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Asthma is a common respiratory childhood disease that results from an interaction between genetic, environmental and immunologic factors. The implication of nucleotide-binding and oligomerization domain 1 and 2 (NOD1/CARD4, NOD2/CARD15) was highlighted in many inflammatory diseases. In this case-control study, we analyzed the association of three NOD2 polymorphisms and one NOD1 variant, in 338 Tunisian asthmatic children and 425 healthy Controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We also assessed NOD1 and NOD2 mRNA and protein levels by qRT-PCR and ELISA techniques. The homozygous AA genotype of rs2075820 was a risk factor for asthma (OR 2.39). The influence of the E266K variant in the presence of the heterozygous AG genotype was higher in male than female groups. The homozygous AA genotype was a risk factor associated with asthma, for patients aged between 6 and 18 years OR 2.39, IC95% (1.04–5.49) p

Purpose: Fibroblast-like synoviocytes (FLS) represent one of the principal effectors of joint damage in rheumatoid arthritis (RA). Recent discovery of the circulating fibrocyte, a potential precursor of FLS, has raised issues regarding the characterization of fibrocytes with respect to their morphology and their biological role. In this study, we evaluated the morphology of fibrocytes in vitro and their ability to produce different extracellular matrix (ECM) components in comparison with two populations of RA FLS: synovial fluid FLS (fd-FLS) and intimal lining FLS (td-FLS). We also studied the expression of ECM regulators and a set of cytokine receptors involved in the pathogenesis of RA. Materials and Methods: Fibrocytes were cultured from peripheral blood of patients with RA. FLS were cultured from synovial fluids and tissues. ECM proteins (collagen I (col I) and fibronectin), Matrix metalloproteinases (MMP) (MMP3, and MMP9), ECM regulators (β catenin, TCF4, and c-fos), and cytokine receptors (CXCR1, CXCR2, CXCR3, IL1RI, IL1RII, and IL6Rα) were analyzed using qRT-PCR and/or western blot. Results: Our results demonstrated that fibronectin and MMP3 levels were higher in FLS compared to fibrocytes. Although MMP9 was expressed in the three cell types, its level was greater in fibrocytes than in td/fd FLS. The three cell types expressed CXCR3, IL1RI, IL1RII, and IL6Rα, while the expression of CXCR1 and CXCR2 was restricted to fibrocytes. Conclusion: Our results demonstrated that fibrocytes express ECM molecules and cytokines receptors. The observed differences between fibrocytes and FLS may be due to their distinct functions or differentiation state during RA.Abbreviations: RA: Rheumatoid ArthritisFLS: fibroblast-like synoviocytestd: tissue derivedfd: fluid derivedSF: Synovial FluidWnt: WinglessMMP: Matrix MetalloproteinaseCIA: murine collagen induced arthritisECM: Extracellular matrixcol I: Collagen ITCF/LEF: T-cell factor/lymphoid enhancer-binding factorAP1: Activator Protein 1.

B and T lymphocyte attenuator (BTLA) is an immune-inhibitory receptor that negatively regulates the lymphocyte activation. A few studies have been devoted to the relationship between BTLA gene variations and cancer's risk. It has been essentially demonstrated to be involved in increasing cancer risk in chronic lymphocyte leukaemia, renal cell carcinoma, breast and colorectal cancer predispositions in Asian population. The aim of this study was to evaluate the association between BTLA gene polymorphisms and the risk of lung cancer in the Tunisian population. In a case-control study, three BTLA single-nucleotide polymorphism (SNP): rs1982809 (A > G), rs9288952 (G > A) and rs9288953(C > T) were genotyped with the use of TaqMan probes in 169 lung cancer patients and in 300 controls. The rs1982809 SNP was significantly associated with an increased risk of lung cancer compared with controls in codominant and dominant models. The heterozygous rs1982809-AG genotype carriers had a higher risk of developing lung cancer when compared to AA genotype carriers in Tunisian population (OR (95%CI) = 1.63 (1.09-2.42), p = .01]. The AG genotype is an important risk factor associated with lymphatic invasion (OR = 3.71) and large-sized lung tumour (OR = 1.80). It is also a risk factor for the development of an adenocarcinoma subtype (OR = 2.08). However, the BTLA rs9288953 and rs9288952 SNPs were not associated with susceptibility for lung cancer (p > .05). Haplotype comparison did not show any significant association in our research. For the survival analysis, there was no impact of BTLA SNPs on the mortality risk associated to lung cancer in Tunisian patients. The current study is the first to demonstrate an association between BTLA rs1982809 polymorphism and an increased lung cancer risk in the Tunisian population.

Purpose To examine the IL-8 expression levels and association of genetic variants with the risk of childhood persistent asthma prognosis. Methods Overall, 170 asthmatic children and 170 healthy controls were included in this case–control study. The human IL-8 serum levels were measured using ELISA. The IL-8 mRNA expression levels were assessed by a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) methods. Results The IL-8 expression at both protein and mRNA levels was found to be significantly elevated in asthmatic children compared to healthy subjects (P

