Vasculitis and the NLRP3 inflammasome.

PURPOSE OF REVIEW: Vasculitis are a group of heterogeneous conditions characterized by chronic inflammation of blood vessels, leading to tissue destruction and organ failure. Vasculitis is an inflammatory process in which immune effector cells infiltrate blood vessels and surrounding tissues. The involvement of inflammasomes seems to occur during inflammatory processes. RECENT FINDINGS: Studies have emphasized that genetic susceptibility is an important aspect of the pathogenesis of vasculitis. The innate immune system is a major contributor to these inflammatory diseases, suggesting that the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role. NLRP3 activation causes the assembly of a large multiprotein and leads to the secretion of bioactive interleukin (IL)-1ß and IL-18 as well as the induction of inflammatory cell death, termed pyroptosis. Accumulating evidence confirms the involvement of this cascade in sterile inflammatory diseases and other vascular diseases. SUMMARY: In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, and discuss the potential of the NLRP3 inflammasome as a therapeutic target.

Strong association of functional polymorphism in IL-12B with susceptibility to chronic hepatitis B in Tunisia.

BACKGROUND: The chronicity or clearance of hepatitis B virus (HBV) infection depends on viral and genetic variables. The immune response against HBV is thought to be responsible for viral persistence or clearance. Cytokines such as interleukin 1-2B (IL1-2B) involved in the T-helper 1 system are key mediators in the defence mechanisms against viral infection and play a role in the regulation of HBV clearance during infection. We aimed to examine whether the polymorphic variant TaqI polymorphism in the 3'-untranslated region (3'-UTR; rs3212227) suspected to modulate interleukin-levels of IL-12B has an influence on the risk of development of chronicity after HBV exposure. METHODS: Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method for 236 patients with chronic hepatitis B (CHB) and 240 controls from different cities of Tunisia recruited in the Pasteur Institute of Tunisia between January 2017 and December 2018. RESULTS: We found that the IL-12B polymorphism was associated with a significantly increased risk of CHB in patients (p = 1 × 10-3 ; χ 2 = 10.31 and odds ratio [OR] = 2.14; 95% confidence interval [CI] = 1.30-3.52) when AC/CC variant genotypes were compared with the wild-type AA homozygote. Statistical significance was found when CHB-males were compared with CHB-females (p = 2 × 10-7 ; χ 2 = 26.62 and p = 1 × 10-3 ; χ 2 = 10.36, for genotypic and allelic frequencies, respectively). Also, CHB-patients carrying C-allele less than 50-years were at an increased risk of developing chronic HBV infection than patients more than 50-years (p = 6.1 × 10-5 ; χ 2 = 16.07). CONCLUSIONS: These results suggest that the C-allele would affect susceptibility to chronicity after HBV exposure in Tunisian patients especially for males less than 50-years. Age and sex have an influence on this polymorphism in CHB Tunisian patients.

GLCCI1 and STIP1 variants are associated with asthma susceptibility and inhaled corticosteroid response in a Tunisian population.

Objective: Pharmacogenetic studies have recognized specific genes that highly correlate with response to inhaled corticosteroids (ICS) treatment in asthma patients. Among the genes identified, we selected glucocorticoid-induced transcript 1 (GLCCI1) and stress-induced phosphoprotein 1 (STIP1) to evaluate the impact of these gene polymorphisms on ICS treatment response in Tunisian asthmatics.Methods: We analyzed four single nucleotide polymorphisms (SNPs): two in GLCCI1 (rs37972 and rs37973), and two in STIP1 (rs2236647 and rs2236648), which are genes associated with susceptibility to asthma and response to ICS in a Tunisian cohort. The SNPs were genotyped using reverse transcriptase polymerase chain reaction (RT-PCR) techniques.Results: This case-control study consisted of 230 adult asthmatic patients and 236 healthy subjects. Seventy-five asthmatics were selected and followed through 12 weeks of routine treatment. The T allele rs2236648 in STIP1 was associated with allergic asthma (OR = 0.38, 95%CI = 0.20-0.69, p = 0.001). The rs37972 and rs37973 of GLCCI1 were associated with a higher risk of asthma (p < 0.001). The T allele rs37972 and G allele rs37973 were correlated with a strong risk for developing severe asthma (p < 0.001). Asthma patients carrying the rs37973 GG genotype had less improvement in the forced expiratory volume in one second (FEV1) than those with the AA or AG genotypes after 12 weeks of treatment (p < 0.001). Also, the G allele of rs37973 was associated with worse response to ICS after 12 weeks of treatment (p < 0.001).Conclusion: The rs37972 and rs37973 polymorphisms can serve as potential asthma risk biomarkers in a Tunisian population.

IL-26 gene variants and protein expression in Tunisian asthmatic patients.

