Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms.

Authors:
Marcial Sebode, Moritz Peiseler, Björn Franke, Dorothee Schwinge, Tanja Schoknecht, Frederike Wortmann, Alexander Quaas, Britt-Sabina Petersen, Eva Ellinghaus, Udo Baron, Sven Olek, Christiane Wiegard, Christina Weiler-Normann, Ansgar W Lohse, Johannes Herkel, Christoph Schramm
Year of publication:
2014
Volume:
-
Issue:
-
Issn:
0168-8278
Journal title abbreviated:
J HEPATOL
Journal title long:
Journal of hepatology : the journal of the European Association for the Study of the Liver
Impact factor:
10.590
Abstract:
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.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.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 Treg-specific 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.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.