Role of IL-12B promoter polymorphism in Adamantiades-Behcet's disease susceptibility: An involvement of Th1 immunoreactivity against Streptococcus Sanguinis antigen.
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.
Yanagihori
Hirokatsu
H
Department of Dermatology, Fukushima Medical University Graduate School of Medicine, Fukushima, Japan. yanagi@fmu.ac.jp
Oyama
Noritaka
N
Nakamura
Koichiro
K
Mizuki
Nobuhisa
N
Oguma
Keiji
K
Kaneko
Fumio
F
D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology*; D001528:Behcet Syndrome / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D059949:HLA-B51 Antigen; D006579:Heterozygote; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics* / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013290:Streptococcal Infections / Q000276:immunology / Q000503:physiopathology; D013298:Streptococcus sanguis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
D000942:Antigens, Bacterial; D015235:HLA-B Antigens; D059949:HLA-B51 Antigen; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D012333:RNA, Messenger; D018664:Interleukin-12