The interleukin-26 (IL-26), a member of the IL-10 family is one of the latest discovered cytokines which contributes in numerous chronic autoimmune and inflammatory disorders. In the current case-control study, we investigated the distribution of three IL-26 single nucleotide polymorphisms (SNPs) (rs7134599, rs2870946 & rs1558744) in 440 Tunisian adults via Taqman genotyping assay. The presence of rs7134599 and rs1558744 polymorphisms considerably reduced the risk of developing asthma while the rs7134599 AA [OR = 0.40, CI: 0.23-0.70] and AG [OR = 0.50, CI (0.32-0.76)] genotypes protected against the asthma risk. The rs7134599 A allele was correlated with a lower risk of developing severe asthma (p < 0.001) while that of the rs2870946 CC genotype was associated with a higher risk of developing asthma in smoking patients (p < 0.001). In addition, we measured the IL-26 levels in the serum by an Enzyme-linked-Immunosorbent Assay (ELISA). During the analysis, we found that IL-26 serum levels were incredibly increased in asthmatic patients compared to the healthy controls. Our study revealed a significant association of IL-26 gene polymorphisms with asthma for the first time which can serve as biomarkers for asthma in the Tunisian population. The significant increase of IL-26 serum protein levels in asthma patients suggested a major role of IL-26 in asthma phenotypes.

Association of BTLA rs1982809 polymorphism with lung cancer risk in Tunisian population.

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.

Gene Variants, mRNA and NOD1/2 Protein Levels in Tunisian Childhood Asthma.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 < 0.01. The mRNA expression of NOD1, but not NOD2, was enhanced in asthma patients compared to Controls. We noted a significant difference between asthmatics and healthy controls in NOD1 protein expression (asthma patients : 31.18 ± 10.9 pg/ml, Controls: 20.10 ± 2.58 pg/ml; p < 0.001). CONCLUSIONS: The NOD1 rs2075820 variant was associated with a higher childhood asthma risk and the NOD1 expression at mRNA and protein levels was significantly increased in asthma patients.

Elevated expression of TSLP and IL-33 in Behçet's disease skin lesions: IL-37 alleviate inflammatory effect of TSLP.

The release of TSLP and IL-33 affect the skin integrity, which unsettled transcription factor regulators. We investigate TSLP and IL-33 in Behçet 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.

IL-33 gene variants and protein expression in pediatric Tunisian asthmatic patients.

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; P<0.001]. 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.

Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults' Asthma.

INTRODUCTION: Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We found that rs12794714 and rs10877012 SNPs were associated with asthma risk.

IL-8 Gene Variants and Expression in Childhood Asthma.

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 < 0.0001, P = 0.004; respectively). Higher levels of IL-8 mRNA are detected in subjects with moderate to severe asthma. The presence of IL8-251 A/T (rs4073) and + 781C/T (rs2227306) polymorphisms was significantly associated with an increased risk of asthma (P = 0.002, P = 0.036, respectively). In addition, we noted a significant association between these polymorphisms and an elevated risk of atopic asthma (P < 0.05). For rs2227306 SNP, the highest median level of IgE was detected for the presence of TT genotype (865 ± 99.74 IU/mL). Although, the rs4073 polymorphism conferred a higher risk to develop asthma at an advanced stage of severity (P = 0.008). The rs4073 T and rs2227306 C alleles are considered as risk factors for asthma development. The rs4073 T allele is represented also as a risk factor for asthma severity in Tunisian children. CONCLUSIONS: Both IL-8 gene and protein expression may play a key role in asthma pathogenesis.

Role of metalloproteinases MMP-2 in asthma.

Background - Many metalloproteinases (MMPs) play a role in the pathogenesis and modulation of the severity of asthma. MMP-9 is the predominant in asthma but other MMPs are involved such as the MMP-2. Aim - To determine the role of single nucleotide polymorphism of the gene MMP2 in susceptibility to asthma and its severity. Methods - Study case-control with prospectively enrolled patients with asthma and healthy subjects. We determined within two groups genotypes corresponding to the MMP2 polymorphism in -735C / T position, using a polymerase chain amplification technique associated with a polymorphism in the length of restriction fragments. Results - We included 150 patients with asthma and 150 healthy controls. Comparison of allele and genotype frequencies of the studied polymorphisms between patients and controls showed that there was no association between the SNP-735C / T and susceptibility to asthma and its severity. Conclusion - The role of MMP 2 in asthma remains unclear and no study has been conducted till date, to determine the role of MMP-2 -735C/T gene polymorphism in asthma. This study does not disprove such association. Further studies are needed to clarify the exact role the pathogenesis of asthma.

Vitamin D receptor TaqI and ApaI polymorphisms: a comparative study in patients with Behçet's disease and Rheumatoid arthritis in Tunisian population.

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 Behçet'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.

Interleukin-17A and -17F genes polymorphisms in lung cancer.

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 (P<0.05). 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 (P>0.05). 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.