Behcet disease (BD) is a multisystemic disease some of whose manifestations are characterized by pulmonary involvements. The purpose of the study was to evaluate the level of T-helper type 9 (Th9) cells and the cytokine interleukin (IL)-9 in peripheral blood and in bronchoalveolar lavage (BAL) of patients with Behcet's disease (BD) affected by pulmonary manifestations. Nevertheless, until recently there have been no studies on its role in BD. The Th9 (CD4+IL-9+T) cell, transcription factor PU.1 and IL-9 mRNA levels, as well as serum and BAL IL-9 concentration, were measured in BD patients and healthy controls. The Th9 cell percentage and absolute number, PU.1 and IL-9 expression levels of BD patients were all increased significantly compared with the control group. Absolute number of Th9 cells was particularly increased in patients with active BD compared to inactive BD patients. The levels of IL-9 associated to Th9 expression depended on BD severity. These parameters were markedly expressed in the BAL of BD patients with pulmonary manifestations. IL-17 and the epithelial inflammatory cytokine TSLP were significantly correlated to IL-9 levels. This cytokine trio decreased in inactive BD patients after corticosteroid treatment. In addition, IL-9 levels were correlated to CD4+ IL-9+ cells in BAL and in PBMCs. LPS stimulated PBMCs and macrophages induced increased secretion of IL-9 and the encoding transcription factors PU.1 and IRF4. In conclusion, the expansion of the Th9 cell subset, up-regulation of the PU.1 transcription factor and increased secretion of the IL-9 cytokine may contribute to the pathogenesis of BD, which may be supported by the increased release of IL-17 and TSLP. We provide evidence that Th9 T cells are increased in BD patients with pulmonary manifestations. This suggests an important role of IL-9 in the pathogenesis of BD particularly in patients suffering from lung involvement.

Chronic kidney disease (CKD) is associated with numerous complications such as bone mineral disorder. The aim of our study was to analyze the correlation of bone turnover markers with Bone Mineral Density (BMD) measurements in Tunisian end stage renal diseases (ESRD) patients.This study included 100 ESRD Tunisian patients. Their estimated glomerular filtration rate (eGFR) was15 mL × minWe observed a statistically significant negative correlation between BALP levels and total body BMD (r = -0.268; P = 0.015) particularly in femoral neck (FN) (r = -0.219; P = 0.037). BALP concentrations were negatively associated with total BMD especially in FN for patients with BMI30, FGF23 concentrations were also negatively correlated with BMD in lumbar spine site (LS) (r = -0.209; P = 0.046). For osteopenic patients we found an inverse correlation between 25(OH)D concentrations and BMD in LS position (r = -0.336; P = 0.038). In men group, we have also found a negative correlation between iPTH and total BMD (r = -0.326; P = 0.015). However we found a positive correlation between calcium expression and BMD in LS site (r = 0.270; P = 0.031).FGF23 and BALP can predict bone loss in ESRD through their strong correlation with BMD in LS and FN sites respectively.Hronično bubrežno oboljenje (CKD) je praćeno brojnim komplikacijama kao što je poremećaj minerala kostiju. Svha ovog izučavanja je bila da analizira korelaciju markera promena u kostima sa mineralnom gustinom kostiju (BMD) i stupnja renalnih oboljenja kod pacijenata u Tunisu.Proučavanje je uključilo 100 ESRD tuniskih pacijenata. Njihova prosečna brzina glomerularne filtracije (eGFR) bila je15 mL × minNađena je značajno negativna statistička korelacija BALP nivoa i ukupnog telesnog BMD (r= -0,268: P = 0,015) u femoralnom delu vrata (FN) (r = -0,219; P = 0,037). BALP je bila u negativnoj korelaciji sa ukupnom BMD naročito kod FN pacijenata sa BMI30, FGF23 koncentracije su bile takođe u negativnoj korelaciji sa BMD u lumbalnom delu (LS) (r = -0,209, P = 0,046). Kod osteopeničnih pacijenata nađene je inverzna korelacija između 25(OH)D koncentracije i DMD u LS polažaju (r = -0,336; P = 0,038). U grupi muških osoba nađena je negativna korelacija između iPTH i ukupnog BMD (r = -0,326; P = 0,015). Međutim, nađena je pozitivna korelacija između ekspresije kalcijuma i BMD u LS (r = 0,270: P = 0,031).FGF23 i BALP mogu da predvide gubitak kosti kod ESRD preko izrazite korelacije sa BMD u LS i FN položajima.

Interleukin-37 (IL-37) exerts broad inhibitory properties on the innate inflammatory and acquired immune responses. This study was set up to investigate the expression of IL-37 in Behçet disease (BD) and to explore its possible regulatory role during inflammation. IL-37 protein levels and mRNA expression in lipopolysaccharides (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from 50 BD (30 patients in active stage) patients and 20 healthy controls were assayed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Cytokines in the serum and the supernatants of stimulated PBMCs and CD4(+) T cells were assayed by ELISA. Active BD patients showed a decreased IL-37 expression and increased IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in serum and in PBMC culture supernatants. Active BD patients treated with corticosteroids showed an enhanced IL-37 production. Recombinant IL-37 (rIL-37) induced a significant decrease of inflammatory cytokines (IL-1β, IL-6, and TNF-α). It also markedly decreased IL-17 expression in PBMCs and CD4(+) T cells from active BD patients. The present study suggests that a decreased IL-37 expression in BD patients is associated with an increased inflammatory response. Corticosteroid treatment of active BD patients is associated with an increased expression of IL-37 mRNA, which suggests that treatment may partly exert its immunosuppressive effect by regulating IL-37 production and reducing inflammatory cytokines.

