title: Changes in circulating Foxp3(+) regulatory T cells and interleukin-17-producing T helper cells during HBV-related acute-on-chronic liver failure.
abstract: OBJECTIVE
  To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression.
  
  
  METHODS
  We measured the expression of seven Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 18 ACHBLF, 18 chronic hepatitis B (CHB) disease controls and 10 healthy controls (HCs) by real-time quantitative PCR and enzyme linked immunosorbent assay. Peripheral Th17 and Treg cell frequencies were analyzed by flow cytometry.
  
  
  RESULTS
  From the onset of ACHBLF, patients presented with a conductive Th17 differentiation cytokine environment accompanied by high Th17 frequency and high serum IL-17 levels, which were sustained throughout the disease course. The Treg-related cytokine IL-2 and Foxp3 were also up-regulated from disease onset, and Foxp3 gene expression showed a gradually increasing trend during ACHBLF. The circular phenotype of Treg and Th17 cells showed changes from the onset of ACHGLF. At disease onset, Th17 frequency increased significantly compared with both CHB and HCs, but Treg cell frequency decreased significantly compared with CHB. During the ACHBLF event, Th17 frequency remained higher compared with HCs, but decreased sharply from the peak point to the recovery point; Treg cell frequency increased gradually during the ACHBLF event. Treg and Th17 cell counts correlated with ACHBLF development; in all patients, serum IL-17 levels significantly correlated with patient serum ALT levels. In survivors, Th17 frequency at the onset point and the Treg to Th17 ratio at the peak point correlated with the patient's model for end stage liver disease (MELD) plus sodium (MELD-Na) score. The Treg to Th17 ratio and the Th17 frequency at onset were significant predictors of patient survival. Low Treg/Th17 cell ratios at the onset predicted poor survival. Survivors exhibited an initial decrease in the circulating Treg/Th17 ratio from the onset to the peak time, and subsequently displayed a continuous increase.
  
  
  CONCLUSIONS
  Treg and Th17 cells showed changes in genes, protein levels and T cell phenotypes during ACHBLF events. An increased Treg/Th17 ratio was associated with the survival of ACHBLF patients.
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xue-Song
authors.initials: XS
authors.lastname: Liang
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Cheng-Zhong
authors.initials: CZ
authors.lastname: Li
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ya-Yun
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Xue-Song Liang, Cheng-Zhong Li, Yin Zhou, Wei Yin, Ya-Yun Liu, Wen-Han Fan, Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Fan
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality / Q000821:virology; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002454:Cell Differentiation; D016207:Cytokines / Q000097:blood / Q000235:genetics; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality; D006801:Humans; D008137:Longitudinal Studies; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
keywords: Hepatitis B virus; Hepatitis B virus-related acute-on-chronic liver failure; Immune; Th17; Treg