Association of vitamin D receptor FokI and ApaI polymorphisms with lung cancer risk in Tunisian population.

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.

IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia.

OBJECTIVES: IL-17A and IL-17F are new pro-inflammatory cytokines implicated in neutrophilic inflammation and thus, involved in the pathogenesis of asthma. We investigated the possible association among asthma and IL-17A -197G/A (rs2275913), IL-17F 7488A/G (rs763780) and IL-17F 7383A/G (rs2397084). METHODS: The study was performed in 171 patients with asthma (mean age 9.5 years, 105 boys, and 66 girls) and 171 healthy individuals matched with patients in age and sex. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect genes' polymorphisms. RESULTS: IL-17A -197G/A and IL-17F 7383A/G were associated with asthma in children (p = 0.008, p = 0.001, respectively). No association was found with IL-17F 7488A/G polymorphism. Haplotype analysis revealed a significant association between GA and AG haplotypes and asthma (p = 0.004, p = 0.02). When patients were stratified according to the atopic status, no significant association was detected with any of the three studied variants. CONCLUSION: Our results suggested that SNPs in IL-17A and IL-17F confer susceptibility to childhood asthma in Tunisia.

Association of vitamin D receptor gene polymorphisms with asthma risk: systematic review and updated meta-analysis of case-control studies.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: TaqI, BsmI, and FokI VDR polymorphisms contribute to asthma susceptibility. The association between FokI polymorphism and asthma risk is influenced by study characteristics.

IL-38 in Behçet's disease: Gene expression in bronchoalveolar lavage from patients having pulmonary involvement.

The etiological complexity of Behçet disease (BD), an immune-mediated rare form of vasculitis characterized by multi-organ involvement, is still elusive due to an incomplete understanding of the synergy between genetic susceptibility, environmental triggers, and an abnormal immune response. The diagnosis of BD relies on clinical symptoms. Lung inflammatory disorders are severe conditions of patients with BD, here we focus on the expression of biomarkers in BD patients with pulmonary manifestations. Aiming to identify additional discriminating biomarker patterns, we measured and compared protein and gene expression of IL-38 and a broad panel of selected genes in bronchoalveolar cells of patients suffering from BD with and without pulmonary involvement compared to controls. ELISA and RT-PCR analysis were applied. The first principal analysis highlighted decreased IL-38 level in BD patients compared to Rheumatoid Arthritis (RA) patients and controls: BD patients expressed lower IL-38 levels, particularly in cases with pulmonary involvement. The area under the curve (AUC) of the receiver-operating characteristic curve showed that IL-38 may be an eventual biomarker for BD. Co-cultured recombinant IL-38 and stimulated memory PBMCs of active BD, were able to suppress IL-17 and NLRP3 inflammasome and ameliorate the secretion of IL-10 and TGFß. Transcription factors of the IL-1 family (IL-1ß, IL-18, IL-32, IL-33 and IL-37) along with IFN-γ, IL-17, RORγt, Foxp3, TGFß, IL-10 and NLRP3 inflammasome were the parameters that are the main contributor to the segregation between BD with and without lung involvement. Our results indicate that IL-38 might be involved in the pathogenesis of BD and the combined gene expression in BAL suggests distinct mechanisms governing the inflammatory disorders in the lung.

Serum IL-33 levels and skin mRNA expression in Behçet's disease.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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] (p<0.0001) and healthy controls [70.03±25.95 pg/mL] (p<0.0001). 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. CONCLUSIONS: Elevated IL-33 level in active BD patients was found to correlate with disease activity. Targeting IL-33 should be approached with caution.

Tumor necrosis factor gene polymorphisms in Tunisian patients with non-small cell lung cancer.

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.

Elevated levels of IL-32 in cerebrospinal fluid of neuro-Behcet disease: Correlation with NLRP3 inflammasome.

Interleukin-32 (IL-32) is a pro-inflammatory cytokine that induces other cytokines involved in inflammation, including tumour necrosis factor (TNF)-α, IL-6 and IL-1ß. The objective of this study was to evaluate IL-32, NLRP3 inflammasome, IL-1ß, IL-6, IL-17A, TNF-a, IL-10 and IL-37 in cerebrospinal fluid (CSF) and paired serum samples of patients with neuro-Behcet disease (NBD) by ELISA, RT-PCR and Western blotting analysis. A receiver operating characteristic (ROC) curve was employed to explore of the predictive value of IL-32 levels. IL-32, IL-1ß, IL-6, IL-17 and TNF-α, were highly expressed in CSF of NBD and multiple sclerosis (MS) patients contrasting with their low levels in patients with noninflammatory neurological diseases (NIND) and Headache attributed to BD (HaBD). IL-32 and NLRP3 inflammasome in NBD, correlate significantly with CRP and ESR. IL-32 should be studied further as potential BD biomarker of inflammation in NBD.