Interleukin-33 is an IL-1 family cytokine which signals via its T1/ST2 receptor, and acts as a key regulator of inflammation. This study aims to measure the expression of soluble ST2 (sST2) and IL-33 in endometriosis. We investigated thirty women with laparoscopic and histopathological confirmed endometriosis and 20 control women without pelvic pathology. Peripheral blood mononuclear cells and peritoneal fluid (PF) were assessed for sST2 and IL-33 levels that are measured by sandwich enzyme-linked immunosorbent assay. Peritoneal fluid IL-33 mRNA expression was quantified by real-time reverse transcription polymerase chain reaction assays. We found that IL-33 levels in PF and in serum were significantly higher in patients with endometriosis compared to women without endometriosis (P0.05). IL-33 increased levels were significantly more important in PF [10.45 ± 14.33 ng/mL] than in serum [2.68 ± 1.54 ng/mL] from endometriosis patients. Higher levels of IL-33 mRNA expression were detected in PF from patients with endometriosis. Soluble ST2 levels in PF were significantly different between patients [2.96 ± 0.98 ng/mL; P0.0001] and controls [0.88 ± 0.076 ng/mL]. Serum sST2 levels were similarly expressed in endometriosis patients and in controls (P0.05). Significant correlation was observed between IL-33 and sST2 levels in PF. In conclusion, IL-33 and sST2 values observed in PF were found to correlate with endometriosis severity. Elevated and correlated PF IL-33 and sST2 levels from patients with endometriosis suggested a potential role as surrogate markers of disease activity.

Single nucleotide polymorphism (SNPs) in genes coding for chemokines may be associated with some cancer. The purpose of this study was to investigate the impact of CCR2-64I and CXCL12-3′A SNPs on the susceptibility and the clinicopathological characteristics of NSCLC (Non-Small Cell Lung Cancer) in the Tunisian population. 170 NSCLC patients and 225 healthy controls screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis were enrolled. A significant association for the homozygous genotype CCR2 64I/64I with lung cancer risk was observed ( P = 0.004). An increased significant frequency of the -64I allele ( P = 0.0006) was noted in the patient’s group. Clinical analysis indicated a positive association of the -64I allele among squamous cell lung carcinoma patients ( P = 0.003). The CCR2 mRNA extracted from peripheral blood mononuclear cells (PBMC) was found highly expressed in NSCLC patients compared to controls. The same higher levels were found in patients carrying the CCR2 64I/64I genotype. No significant association was retrieved with CXCL12-3′A polymorphism. In conclusion, our results revealed that the subjects with -64I allele of CCR2-64I gene polymorphism, expressed a significantly higher risk for NSCLC risk without influence on its pathological progression.

The human matrix metalloproteinases (MMPs) are importantly involved in aneurysm formation. Since the clinical manifestations in Behçet disease (BD) include aneurysm formation among major symptoms, polymorphisms in MMP-9 might be associated with BD susceptibility. The aim of the current case-control study was to investigate the association of four single nucleotide polymorphisms (SNPs) in MMP-9 gene: -1562 C/T, 2003 G/A (R668Q), 836 A/G (Q279R) and 1721 C/G (R574P) with BD risk in the Tunisian population. The distribution of MMP-9 gene polymorphisms was analyzed by polymerase chain-reaction (PCR) and restriction fragment length polymorphism (RFLP) for 240 BD patients and 288 controls. Our study indicated that the MMP-9 -1562 C/T polymorphism (rs3918242) was not associated with BD risk. We found a significant association of the MMP-9 2003 G/A (rs17577) with an increased susceptibility to BD. However, the MMP-9 1721 C/G polymorphism (rs2250889) had a protective role against the development of BD. Subgroup analysis based on stratification by gender revealed that the MMP-9 2003 G/A polymorphism was associated with a highly significant BD risk in women's group (G vs. A: P=0.0000001). However, the MMP-9 836 A/G polymorphism had a protective role in men's group (G vs. A: P=0.00043). The MMP-9 1721 C/G polymorphism was associated with a protective effect in both men and women groups (CG+GG vs. CC: P=0.04 and P=0.0002, respectively). The haplotype analysis did not show any association with BD risk. A significant difference in the MMP-9 serum levels were observed in the patient subgroup with ocular lesions manifestations.

Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function. Study the relationship between vitamin D and the severity of asthma by targeting five SNPs of vitamin D metabolism gene pathway in a Tunisian adult asthmatics population. Our case–control study includes 154 adult asthmatic patients and 154 healthy Tunisian subjects. We genotyped many variants in three human genes encoding key components of the vitamin D metabolism, CYP2R1, CYP27B1, GC. The GC gene rs4588 and rs7041 polymorphisms were analysed using the PCR-RFLP method, while rs10741657 and rs12794714 for CYP2R1 gene and rs10877012 of CYP27B1 gene were investigated using TaqMan PCR genotyping techniques. We found that the presence of at least one copy of the rs12794714 A, allele was associated with lower risk of developing asthma (OR 0.61). Further, the rs12794714 is a protector factor against asthma severity (OR 0.5). However, the presence of rs10877012 TG genotype is a risk factor related to asthma severity (OR 1.89). When we classified the population according to sex, our results showed that rs10877012 TT genotype was a risk factor for women subjects (OR 6.7). Moreover, the expression of TT genotype was associated with a higher risk of asthma in non-smoker patients (OR 7.13). We found a significant lower VD serum levels in asthmatics than controls but no impact of the polymorphisms on VD levels. We found that rs12794714 and rs10877012 SNPs were associated with asthma risk.

