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.

Decreased Level of IL-37 Correlates Negatively with Inflammatory Cytokines in Cerebrospinal Fluid of Patients with Neuro-Behcet's Disease.

BACKGROUND: Behçet's disease (BD) is a systemic inflammatory disease with a chronic, relapsing-remitting course of unknown etiology. Neuro-Behcet's disease (NBD) induces serious CNS complications and is known to be the main cause of long-term morbidity and mortality. IL-37 is a natural suppressor of innate inflammation which its role in NBD has not been fully understood. OBJECTIVE: To determine the expression of IL-37 in cerebrospinal fluid (CSF) and its relationship with other inflammatory cytokines. METHODS: Level of IL-37, IL-6, IL-17, IL-21, TSLP and TGF-ß were measured in CSF of 22 patients with NBD and 12 non-inflammatory neurological disease (NIND) and 10 headache attributed to Behçet's disease (HaBD) by enzyme-linked immunosorbent assay (ELISA). In addition, IL-37 mRNA relative expression was detected by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: CSF level and mRNA expression of IL-37 were elevated in NBD patients compared to those in NIND and HaBD patients. Levels of IL-6, IL-17, IL-21 and TSLP were found to be increased in NBD patients and were inversely associated with IL-37 level. Moreover, TGF-ß level in CSF of NBD patients was positively correlated with IL-37 levels. IL-37 increased significantly after treatment and in remission group, but TGF-ß was only increased in treatment group. CONCLUSION: IL-37 expression increased in NBD patients, and correlated with disease activity. Our data conclude that IL-37 could be a disease marker in NBD, however it requires further studies.

Association of small ubiquitin-like modifier 4 (SUMO4) polymorphisms in a Tunisian population with Behçet's disease.

OBJECTIVES: An association of SUMO4 gene, which has recently been shown to be a negative feedback regulator for nuclear factor NF-κB, has been reported in several autoimmune/inflammatory diseases. A case-control study was set up to investigate the contribution of SUMO4 locus to the genetic susceptibility to Behçet's disease (BD). METHODS: One hundred and thirty-five Tunisian BD patients and 167 healthy blood donors from the same geographical area were genotyped by polymerase chain reaction for the SUMO4 polymorphisms. RESULTS. The SUMO4+438 C allele frequency is significantly increased in BD patients (p=0.03; χ2=4.71; OR=1.44; 95% CI=1.02-2.04) and highly significantly increased in HLA-B51 positive BD patients (p=3 10-6; χ2=21.62; OR=4.44; 95% CI=2.21-8.98). Similarly, the SUMO4 -847 G allele frequency is significantly increased in BD patients (p=0.03; χ2=4.34; OR=1.41; 95% CI=1.01-1.97). The studied polymorphisms were also associated with disease severity, skin lesions and vascular involvement. CONCLUSIONS: SUMO4+438 C and -847 G alleles seem to be associated with susceptibility to BD in Tunisian population. We suggest that SUMO4 gene polymorphisms may be involved in the development of skin lesions, vascular BD, as well as the severity of the disease.

Vitamin D modulates peripheral immunity in patients with Behçet's disease.

BACKGROUND AND OBJECTIVES: There is little knowledge about clinical and immunological variables associated with vitamin D insufficiency in inflammatory diseases. We sought to investigate disease variables associated with vitamin D levels in patients with Behçet's disease (BD) and its interaction with inflammatory responses. METHODS: One hundred and sixty BD patients (102 patients in active stage) were enrolled in a study assessing the relationship between serum vitamin D concentrations and disease activity. As control diseases we studied 22 Rheumatoid arthritis (RA) and 30 multiple sclerosis (MS) patients. Serum concentrations of vitamin D were assayed with a radioimmunoassay kit. To assess the correlation between inflammatory mediators, immune cell expression and vitamin D, 20 active BD patients and 18 healthy controls were investigated: T-cell subsets and Treg cells were quantified by flow cytometry. Th1/Th2 ratio and Th17 were studied by intracytoplasmic cytokines expression (IFN-γ, IL-4, IL-10 and IL-17). RESULTS: Decreased levels of vitamin D were observed in active BD patients compared to patients in the inactive stage and to healthy controls (p=0.0246; p=0.0001). A low significant difference was observed between inactive BD and healthy controls (p=0.004). Active BD expressed higher vitamin D levels than RA (p=0.007) and MS (p=0.044) patients (p=0.0238). In active BD, vitamin D levels were correlated with CRP and ESR. Serum levels of vitamin D correlated positively with the number of Treg cells (r=0.640; p=0.0024). The IFN-γ/IL-4 ratio (Th1/Th2) was inversely correlated with serum 25(OH)D levels (r=-0.599; p=0.0053). CONCLUSIONS: Active BD was associated with lower serum Vitamin D levels. Our results showed that low levels of vitamin D were associated with a decrease in Treg cells and a skewing of the Th1/Th2 balance towards Th1. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in BD patients. As suggested in other inflammatory/autoimmune diseases, vitamin D may modulate inflammatory mediators.

Endothelial nitric oxide synthase gene polymorphism is associated with Behçet's disease in Tunisian population.

Nitric oxide (NO) is a molecule that plays a key role in many physiologic and pathologic processes. It is produced in vivo from the aminoacid l-arginine by a family of nitric oxide synthases (NOS). Endothelial NOS (eNOS) is a constitutively expressed isoform of NOS. The eNOS gene entails several polymorphisms, of which certain were investigated in Behçet's disease (BD). We sought to establish the association of eNOS gene Glu298Asp polymorphism in exon 7 with susceptibility to BD. In this study, 135 Tunisian patients with BD and 157 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction technique for eNOS polymorphism in exon 7. Our results showed that the distribution of the Glu298Asp genotype differed between BD patients and controls but did not reach statistical significance (p = 0.06). Allele Asp298 was significantly more frequent in healthy controls than in BD patients (p = 0.037, chi(2) = 4.33, OR = 1.01, 95% CI = 1.41-1.99). A significant difference was found (p = 0.004, OR = 1.26, 95% CI = 2.13-3.62) between BD patients with skin lesions and patients without this manifestation. Our findings suggest that Glu298Asp polymorphism of eNOS gene is associated with BD susceptibility as well as skin lesions.