期刊
JOURNAL OF HEPATOLOGY
卷 60, 期 5, 页码 1010-1016出版社
ELSEVIER
DOI: 10.1016/j.jhep.2013.12.027
关键词
Cholangitis; Treg; Immune regulation; Primary sclerosing cholangitis; IL2RA
资金
- Deutsche Forschungsgemeinschaft [SFB841, WE4690/1-1]
Background & Aims: Recently, genome wide association studies in primary sclerosing cholangitis (PSC) revealed associations with gene polymorphisms that potentially could affect the function of regulatory T cells (Treg). The aim of this study was to investigate Treg in patients with PSC and to associate their numbers with relevant gene polymorphisms. Methods: Treg frequency in blood was assessed by staining for CD4+ CD25(high)FOXP3(+)CD127(low) lymphocytes and determination of Treg-specific FOXP3 gene locus demethylation. Single nucleotide polymorphisms (SNP) in the interleukin-2 receptor alpha (IL2RA), the interleukin-2 (IL2) and interleukin-21 (IL21) gene locus were analysed. Liver biopsies taken at the time of diagnosis were stained for FOXP3 and CD3. Treg function was assessed in a CFSE-based suppression assay. Results: The frequency of Treg in peripheral blood of PSC patients was significantly decreased. We confirmed this finding by demonstrating a reduction of non-methylated DNA in the Tregspecific demethylated FOXP3 gene region of peripheral blood cells in PSC patients. Reduced peripheral Treg numbers were significantly associated with homozygosity for the major allele of the SNP rs10905718'' in the IL2RA gene. Intrahepatic FOXP3(+) cell numbers at the time of initial diagnosis were decreased in PSC as compared to PBC. In addition to reduced numbers, the suppressive capacity of Treg isolated from PSC patients seemed to be impaired as compared to healthy controls. Conclusions: Our findings indicate that Treg impairment may play a role in the immune dysregulation observed in PSC. Reduced Treg numbers in patients with PSC are associated with polymorphisms in the IL2RA gene. (c) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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