Behcet's disease (BD) is a multi-systemic inflammatory disorder characterized by the "triple symptom complex". Several pro-inflammatory cytokines, mainly derived from the immune Th17 axis, seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. Here, we have analyzed the expression and role of IL-26 in active BD patients, an inflammatory disorder characterized by bronchoalveolar lavage fluid (BAL) and cerebrospinal fluid (CSF) inflammation. On this basis, the primary aim of our work was to study IL-26 levels in serum, BAL CSF) from active BD patients. Samples were collected from 95 BD patients (55 patients were in active stage) and 50 healthy controls (HC). They were investigated with ELISA for estimation of cytokines levels. Serum concentration of IL-26 resulted higher in both active [4.80±1.32] and inactive [2.77±1.026] BD than HC [0.31±0.14ng/ml; p

Purpose: We aimed to assess Vitamin D (VD) abnormalities in patients with severe obstructive sleep apnea–hypopnea syndrome (OSAHS), to study its association with clinical and polygraphic data, and to correlate VD levels with interleukin-17 (IL-17). Methods: Ninety-two patients with severe OSAHS were consecutively enrolled between September 2014 and February 2016 and compared to age-, sex-, and body mass index (BMI)-matched controls. Anthropometric parameters and medical history were collected. The serum levels of VD and IL-17 were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Results: Ninety-two severe OSAHS patients and thirty controls were enrolled in the study. All OSAHS patients had VD deficiency. The mean level of VD was at 7.9 ng/ml among OSAHS group versus 16.8 ng/ml among control group. IL-17A levels were elevated (20.3 pg/ml) in OSAHS group compared to healthy group (10.05 pg/ml). VD levels were negatively correlated with nocturia severity ( r = −0.26; P = 0.01) and positively correlated with mean O 2 saturation ( r = 0.59; P = 0.02) and lowest O 2 saturation ( r = 0.3; P = 0.03). IL-17 levels were positively correlated with nocturia severity ( r = 0.24; P = 0.03) and negatively correlated with mean O 2 saturation ( r = −0.42; P = 0.03). A significant negative association was observed between IL-7 and VD levels ( r = −0.64, P = 0.2 10 −4 ). The magnitude of this correlation was higher for important nocturia, lower MSaO 2 , or higher BMI. Conclusions: VD deficiency in patients with severe OSAHS is common with a negative association between IL-17 and VD serum levels. Hypoxia could play an important role in this association. Further studies are needed to clarify this relationship.

Vitamin D [25(OH)D3] deficiency has been associated with asthma as in many inflammatory and autoimmune pathologies; however, there is still a lack of data about the effects of administration of vitamin D in immune regulation in young asthmatic patients. In this study, we investigated its inhibitory effect on the immune response in young asthmatic patients and the possible mechanisms involved. Peripheral blood CD4(+) T cells from 10 asthmatic patients and 10 healthy controls were cultured under Th17 polarizing conditions in the presence or absence of [25(OH)D3], IL-17 cytokine production was determined by ELISA and flow cytometry. Messenger RNA (mRNA) expression of several factors related to Th17 cell function was determined by real-time PCR. The effect of [25(OH)D3]-treated dendritic cells (DCs) on CD4(+) T cell response was determined by ELISA and flow cytometry. Stimulation of naive CD4(+) T cells under Th17 polarizing conditions showed a higher Th17 cell differentiation in asthmatic patients than healthy controls. The addition of [25(OH)D3] significantly inhibited Th17 cell differentiation both in patients [P

Purpose Asthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: 'TLR', 'polymorphism', 'asthma', and their combinations. Results Meta-analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652-1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models (P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163-1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055). Conclusions The results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings.

The association between vitamin D receptor (VDR) polymorphisms and asthma risk has been inconsistently investigated, but published studies demonstrated conflicting results. The aim of the current study was to investigate the impact of TaqI, BsmI, ApaI, and FokI VDR polymorphisms on asthma disease by using a meta-analysis approach.Following the preferred reporting items for systematic reviews and meta-analyses guidelines, a systematic search and meta-analysis of the literature were conducted. Subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics.A total of 2,097 cases and 1,968 controls in eight case-control studies were included in meta-analyses. A significant association was found between TaqI polymorphisms and asthma risk [OR 1.488 (95 % CI 1.019-2.174); P = 0.040] in a codominant model. In the same way, BsmI was significantly associated with asthma risk [OR 2.017 (95 % CI 1.236-3.851); P = 0.017] in the codominant model. The homozygote BB BsmI genotype was found to confer significant asthma risk. FokI polymorphism was marginally associated with asthma risk [OR 1.187 (95 % CI 0.975-1.446); P = 0.088] in the codominant model. In contrast, no significant association was found between ApaI polymorphism and asthma risk. Subgroup analyses revealed that gender and age modified significantly the association between FokI polymorphisms and asthma risk (P = 0.035 and 0.013, respectively). Publication year and serum 25(OH) D level tended, marginally, to moderate the association between FokI polymorphism and asthma risk.TaqI, BsmI, and FokI VDR polymorphisms contribute to asthma susceptibility. The association between FokI polymorphism and asthma risk is influenced by study characteristics.

