin domain 3 (TIM‐3) is an Ig‐superfamily member expressed on IFN‐γ‐secreting Th1 and Tc1 cells and was identified as a negative regulator of immune tolerance. TIM‐3 is expressed by a subset of activated CD4⁺ T cells, and anti‐CD3/anti‐CD28 stimulation increases both the level of expression and the number of TIM‐3⁺ T cells. In mice, TIM‐3 is constitutively expressed on natural regulatory T (Treg) cells and has been identified as a regulatory molecule of alloimmunity through its ability to modulate CD4⁺ T‐cell differentiation. Here, we examined TIM‐3 expression on human Treg cells to determine its role in T‐cell suppression. In contrast to mice, TIM‐3 is not expressed on Treg cells ex vivo but is upregulated after activation. While TIM‐3⁺ Treg cells with increased gene expression of LAG3, CTLA4, and FOXP3 are highly efficient suppressors of effector T (Teff) cells, TIM‐3^? Treg cells poorly suppressed Th17 cells as compared with their suppression of Th1 cells; this decreased suppression ability was associated with decreased STAT‐3 expression and phosphorylation and reduced gene expression of IL10, EBI3, GZMB, PRF1, IL1Rα, and CCR6. Thus, our results suggest that TIM‐3 expression on Treg cells identifies a population highly effective in inhibiting pathogenic Th1‐ and Th17‐cell responses.     

Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease

In this study we aimed to investigate IVS3 +17T/C single nucleotide polymorphism (SNP) of CD28 gene, +49A/G and ?318C/T SNPs of CTLA‐4 gene in patients with Behçet's disease (BD) and their potential association to the main clinical features of the disease. These polymorphisms were investigated in a Turkish population of 123 patients with BD and 179 healthy controls, by using PCR‐RFLP technique. HLA‐B*51 genotype was also studied in both groups by using PCR‐SSP. The frequency of IVS3 +17TC genotype of the CD28 gene was significantly increased in BD patients compared to controls (43.6% vs. 31.2%, OR = 1.663, 95% CI = 1.033–2.679, P = 0.039). CTLA‐4 +49GG genotype frequency was found to be significantly lower in patients with BD than those of healthy controls (4% vs. 10.6%, OR = 0.357, 95% CI = 0.130–0.983, P = 0.05). Genotype and allele frequencies of the CTLA‐4–318C/T polymorphism between the BD and healthy control groups were not significantly different (12.2% vs. 10.6%, OR = 1.170, 95% CI = 0.570–2.402, P = 0.713). There were no associations between the studied polymorphisms and the main clinical features of BD. The frequencies of HLA‐B*51 were 60.3% and 30.7% in BD and control groups, respectively (OR = 3.429, 95% CI = 2.115–5.559, P = 0.0001). Association between HLA‐B*51 and each studied polymorphism did not reach to significant levels (OR = 0.479, 95% CI = 0.228–1.004, P = 0.064 for CD28 IVS3 +17TT genotype; OR = 2.180, 95% CI = 1.025–4.639, P = 0.061 for TC genotype; OR = 1.570, 95% CI = 0.870–2.836, P = 0.146 for C allele). These results may suggest that CD28 IVS3 +17TC genotype may be a risk factor for the development of BD, on the contrary CTLA‐4 +49GG genotype may be protective in the studied Turkish population.     

Associative role of HLA‐DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis: A North‐east Indian population‐based study

Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA‐DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA‐DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North‐east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA‐DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North‐east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community‐based age and sex‐matched healthy controls (n = 156) with informed consent. The HLA‐DRB1 SNP analysis was performed for all the RA and control cases using ARMS‐PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA‐DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA‐DRB1 are associated with RA susceptibility. HLA‐DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North‐east Indian cases and has prognostic significance in RA.