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.

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.

Giant pulmonary hydatid cyst in children.

Hydatid disease is still endemic in Tunisia. It is mostly seen in young people less than 40 years and children are affected in one third of cases. The lungs are the predominant location in children. Our study aims to define the particularities of children PHC's (pulmonary hydatic cyst) management, the characteristics of giant cyst and to study predictive factors of complications. We included retrospectively 105 children with PHC followed between 1999 and 2019. Patients were aged less than 16 years with surgically confirmed diagnosis of PHC. Two groups of cysts were defined: giant cysts which were 10 cm across or more, and no giant cysts.The sex-ratio was 1.38 with a mean age of 10.5±3 years. The symptomatology was dominated by cough (59%), thoracic pain (51%) and hemoptysis (46%). Giant cysts were observed in 24 (22.9%) patients. Dyspnea (29% vs 5% p<0.001) and thoracic pain (88% vs 41% p<0.001) were significantly more frequently reported in giant cysts. Eighty-six patients had a single cyst (83%) and 19 had multiple cysts (17%). Giant cysts accounted for 22,9% (24 cases). Thoracic ultrasonography was diagnostic in 77.4%. The thoracic CT scan was performed in 27 children with inaccessible cysts in thoracic ultrasonography or in diagnostic doubt.Patients were all treated surgically. Surgical procedures consisted of cystectomy (59%), pericystectomy (18%) and pulmonary resection when parenchyma was destroyed (23%). Parenchymal resection was more often performed in complicated cysts (27% vs 20% p>0.05) and in giant cysts (41% vs 18% p<0.05). A two-stage thoracotomy was performed in the 4 patients with bilateral cysts. Thirteen patients presented immediate post-operative complications which occurred more frequently in complicated and giant cysts. Hospital stay was longer in complicated cysts (16±9 days vs 7±3 days; p<0.001) and in giant cysts (14±9 days vs 11±8 days; p>0.05). In endemic regions, the diagnosis of PHC in children should be based on the combination of thoracic radiography and ultrasonography which are effective, not costly, safe and accessible. Complicated and giant PHC cause lung damage leading to extensive parenchymal resection. They are more associated with post-operative complications prolonging hospital stay and increasing expenses.

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.

Cost estimation of medical care management of lung cancer in Tunisia.

BACKGROUND: Lung cancer management is very expensive for the Tunisian healthcare system. AIM: The aim of this study was to evaluate the direct costs of treating lung cancer in Tunisia, and to identify the main treatment of high expenditure. METHODS: A retrospective study was conducted in 2012 including all patients admitted between 2008 and 2010 for lung cancer management. The hospital payment system was used to estimate the direct costs of the medical care management of lung cancer. RESULTS: We collected 549 patients and the majority of patients were diagnosed with advanced stages of the disease: 60 % in stage T4 and 59 % in stage M1. 26 % of patients underwent surgery and 44.1 % chemotherapy. The total direct costs of lung cancer management were estimated to be TND 3900 (US$ 1980) per patient. CONCLUSIONS: Chemotherapy accounted for the largest percentage of direct costs (46 %) followed by the cost of the hospital stay. Primary prevention, based on the application of policies to control tobacco, is the best strategy to reduce this morbidity.

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.

The role of the pathologic exam in the acute exacerbations of the interstitial pneumonia.

Acute exacerbation of interstitial pneumonia is a new terminology with recent debated criteria. Its prognosis is bad and its management remains non consensual. This lack of consensus seems to be due to the lack of knowledge concerning the physiopathologic phenomenon. This lack of knowledge results in few efficient therapeutics. The diagnosis of acute exacerbation is challenging for clinicians and the real place of the pathologic exam remains unknown. Our aim was to assess the different situations faced by the pathologists by emphasizing their real role.

Diagnostic value of the bronchoalveolar lavage in interstitial lung disease.

