Jiang Tingwang, Han Zhijun, Chen Sunxiao, Wu Chuanyong, Tang Yujie, Qian Cheng, Chen Yan, Zhou Ye, Zhu Ye, Gu Mingli, Zhu Liang, Yao Dingkang, Deng Anmei, Zhong Renqian
Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, 200003, Shanghai, China.
Clin Exp Med. 2009 Dec;9(4):269-76. doi: 10.1007/s10238-009-0052-2. Epub 2009 May 6.
Primary biliary cirrhosis (PBC) is a type of organ-specific autoimmune disease in which immune tolerance is impaired by an unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyI:C to study activation-induced cell death (AICD) in CD4+ T lymphocytes and changes of apoptosis-associated molecules as a first step to understand the immune tolerance of PBC mice. Obvious inflammatory cell infiltration was observed in the portal area of the liver tissues in model mice and antimitochondrial antibodies (AMA) positive rate was 80%. The AICD level in both splenic and hepatic CD4+ T cells in the model group were all lower than those in controls, and in the model group the level for hepatic CD4+ T cells were significantly lower than that for splenic CD4+ T cells. Quantitative PCR revealed that FasL mRNA and TRAIL expression in CD4+ T cells in the model group decreased significantly compared with that in the control group. Western blots revealed that the expression of the anti-apoptotic protein FLIP(L) in the model group increased significantly with the FLIP(L) expression in hepatic CD4+ T cells significantly higher than that in splenic CD4+ T cells. There was a positive linear correlation between the number of infiltrated portal areas and relative expression of FLIP(L) in splenic CD4+ T cells in model group. There were no obvious changes for caspase-8 in either group. These results show that the anti-apoptotic ability of CD4+ T lymphocytes play an important role in immune tolerance in the PBC mouse model, and elevated FLIP(L) expression may enhance this ability. The inhibition of FasL and TRAIL expression may also help enhance this anti-apoptotic ability in CD4+ T lymphocytes and contribute to the aggravation of portal area inflammation.
原发性胆汁性肝硬化（PBC）是一种器官特异性自身免疫性疾病，其免疫耐受因未知机制而受损。我们通过向C57BL/6小鼠注射聚肌胞苷酸（polyI:C）建立了PBC动物模型，以研究CD4+ T淋巴细胞中的激活诱导细胞死亡（AICD）及凋亡相关分子的变化，作为理解PBC小鼠免疫耐受的第一步。在模型小鼠肝脏组织的门管区观察到明显的炎性细胞浸润，抗线粒体抗体（AMA）阳性率为80%。模型组脾脏和肝脏CD4+ T细胞中的AICD水平均低于对照组，且模型组肝脏CD4+ T细胞的水平显著低于脾脏CD4+ T细胞。定量PCR显示，与对照组相比，模型组CD4+ T细胞中FasL mRNA和TRAIL表达显著降低。蛋白质免疫印迹显示，模型组抗凋亡蛋白FLIP(L)的表达显著增加，且肝脏CD4+ T细胞中的FLIP(L)表达明显高于脾脏CD4+ T细胞。模型组门管区浸润数量与脾脏CD4+ T细胞中FLIP(L)的相对表达呈正线性相关。两组中caspase-8均无明显变化。这些结果表明，CD4+ T淋巴细胞的抗凋亡能力在PBC小鼠模型的免疫耐受中起重要作用，FLIP(L)表达升高可能增强了这种能力。FasL和TRAIL表达的抑制也可能有助于增强CD4+ T淋巴细胞的这种抗凋亡能力，并导致门管区炎症加重。
