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

B和T淋巴细胞衰减器(BTLA)是一种表达在淋巴细胞上的受体，最近被认为是一种抑制性辅助受体，可以负向调节淋巴细胞的激活。提示BTLA可能参与免疫耐受的维持，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缺陷小鼠表现出高γ球蛋白血症，核抗原自身抗体，以及外周活化的CD4T细胞增加，而年轻BTLA缺陷小鼠则没有。BTLA缺乏导致自身免疫性肝炎(AIH)的自发发展，其特征是转氨酶升高、交界性肝炎和肝脏点状坏死，导致BTLA^&lt；-/-&gt；小鼠过早死亡。此外，老龄BTLA^&lt；-/-&gt；小鼠的唾液腺、肺和胰腺等多个器官中都有炎性细胞浸润，这与干燥综合征相似，干燥综合征是AIH的常见并发症。我们还通过进行病例对照遗传关联研究，研究了BTLA与类风湿性关节炎(RA)、系统性红斑狼疮(SLE)和干燥综合征(SS)之间的可能联系。对87例RA患者、SLE患者、60例SS患者和71例健康对照进行BTLA基因单核苷酸多态(SNPs)基因分型。我们发现BTLA基因590C SNP与RA的易感性显著相关(P=0.014，相对危险度2.19)，而与系统性红斑狼疮和SS无关。此外，携带此590C SNP的RA患者明显比未携带此等位基因的患者发病更早。我们还发现，含有590C等位基因的BTLA缺乏抑制ConA诱导的IL-2产生的活性。这些结果表明，BTLA在维持免疫耐受和预防自身免疫性疾病中起着重要作用。

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.