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Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A

 Yoon Seok Choi  ;  Min Kyung Jung  ;  Jeewon Lee  ;  Seong Jin Choi  ;  Sung Hoon Choi  ;  Hyun Woong Lee  ;  Jong-Joo Lee  ;  Hyung Joon Kim  ;  Sang Hoon Ahn  ;  Dong Hyeon Lee  ;  Won Kim  ;  Su-Hyung Park  ;  Jun R Huh  ;  Hyoung-Pyo Kim  ;  Jun Yong Park  ;  Eui-Cheol Shin 
 GASTROENTEROLOGY, Vol.154(4) : 1047-1060, 2018 
Journal Title
Issue Date
Acute Disease ; CD/immunology/metabolism Antigens ; Apyrase/immunology/metabolism ; Case-Control Studies ; Cultured Cells ; DNA Methylation ; Genetic Epigenesis ; Forkhead Transcription Factors/immunology/metabolism ; Hepatitis A/diagnosis/immunology/*metabolism/virology ; Hepatitis A virus/immunology/pathogenicity ; Host-Pathogen Interactions ; Humans ; Interleukin-2 Receptor alpha Subunit/immunology/metabolism ; Liver/immunology/*metabolism/pathology/virology ; Group F Nuclear Receptor Subfamily 1, Member 3/immunology/metabolism ; Phenotype ; Severity of Illness Index ; Signal Transduction ; Regulatory/immunology/*metabolism/virology T-Lymphocytes ; Th17 Cells/immunology/metabolism/virology ; Time Factors ; Tumor Necrosis Factor-alpha/immunology/*metabolism
ALT ; Hepatitis A Virus Infection ; Inflammation ; Liver Injury
BACKGROUND AND AIMS: CD4(+)CD25(+)Foxp3(+) T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. METHODS: We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4(+)CD25(+)Foxp3(+)) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORgammat inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. RESULTS: A higher proportion of CD4(+)CD25(+)Foxp3(+) Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up-regulation of RORgammat, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. CONCLUSIONS: Treg cells from patients with AHA have altered functions compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA.
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1. College of Medicine (의과대학) > Dept. of Environmental Medical Biology (환경의생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyoung Pyo(김형표) ORCID logo https://orcid.org/0000-0003-1441-8822
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
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