| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Hiroshi Chiba University, Graduate School of Medicine, Professor, 大学院医学研究院, 教授 (00322024)
HIROSE Koichi Chiba University Hospital, School of Medicine, Research Associate, 医学部附属病院, 助手 (90400887)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
B and T lymphocyte attenuator (BTLA), a corereceptor expressed on lymphocytes, has recently been described as an inhibitory coreceptor that negatively regulates lymphocyte activation. It is suggested that BTLA may be involved in the maintenance of immune tolerance, but the role of BTLA in the pathogenesis of autoimmune diseases remains unknown. In this study, we investigated the role of BTLA in regulation of immune homeostasis and pathogenesis of autoimmunity. We found that aged BTLA-deficient (BTLA^<-/->) mice but not young BTLA^<-/-> mice exhibited hyper-γ-globulinemia, autoantibodies to nuclear antigens, and increase of activated CD4^+ T cells in the periphery. Lack of BTLA led to spontaneous development of autoimmune hepatitis (AIH) characterized by elevation of transaminases, interface hepatitis and spotty necrosis in the liver, causing early death of BTLA^<-/-> mice. Furthermore, aged BTLA^<-/-> mice showed inflammatory cell infiltration in multiple organs including salivary glands, lungs, and pancreas, similar to Sjogren's syndrome, a frequent complication of AIH. We also examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SS) by conducting case-control genetic association studies. Eighty-seven RA patients, 64 SLE patients, 60 SS patients and 71 health control subjects were recruited and genotyped for single nucleotide polymorphisms (SNPs) of BTLA gene. We found that 590C SNP of BTLA gene was significantly associated with susceptibility to RA (P=0.014, relative risk 2.19), but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on ConA-induced IL-2 production. These results suggest that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.
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