Recent genetic surveys have identified vitamin D receptor (VDR) as a susceptibility gene for several autoimmune diseases. This study was designed to investigate the association of VDR gene polymorphisms with Behcet's disease (BD) and Rheumatoid arthritis (RA). A case-control study including 151 BD, 106 RA patients and an appropriate number of healthy control subjects were performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. Association between TaqI polymorphism and BD was marginal under codominant and recessive models (P=0.078 and P=0.058, respectively). After stratification, we found evidence for a significant association between TaqI polymorphism and BD in the elderly subjects (P=0.037). The minor ApaI a allele tended to confer an increased risk for BD susceptibility (P=0.087). BD patients with VDR homozygous AA or aa genotypes were at increased risk for development of erythema nodosum (EN) skin manifestation (P=0.038). No significant association was observed for VDR ApaI and TaqI polymorphisms with RA risk (P>0.05). TaqI and ApaI polymorphisms might be modestly implicated in BD pathogenesis. They could be considered as potential biomarkers in BD rather than susceptibility genes. However, TaqI and ApaI seemed not to be implicated in RA pathogenesis.

Increased interleukin 33 in patients with neuro-Behcet's disease: correlation with MCP-1 and IP-10 chemokines

Interleukin-17 (IL-17) is a proinflammatory cytokines produced by T helper 17 (Th17) cells, which plays an important role in both innate and adaptive immune systems. Genetic variants in the IL-17 genes may influence the immunopathogenesis of many cancers. In our study, we investigated the association of three single-nucleotide polymorphisms (SNPs: -152 G/A, 7488 A/G and 7383 A/G) in the IL-17A and IL-17F genes with lung cancer risk, in the Tunisian population. The genotypic and allelic distributions of IL-17A and IL-17F genes polymorphisms were analyzed by Polymerase Chain-Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) for 239 patients and 258 healthy controls. Our results revealed a statistically significant association between IL-17F 7488G allele and increased lung cancer risk (P=0.028). Stratification analysis indicated that IL-17F 7488G allele enhances the risk of lung cancer development among men and oldest age subject groups (P0.05). Patients with IL-17F 7488G allele were also more likely to be diagnosed at advanced stage (P=0.04), or with metastatic lung cancer (P=0.035). Furthermore, no significant association between IL-17F 7383 A/G, IL-17 -152G/A polymorphisms and lung cancer risk was observed (P0.05). However, we reported contradictory findings on the association of IL-17 -152 G/A polymorphisms with lung cancer risk. In addition, we suggested the existence of a biological interaction between IL-17A, but not IL-17F polymorphisms and smoking. Our findings suggest that IL-17F 7488G allele is associated with increased lung cancer risk in the Tunisian population.

Interleukin 8 (IL-8), is a proinflammatory chemokine, has been reported to have angiogenic activity and to be responsible for tumor-associated angiogenesis in several cancers. In this study, we aimed to study the (IL-8) gene polymorphism in relation with risk development of non small cell lung cancer in Tunisian patient. Two single nucleotide polymorphisms (-251T/A [rs4073], +781C/T [rs2227306]) of the IL-8 gene were screened in 170 patients with NSCLC and 225 healthy controls by PCR-RFLP. Significant association for the IL-8 -251T/T genotypes (P=0.004) and an increased significant frequency of IL-8 -251T allele were noted in the patient's group (P=0.0007). Clinical analysis indicated a borderline positive association of IL-8 -251T allele among adenocarcinoma patients (P=0.003). Our study indicated that IL-8 -251T allele was highly associated with large tumor size and high grade stage of NSCLC. Moreover, a significantly increased risk of NSCLC was associated with IL-8 +781C allele in patients with large tumor size (T3 and T4) (P=0.004). IL-8 mRNA expression was found highly expressed in NSCLC patients compared to healthy controls. The same higher level was even found in patients carrying IL-8 -251T/T genotype. Our results indicated that the IL-8 promoter polymorphism is associated with NSCLC risk.

Interleukin-33 (IL-33) is one of the last discovered members of the human IL-1 family. It is involved in the pathogenesis of many inflammatory diseases. This study investigates the relationship between IL33 gene variants and serum protein levels with the development of childhood asthma. We analyzed in this case-control study the distribution of two IL33 polymorphisms, rs7044343 and rs1342326, within 200 Tunisian children, using predefined Taqman genotyping assays. IL-33 serum levels were assessed by commercial sandwich Enzyme-linked immunosorbent assay (ELISA). The presence of rs1342326 polymorphism was significantly associated with a lower risk of asthma development. The CC [OR=0.20, CI (0.08-0.50)] and AC [OR=0.24, CI (0.11-0.49)] genotypes, as well as the C-allele [OR=0.40; CI: 0.26-0.61, P=0.00001] were associated significantly with a decreased asthma risk. However, the C-allele was more frequent in severe asthma patients than in milder ones. No association was found between rs7044343 variant and asthma. The level of IL-33 in sera was significantly increased in asthmatic children [1.48±0.47pg/mL] compared to controls [0.70±0.18pg/mL; P0.001]. Furthermore, this increase of IL-33 was associated with the presence of rs1342326 C allele. The IL33 rs1342326 polymorphism was associated with a lower childhood asthma risk in the Tunisian population and a higher IL-33 protein expression.

