title: Involvement of Th17 and Th1 effector responses in patients with Hepatitis B.
abstract: BACKGROUND
  Local production of cytokines within the liver may play a pivotal role in the regulation of pathophysiological processes during inflammation. CD4+ T cells are regarded as the most prolific cytokine producers. The purpose of this study was to quantify intrahepatic expression of Th1, Th2, Th17, and Treg-associated cytokines or transcription factors in patients with acute hepatitis B or chronic hepatitis B (CHB) and to analyze their relative roles in the promotion and regulation of hepatitis B virus (HBV)-associated liver diseases.
  
  
  METHODS
  Distribution and expression of IL-17, IFN-gamma, IL-4, Foxp3, and other cytokines in liver tissues were detected by immunohistochemistry and real-time quantitative PCR. Patients with hepatitis B were compared with patients with chronic hepatitis C, primary biliary cirrhosis, alcoholic liver cirrhosis, and healthy controls.
  
  
  RESULTS
  The frequencies of intrahepatic IL-17 and IFN-gamma-producing cells in patients with HBV-associated liver dysfunction were much higher than that of IL-4 and Foxp3-positive cells. The level of the IL-17/IFN-gamma-positive cell ratio of patients with Child-Pugh class C (1.57+/-0.09) was much higher than that of patients with Child-Pugh class B (1.00+/-.02) or A (0.93+/-0.05). There are more IL-17-producing cells than IFN-gamma-producing cells accumulating in the liver with severe hepatocellular damage. Liver IL-17-producing cell infiltration was positively associated with the grade of liver inflammation in CHB and positively correlated to intrahepatic IL-8 expression (r=0.801, p<0.01) or neutrophil infiltration (r=0.917, p<0.01).
  
  
  CONCLUSIONS
  These results suggest that the balance of effector CD4+ Th responses (Th17 and Th1 responses) and regulatory response is an important element of immune regulation. Inappropriate, excessive, and non-specific Th17 and Th1 effector responses may be involved in the pathogenesis of HBV-associated liver inflammation and hepatocellular damage. