Adamantiades-Behcet’s disease(ABD)is a chronic inflammatory multisystem disorder.Although the precise etiology is unclear,high prevalence of human leukocyte antigen(HLA)-B51 predisposition and predominantly involved T-helper type 1 cells(Th1)-type proinflammatory cytokines and extrinsic Streptococcal infection suggest a substantial association with an immunogenetic basis and strengthens the hypothesis that IL-12,a potent inducer of Th-1 immune reaction,is a putative candidate in its pathogenesis.These clinicopathological findings led us to examine interleukin 12 p40(IL-12B)promoter polymorphism,for which the 4-base pair(bp)heterozygous insertion has been shown to affect the gene transcription and subsequent protein production.We analyzed IL-12B promoter genotypes in 194 Japanese subjects(92 with ABD and 102 normal controls)-by PCR-based restriction enzyme digestion.The frequency of the insertion heterozygosity was significantly higher in patients than in controls(49/92,53.3%vs 39/102,38.2%,respectively)-Comparing these with HLA haplotype data,this trend was more significant in HLA-B51-negative patients(29/42,69.0%vs 20/50,40.0%;P=0.005).As assessed by semiquantitative reverse transcription-PCR and ELISA,stimulation with Streptococcal antigens specifically increased expression of IL-12 p40 mRNA and protein,in conjunction with IL-12 p70 induction,in peripheral blood mononuclear cells from heterozygous patients.Our results provide evidence for anti-bacterial host response toward Th1-immunity mediated by IL-12 in patients with ABD,and the possible insight into the genetic susceptibility that is independent of HLA background.
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