Interleukin-37 (IL-37) has been identified as a novel anti-inflammatory cytokine. The present study aimed to evaluate the expression of IL-37 in serum and in peritoneal fluid to determine its clinical significance in endometriosis. Enzyme-linked immunosorbent assay (ELISA) was performed to examine serum IL-37 levels in patients with endometriosis and healthy controls. Peritoneal fluid IL-37 mRNA and NFκB expression were quantified by real-time reverse transcription polymerase chain reaction assays. The association of IL-37 levels with clinical factors and prognosis of endometriosis was analysed. We found that IL-37 levels in PF and in serum were significantly higher in patients with endometriosis compared to women without endometriosis (P=0.0005). IL-37 levels were highly expressed in PF [132.38±34.62pg/mL; P

The release of TSLP and IL-33 affect the skin integrity, which unsettled transcription factor regulators. We investigate TSLP and IL-33 in Behcet disease (BD) and we prove the effect of the anti-inflammatory cytokine IL-37 in BD skin lesions on TSLP production. TSLP, IL-33 and GATA-3/T-bet, were measured using PCR in BD skin lesions. We tested the suppressive effect of IL-37 on skin samples stimulated with a cytokine mixture inducing TSLP expression. TSLP and IL-33 were increased in BD patients particularly in patients having skin manifestations and correlate with indexed skin lesions. TSLP expression in BD with skin lesions correlates significantly with the transcription factors GATA3/Tbet ratio. The anti-inflammatory mediator IL-37 acted as a suppressor of TSLP-skin synthesis. The microenvironment in cutaneous lesions of BD patients' skin lesions is dominated by the expression of IL-33 and TSLP along an inflammatory Th2-type current. IL-37 acts as a booster to restore homeostasis.

The pathogenesis of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is uncertain and likely to be a multifactorial process. The molecular mechanisms of the relationship between vitamin D status and inflammatory biomarkers are still not well understood. We aimed to investigate the relationship between Interleukin 17 (IL-17) and vitamin D among severe OSAHS patients. It was a coss-sectional survey carried between September 2014 and September 2015 in RABTA Pulmonary Department, Tunis. Patients with a severe OSAHS were randomly enrolled. Included patients had to show none of the following criteria: clinical signs of heart failure, autoimmune or acute inflammatory disease, cancer, parathyroid disorders, chronic liver disease, chronic renal disease, sarcoidosis, or osteoporosis. Anthropometric parameters and medical history were collected. The serum levels of IL-17 and 25-hydroxyvitamin D (25(OH) D) were determined by ELISA. Ninety two patients were enrolled with a mean age of 52.3 years (52% male, 48% female). All patients had a vitamin D deficiency (mean level: 7.9ng/ml). IL-17 levels were elevated (mean level: 20.3pg/ml). A negative association was observed between plasma IL-7 levels and serum 25(OH)D (r=-0,64540, p -4 ). The level of 25(OH)D was positively correlated with hypertension (p=0,026), diabetes (p=0.006), nycturia (p=0,026), the mean O2 saturation (p=0,034) and lowest O2 saturation (p=0,015). IL-17 levels were positively correlated only with nycturia (p=0,024). Both 25(OH)D and IL-17 may be involved in the pathogenesis of OSAHS and may represent a target for therapeutic intervention. Furthers studies are needed to clarify this association.

The aim of this study was to look for a relationship between vitamin D receptor (VDR) genetic polymorphisms and platinum-based chemotherapy responses in addition to prognosis in a group of Tunisian patients with advanced non-small-cell lung cancer (NSCLC). It was a cross-sectional study. Patients with NSCLC refered to La Rabta Pulmonary Departement, Tunis, were randomly enrolled. Platinum-based chemotherapy was given to each patient and the therapeutic effect was evaluated. The genotype frequencies of two VDR polymorphisms, FokI (rs2228570) and ApaI (rs7975232) were studied. Sixty five patients were enrolled.When patients were stratified according to gender, age, and smoking, significant associations were detected with FokI and ApaI polymorphisms. Among the enrolled patients, 72.7% responded to chemotherapy and 28.3% patients were non responders. The genotypic and allelic frequencies of FokI were not significantly different between chemotherapy responders and non responders. However, the genotypic and allelic frequencies of ApaI were significantly different between the responders and non responders. The subjects carrying the homozygous AA genotype had a significant increased risk to non response (66.6% vs 42.8%). The FF genotype carriers of FokI polymorphisms had a longer mean overall survival (OS) compared with Ff carriers (10.7 vs 5.8 months). Our study demonstrated the effect of ApaI and FokI polymorphisms of the VDR gene on the chemotherapy response in Tunisian patients with NSCLC, as well as a prognostic role of the VDR gene polymorphisms.

The vascular endothelial growth factor (VEGF), a major angiogenic factor, is known to play an important role in the development of endometriosis. The aim of this study was to investigate the association of three VEGF (-460 C/T, +405 G/C, and +936 C/T) polymorphisms with the risk of endometriosis in the Tunisian population. This study includes 105 women with endometriosis and 150 women with no laparoscopic evidence of disease. Genotyping of the VEGF -460 C/T, +405 G/C, and +936 C/T polymorphisms were performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The distribution of genotypes (P = 0.006) and allele (P = 0.0009) frequencies of the +936 C/T polymorphism was significantly different between patients and controls. Patients with stages III-IV endometriosis showed a higher VEGF + 936T allele frequency than controls (P = 0.0001). However, the distribution of genotypes and allele frequencies of the VEGF -460 C/T and +405 G/C polymorphisms did not differ significantly between endometriosis patients and controls. These findings suggest that the VEGF +936 C/T polymorphism may be a risk factor for endometriosis development and the VEGF +936 T allele is associated with an increased risk of stages III-IV endometriosis in the Tunisian population.

