Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis

Ruth Y. Lan, Chunmei Cheng, Zhe Xiong Lian, Koichi Tsuneyama, Guo Xiang Yang, Yuki Moritoki, Ya Hui Chuang, Takafumi Nakamura, Shigeru Saito, Shinji Shimoda, Atsushi Tanaka, Christopher L. Bowlus, Yasuo Takano, Aftab A. Ansari, Ross L. Coppel, M. Eric Gershwin

Research output: Contribution to journalArticlepeer-review

236 Citations (Scopus)

Abstract

CD4+CD25high 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+CD25high T cells in CD4+TCR-αβ+ 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.

Original languageEnglish
Pages (from-to)729-737
Number of pages9
JournalHepatology
Volume43
Issue number4
DOIs
Publication statusPublished - Apr 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology

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