Role of IL-12B Promoter Polymorphism in Adamantiades–Behcet's Disease Susceptibility: An Involvement of Th1 Immunoreactivity against Streptococcus Sanguinis Antigen

• Published in: Journal of investigative dermatology Vol. 126; no. 7; pp. 1534 - 1540
• Main Authors: Yanagihori, Hirokatsu, Oyama, Noritaka, Nakamura, Koichiro, Mizuki, Nobuhisa, Oguma, Keiji, Kaneko, Fumio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2006; Elsevier Limited
• Subjects: Adult; Aged; Antigens, Bacterial - immunology; Behcet Syndrome - genetics; Behcet Syndrome - immunology; Behcet Syndrome - physiopathology; Case-Control Studies; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Genetic Predisposition to Disease - genetics; Heterozygote; HLA-B Antigens - genetics; HLA-B Antigens - immunology; HLA-B51 Antigen; Humans; Interleukin-12 - genetics; Interleukin-12 - physiology; Interleukin-12 Subunit p40; Leukocytes, Mononuclear; Male; Middle Aged; Polymorphism, Genetic; Promoter Regions, Genetic - genetics; Protein Subunits - genetics; Protein Subunits - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; RNA, Messenger - genetics; Streptococcal Infections - immunology; Streptococcal Infections - physiopathology; Streptococcus sanguinis; Streptococcus sanguis - immunology; Th1 Cells - immunology
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/sj.jid.5700203

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.