Vitamin D receptor (VDR) polymorphisms have been studied as potential contributors to multiple sclerosis (MS). However, published studies differ with respect to study design and the significance of the effects detected. The aim of this study was to quantify the magnitude of the risk associated with the TaqI, BsmI, ApaI and FokI VDR polymorphisms in MS using a meta-analysis approach. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic search and meta-analysis of the literature. Subgroup analyses were performed to detect potential sources of heterogeneity from the selected study characteristics. The stability of the summary risk was evaluated using sensitivity analyses. The meta-analysis included a total of 3300 cases and 3194 controls from 13 case–control studies. There were no significant associations found between TaqI and BsmI polymorphisms and MS risk. The association between the ApaI polymorphism and MS risk was significant in the homozygous and codominant models (P=0.013 and P=0.031, respectively), suggesting that the AA ApaI genotype might be a significant MS risk factor. Publication year and age significantly affected the association between TaqI polymorphisms and MS (P=0.014 and P=0.010, respectively), which indicates a protective effect of the major T allele. The AA ApaI and FF FokI genotypes are significant risk factors for MS. The association between the TaqI polymorphism and MS risk is significantly affected by study characteristics.

Objective Rheumatoid arthritis (RA) is thought to be triggered by various genetic and environmental factors. Few human epidemiologic studies demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are associated with RA. We aimed to evaluate the effects of TLR polymorphisms on the risk of RA pathogenesis by using a meta-analysis approach. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature was conducted. We screened the medical literature based on keywords search in MEDLINE and EMBASE ‘Toll-like receptor’, ‘polymorphism’, and rheumatoid arthritis. Meta-analyses were performed under the random-effects model by using: (1) recessive, (2) homozygous, (3) dominant, (4) codominant and allele contrast models. Results A total of 3086 cases and 3756 controls in nine studies were included in the meta-analysis. Association between TLR4 Asp299Gly and RA risk was marginally significant [OR = 0.856 (95% CI, 0.716–1.022); P = 0.086] in the homozygous model. AA and GG homozygote genotypes tended to be significant protective factors against RA risk. Conclusion Our overall analyses indicated that TLR4 Asp299Gly polymorphism might contribute to RA pathogenesis.

Vitamin D receptor (VDR) polymorphisms have been inconsistently investigated in type 1 diabetes (T1D). However, the results are inconsistent and inconclusive. The current study aimed to investigate the role of TaqI, BsmI, ApaI and FokI VDR polymorphisms in T1D disease. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature, since 1998 until december 2013, was conducted. Subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics. Meta-analyses yielded a non-significant association of TaqI polymorphism with T1D [OR = 1.014 (0.783–1.312); P = 0.918] in the recessive model. The BsmI polymorphism was not associated with T1D [OR = 1.44 (0.944–1.386); P = 0.171] in the dominant model. Also, ApaI polymorphism was not associated with T1D risk [OR = 0.996 (0.859–1.155); P = 0.960] in the homozygous model. The FokI polymorphism was not associated with T1D risk [OR = 0.968 (0.743–1.263); P = 0.813] in dominant model. Stratification according to study characteristics showed that publication year, age, gender, estimated vitamin D levels and latitude moderated significantly association between VDR polymorphisms and T1D disease. Meta-analysis on haplotypes revealed that BAT might be a significant risk factor for T1D [OR = 1.331 (0.957–1.850; P = 0.089]. However, the bAT was found to be a significant protective factor [OR = 0.639 (0.460–0.887); P = 0.007]. As conclusion, individual VDR polymorphisms seemed not to be associated with T1D risk. However, haplotypes contributed significantly to disease susceptibility. Study characteristics moderated the association between VDR polymorphisms and T1D. These results suggested that, in T1D pathogenesis, VDR polymorphisms interact with each other and with environmental factors.

Many studies reported that Vitamin D Receptor (VDR) gene polymorphisms might influence the cancer risk due to their antiproliferative, antiangiogenic, and apoptotic effects. The aim of this study was to explore the genetic association of VDR polymorphisms with lung cancer risk in Tunisian population. The genotype and haplotype frequencies of four VDR polymorphisms, FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) were studied using polymerase chain reaction and restriction fragment length polymorphism analysis in 240 patients with lung cancer and 280 healthy controls. The distribution of genotype frequencies differed significantly between lung cancer subjects and controls (FokI P adj = 0.002; ApaI P adj = 0.013). Haplotype analyses revealed a significant association between G-A-C and A-C-T haplotypes and lung cancer risk (P corr = 0.0128, P corr = 0.008). When patients were stratified according to gender, age, and smoking, significant associations were detected with FokI and TaqI polymorphisms. We found a lack of association between BsmI, TaqI polymorphisms and lung cancer risk (P > 0.05). Only, the attributable proportion due to interaction and the synergic index for interaction between ApaI polymorphism and smoking were statistically significant (P adj = 0.74, 95 % CI = 0.38-1.20) and (P adj = 0.63, 95 % CI = 0.05-1.21), respectively. Both the additive interaction measures suggested the existence of a biological interaction between SNP ApaI, but not FokI, and smoking. The multiplicative interaction measure was not statistically significant (P > 0.05). This is the first study in Tunisia, which suggested that VDR FokI and ApaI polymorphisms might be risk factors for lung cancer development.

