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The role of B and T Lymphocyte Attenuator (BTLA) in the pathogenesis of autoimmune diseases

B 和 T 淋巴细胞衰减因子 (BTLA) 在自身免疫性疾病发病机制中的作用

基本信息

批准号：
17591030
负责人：
WATANABE Norihiko
金额：
$ 2.18万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591030/
关键词：
costimulatory molecule B and T lymphocyte Attenuator T cell autoimmune disease knockout mouse 遺伝子多型 BTLA トラフィッキング免疫シナプス

项目摘要

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.

B和T淋巴细胞衰减器（BTLA）是一种表达于淋巴细胞上的受体，最近被描述为一种抑制性辅助受体，可负性调节淋巴细胞的激活。提示BTLA可能参与维持免疫耐受，但BTLA在自身免疫性疾病发病机制中的作用尚不清楚。在本研究中，我们探讨了BTLA在调节免疫稳态和自身免疫发病机制中的作用。我们发现，老年BTLA缺陷（BTLA^<-/->）小鼠而非年轻BTLA^<-/->小鼠表现出高γ-球蛋白血症、核抗原自身抗体和外周活化CD4^+ T细胞的增加。缺乏BTLA可导致以转氨酶升高、界面肝炎和肝脏点状坏死为特征的自身免疫性肝炎（AIH）的自发发展，导致BTLA^<-/->小鼠早期死亡。此外，老年BTLA^<-/->小鼠在包括唾液腺、肺和胰腺在内的多个器官中出现炎症细胞浸润，类似于AIH常见并发症干燥综合征。我们还通过病例对照遗传关联研究，研究了BTLA与类风湿关节炎（RA）、系统性红斑狼疮（SLE）和干燥综合征（SS）之间的可能关联。本研究招募了87例RA患者、64例SLE患者、60例SS患者和71例健康对照者，对BTLA基因的单核苷酸多态性（snp）进行基因分型。我们发现BTLA基因590C SNP与RA易感性显著相关（P=0.014，相对危险度2.19），但与SLE或SS无关。此外，携带该590C SNP的RA患者发病明显早于不携带该等位基因的患者。我们还发现含有590C等位基因的BTLA对cona诱导的IL-2产生缺乏抑制活性。这些结果提示BTLA在维持免疫耐受和预防自身免疫性疾病中起重要作用。