Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis
Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis
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DOI：
10.1002/hep.21123
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发表时间：
2006-04-01
期刊：
影响因子：
13.5
通讯作者：
Gershwin, ME
中科院分区：
文献类型：
--
作者：
Lan, RY;Cheng, C;Gershwin, ME
CD 4（+）CD 25（高）调节性T细胞（TCD 4）在自身免疫耐受中起关键作用，如在小鼠自身免疫中所见。对人自身免疫中的TdR的研究主要集中在外周血样品上。针对病变组织的研究应确定TcB和自身免疫之间的直接关系。从91名原发性胆汁性肝硬化（PBC）患者、28名直系亲属和41名健康对照者中采集外周血样本，并将Treg频率确定为CD 4（+）CD 25（高）T细胞在CD 4（+）TCR-α β（+）T细胞中的百分比。还对90个不同的肝组织标本进行了FoxP 3（+）TbR的频率和分布的组织靶向测定，所述肝组织标本表现为PBC（n = 52）、慢性丙型肝炎（CHC）（n = 30）和自身免疫性肝炎（AIH）（n = 8）。对50例PBC患者和27例对照者进行Treg抑制研究。PBC患者与对照组相比，TbR相对降低（P <0.0002）。有趣的是，与对照组相比，PBC患者的女儿和姐妹篇中也发现了CD 4（+）CD 25（+）T细胞的缺乏（P <0.0007）。然而，功能性研究并未揭示整体PBC Treg缺陷。与CHC和AIH相比，PBC汇管区中FoxP 3表达的TcR水平显著降低（P <0.001）。此外，晚期PBC患者肝脏中CD 8（+）T细胞/FoxP 3（+）Treg比值显著高于CHC（P <0.001）和早期AIH（P <0.001）。总之，这些数据为Treg频率的遗传调节提供了支持，并说明了Treg在PBC耐受性丧失中的作用。
CD4(+)CD25(high) regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4(+)CD25(high) T cells in CD4(+)TCR-alpha beta(+) T cells. A tissue-targeted determination of frequency and distribution of FoxP3(+) Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4(+)CD25(+) Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8(+) T cell/FoxP3(+) Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.