Background The bronchoalveolar lavage (BAL) cellular analysis is an invasive method of exploration of the lung. Its diagnostic value in interstitial lung disease (ILD) is integrated to a multi-disciplianry approach implicating clinicians, radiologists and pathologists. Aim We targeted to evaluate the diagnostic value of the BAL. Methods We reported a retrospective study about patients hospitalized for an ILD since the 1st January 2011 to the 31th December 2013. Thirty three patients were admitted in the Department of Pulmonology and the BAL analyses were studied in the Department of Pathology of the same hospital. The different cell patterns were compared to the final diagnostics. Results our study contained 4 non specific interstitial pneumonia (NSIP), 10 usual interstitial pneumoniae (UIP), 4 organizing pneumoniae (COP), 8 sarcoidosis, 2 hypersensitivity pneumonitis, 3 infectious pneumonitis, 1 lymphoma and a pulmonary adenocarcinoma. We considered positive results those that were compatible with the final diagnosis. The profile lavage was typical in 1 NSIP, 3 UIP, 3 COP, 1 hypersensitivity pneumonitis, 6 sarcoidosis, 3 infectious pneumonitis and 1 adenocarcinoma. Among the 17 cases with an atypical profile lavage, radiological features were diagnostic in 10 cases. This finding highlights the fact that 7 cases/ 33 presented simultaneously an atypical profile lavage and non specific radiological findings Conclusion Our results put emphasis on the diagnostic value of BAL especially when it is integrated to a multi-disciplinary approach. Its value in the follow up, the evaluation of the activity of the disease and the prognosis is being more and more reported.

Childhood tuberculosis: A descriptive study in a pneumo-pediatrics department in Tunisia.

Objective to assess the different localizations of tuberculosis (TB) in children in a pneumopediatric department in Tunisia and to describe its diagnosis tools since clinical investigations of childhood TB are challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Methods Forty-six cases of TB in children were studied between 2008 and 2013. Clinical history, examination and chest radiography were reported. Several investigations have been conducted to confirm the diagnosis of TB such as: tuberculin skin test (TST), bacteriological and histological investigations. Anti-tuberculosis treatment was prescribed according to the national guidelines. Results Cough and deterioration in general condition were the most frequent symptoms (47.8% and 43.7%). The other children presented cervical swelling (19.5%), chest pain (17.4%) and hemoptysis (4.3%). Abnormalities have been found in chest radiography in 35 cases (76%). TST was positive in 73% of cases. Diagnosis of TB was confirmed in 56.6% of cases by Mycobacterium tuberculosis (MT) isolation and/or biopsy. The diagnosis was made on presumptive arguments in 20 cases (43.4%) based on a history of TB contact, suggestive symptoms and a positive TST. A surgical biopsy was necessary for diagnosis in 17 cases (nasopharynx, bone, cervical, mediastinal and mesenteric lymph nodes). Pulmonary TB was diagnosed in 52% of cases. Two children were diagnosed with disseminated TB. A diagnosis delay was noted with an average of 20 days and a contact history was found in 52% of the children. All children were treated according to the national guidelines without major side effects. Healing without sequelae was achieved in 91% of cases. Conclusion Children represent a population at high risk for TB especially after a household contact with a higher frequency of multifocal forms compared to adults. The difficulty of the diagnosis in children may explain partially the diagnosis delay, but efforts must be done to improve prevention and diagnosis in our country.

Report of the Tunisian Registry of Primary Immunodeficiencies: 25-Years of Experience (1988-2012).

PURPOSE: Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to not only recurrent infections but also autoimmune diseases and malignancies. The aim of this study was to describe and analyze the distribution, clinical features and eventual outcome of PID among Tunisian patients. METHODS: We reviewed the record of 710 patients diagnosed with Primary Immunodeficiency Diseases (PIDs) from the registry of the Tunisian Referral Centre for PIDs over a 25-year period. RESULTS: The male-to-female ratio was 1.4. The median age at the onset of symptoms was 6 months and at the time of diagnosis 2 years. The estimated prevalence was 4.3 per 100,000 populations. The consanguinity rate was found in 58.2 % of families. According to the International Union of Immunological Societies classification, spectrums of PIDs were as follows: combined T-cell and B-cell immunodeficiency disorders account for the most common category (28.6 %), followed by congenital defects of phagocyte (25.4 %), other well-defined immunodeficiency syndromes (22.7 %), predominant antibody deficiency diseases (17.7 %), diseases of immune dysregulation (4.8 %), defect of innate immunity (0.4 %) and complement deficiencies (0.4 %). Recurrent infections, particularly lower airway infections (62.3 %), presented the most common manifestation of PID patients. The overall mortality rate was 34.5 %, mainly observed with combined immunodeficiencies. CONCLUSION: The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of Combined Immunodeficiencies and phagocyte defects in number and/or function. More is needed to improve PID diagnosis and treatment in our country.

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.

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.