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Liver‐targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis
Author(s) -
Lan Ruth Y.,
Cheng Chunmei,
Lian ZheXiong,
Tsuneyama Koichi,
Yang GuoXiang,
Moritoki Yuki,
Chuang YaHui,
Nakamura Takafumi,
Saito Shigeru,
Shimoda Shinji,
Tanaka Atsushi,
Bowlus Christopher L.,
Takano Yasuo,
Ansari Aftab A.,
Coppel Ross L.,
Gershwin M. Eric
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21123
Subject(s) - foxp3 , primary biliary cirrhosis , autoimmunity , autoimmune hepatitis , immunology , regulatory t cell , il 2 receptor , medicine , cd8 , t cell , hepatitis , antigen , immune system
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‐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. (H EPATOLOGY 2006;43:729–737.)