BACKGROUND Lung cancer (LC) is one of the most lethal malignant disorders; it is generally divided into two groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In our present study we have been interested to NSCLC. Several approaches were adopted to study the etiology or pathophysiology of this disease. As recent reports have focused on the genetic susceptibility to this disease, with many candidate genes studied, we chose TNF in view of the major role it plays in the immune pro inflammatory system and its association with increased risk of a variety of human cancers. We have investigated three polymorphisms in the promoter region of the TNFalpha gene (-308 G/A and -238 G/A) and TNFbeta + 252A > G for their susceptibility to non-small cell lung cancer (NSCLC) in Tunisian population. METHODS We compared the distribution of these polymorphisms between 133 NSCLC patients and 174 healthy controls using a polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequencies of the two TNFalpha (-238 and -308) "A" alleles were significantly higher in NSCLC patients than in healthy controls respectively (p = 0.01; OR = 1.92; 95% CI 1.14 - 3.23 and p = 0.0000008; OR = 3.65; 95% CI 2.12 - 6.30), whereas the frequency of the TNFbeta + 252 G allele was approximately similar in the two compared groups. RESULTS This study supports a relationship between TNFalpha -238G/A and TNFalpha -308G/A polymorphisms and the susceptibility to lung cancer. Contrary to other studies, the -308 A and -238A alleles have an inductive action on lung cancer development and progression in our Tunisian population. CONCLUSIONS This study indicates that the TNFalpha -308G > A and TNFalpha -238G > A would be associated with increased susceptibility to lung cancer but no significant association was found in TNFbeta + 252A > G polymorphism.

Background: Behçet’s disease (BD) is a systemic vasculitis with unknown aetiology, where, besides genetic predisposition, an immune dysregulation involving T and B lymphocytes and hyperactive neutrophils contribute to disease pathogenesis. The aim of this study was to determine the cytotoxicity of natural killer (NK) cells in bronchoalveolar lavage (BAL) from BD patients with pulmonary manifestations. Methods: BAL was performed in 27 patients with BD and pulmonary manifestations, 14 patients with Rheumatoid Arthritis (RA) and 23 healthy controls (HC). Related orphan receptor C (RORC) and forkheadbox P3 (FOXP3) mRNA transcript were determined in BAL by reverse transcription–polymerase chain reaction (RT-PCR). NK cells, NK cell cytotoxicity, and lymphokine-activated killer (LAK) activity against K562 cells were measured by flow cytometry. Proportions of NK precursors and expression of genes for IL-2 receptor β (IL-2Rβ; CD122), perforin, and granzyme in NK cells were measured by flow cytometry or RT-PCR. Results: The analysis of transcription factors revealed an increase in the RORC/FOXP3 ratio (Th17/Treg cells) in BAL from BD patients. Percentages of NK were significantly lower in BD than in RA patients and healthy controls. Purified NK cells derived from BD patients were found to have lower cytotoxicity and LAK activity than those from controls. This defect of NK cells in BD patients was related to down-regulation of perforin and granzyme expression in NK cells. Conclusion: In BD patients, the increased RORC/FOXP3 ratio indicated an inflammatory state of the lung. NK cells were decreased together with an impairment of their activity due to a defective expression of granzyme and perforin. These abnormalities possibly contribute to immune system dysregulation found in BAL of BD patients with pulmonary manifestations.

Behçet's disease (BD) is an autoimmune/inflammatory disease characterised by abnormal production of proinflammatory cytokines. Interleukin-33 (IL-33) is a novel cytokine of the IL-1 cytokine family that has been recently implicated in several inflammatory and autoimmune diseases and the association of IL-33 with BD has remained unknown. Here we document for the first time, IL-33 level and its association with BD.Serum IL-33 levels were measured in 46 BD patients (20 patients in active stage) and compared to multiple sclerosis (MS), rheumatoid arthritis (RA) patients and to healthy controls. In parallel, the transcription factor NF-κB that mediates IL-33 transcription was also measured. IL-33 mRNA was also quantified in freshly isolated PBMCs and in skin biopsies by real-time RT-PCR analysis. IL-6 and IL-17 were measured by ELISA.Serum IL-33 level was significantly higher in active BD patients [159.65 ± 61.7 pg/mL] compared to inactive BD patients [85.57 ± 21.07 pg/mL] (p0.0001) and healthy controls [70.03±25.95 pg/mL] (p0.0001). Active BD patients expressed lower IL-33 levels than the control disease group, RA and MS patients [p=0.00021]. The serum IL-33 level in active BD patients was corroborated by IL-33 mRNA expression in fresh PBMC. Patients with active BD with retinal vasculitis showed the highest serum IL-33 level. We further stimulated cultured PBMCs with phorbol myristate acetate (PMA) and ionomycin and macrophages with LPS for 24 h. Following stimulation the levels of IL-33 were increased similarly in PBMC [92.35±24.81 pg/ml] and macrophages [93.10±21.58 pg/ml] in active BD patients compared to healthy controls. NF-κB DNA binding activity was significantly increased in PBMCs of active BD patients particularly in LPS-stimulated macrophages compared to healthy controls. IL-33 mRNA expression in the skin lesions of patients with active BD was significantly increased compared to that in healthy skin biopsies [p=0.00016]. A significant relationship was found between the levels of IL-33 and IL-17 [r=0.533; p=0.0024] and IL-33 and IL-6 [r=0.661, p=0.0015] in 20 active BD patients.Elevated IL-33 level in active BD patients was found to correlate with disease activity. Targeting IL-33 should be approached with caution.