Role of HLA-DRB1 and PTPN22 genes in susceptibility to juvenile idiopathic arthritis in Hungarian patients.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a complex immune-mediated disease characterized by environmental influences along with several predisposing genes in the pathogenesis. The present study was undertaken to investigate the association of polymorphisms in two candidate genes for autoimmunity, human leukocyte antigen (HLA) DRB1 and protein tyrosine phosphatase N22 (PTPN22) with JIA in Hungarian patients. METHODS: A case-control study including 150 Hungarian JIA patients and 200 sex and ethnically matched healthy controls was conducted. Genotyping for HLA-DRB1 and PTPN22 C1858T single nucleotide polymorphism (SNP) (rs2476601) was carried out by group-specific PCR amplification and by real-time PCR allelic discrimination, respectively. RESULTS: In Hungarian patients JIA was associated with HLA-DRB1*01, DRB1*08, DRB1*13 (p=0.048, p=0.002, p=0.019, respectively) with marked differences between the disease subtypes classified according to the ILAR criteria. There was no association of the PTPN22 C1858T SNP with JIA (p=0.66). No correlation was found between the presence of this PTPN22 SNP and HLA-DRB1 alleles. CONCLUSIONS: Our results confirm that certain HLA-DRB1 alleles reported previously as susceptibility factors are strongly associated with JIA in a Hungarian population. However, C1858T polymorphism of PTPN22, another candidate gene of autoimmunity seems to be independent of JIA in Hungarian patients. Our data taken together with various findings in different populations suggest that associations related to PTPN22 seem to be more ethnicity-specific in contrast to the general and less population-dependent role of HLA-DRB1 in JIA.

Lipopolysaccharide exposure makes allergic airway inflammation and hyper-responsiveness less responsive to dexamethasone and inhibition of iNOS.

Allergic airway disease can be refractory to anti-inflammatory treatment, whose cause is unclarified. Therefore, in the present experiment, we have tested the hypothesis that co-exposure to lipopolysacharide (Lps) and allergen results in glucocorticoid-resistant eosinophil airway inflammation and hyper-responsiveness (AHR). Ovalbumin (Ova)-sensitized BALB/c mice were primed with 10 microg intranasal Lps 24 h before the start of Ova challenges (20 min on 3 consecutive days). Dexamethasone (5 mg/kg/day) was given on the last 2 days of Ova challenges. AHR, cellular build-up, cytokine and nitrite concentrations of bronchoalveolar lavage fluid (BALF) and lung histology were examined. To assess the role of iNOS-derived NO in airway responsiveness, mice were treated with a selective inhibitor of this enzyme (1400W) 2 h before AHR measurements. More severe eosinophil inflammation and higher nitrite formation were found in Lps-primed than in non-primed allergized mice. After Lps priming, AHR and concentrations of T-helper type 2 cytokines in BALF were decreased, but still remained significantly higher than in controls. Eosinophil inflammation was partially, while nitrite production and AHR were observed to be largely dexamethasone resistant in Lps-primed allergized animals. 1400W effectively and rapidly diminished the AHR in Ova-sensitized and challenged mice, but failed to affect it after Lps priming plus allergization. In conclusion, Lps inhalation may exaggerate eosinophil inflammation and reduce responsiveness to anti-inflammatory treatment in allergic airway disease.