title: Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis.
abstract: OBJECTIVE
  Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) control immune responses, but their role in acute viral hepatitis remains elusive. Herein, we investigated alteration in the peripheral blood Treg population during acute hepatitis A (AHA) and its implication in the immune-mediated liver injury.
  
  
  METHODS
  The study included 71 patients with AHA, and peripheral blood mononuclear cells (PBMCs) were isolated. The suppressive activity of Treg population was determined by assessing anti-CD3/CD28-stimulated proliferation of Treg-depleted and reconstituted PBMCs. Treg cell frequency, phenotype and apoptosis in PBMCs were analysed by flow cytometry.
  
  
  RESULTS
  The frequency of circulating Tregs was reduced during AHA. Moreover, the suppressive activity of the total Treg pool in the peripheral blood was attenuated during AHA. Treg frequency and suppressive activity of the Treg population inversely correlated with the serum alanine aminotransferase level. Fas was overexpressed on Tregs during AHA, suggesting their susceptibility to Fas-induced apoptosis. Indeed, increased apoptotic death was observed in Tregs of patients with AHA compared with healthy controls. In addition, agonistic anti-Fas treatment further increased apoptotic death of Tregs from patients with AHA. The decreased Treg frequency and Fas overexpression on Tregs were not observed in other acute liver diseases such as acute hepatitis B, acute hepatitis C and toxic/drug-induced hepatitis.
  
  
  CONCLUSIONS
  The size of the Treg pool was contracted during AHA, resulting from apoptosis of Tregs induced by a Fas-mediated mechanism. Decrease in Treg numbers led to reduced suppressive activity of the Treg pool and consequently resulted in severe liver injury during AHA.
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Jeewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Woong
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Dong-Yeop
authors.initials: DY
authors.lastname: Chang
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Pil Soo
authors.initials: PS
authors.lastname: Sung
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ja Kyung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Il
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cheong
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung-Suk
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea.
authors.forename: June Sung
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
mesh_terms: D000208:Acute Disease; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006506:Hepatitis A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000998:Antiviral Agents
keywords: ACUTE HEPATITIS; APOPTOSIS; HEPATITIS A; IMMUNE-MEDIATED LIVER DAMAGE; IMMUNOLOGY IN HEPATOLOGY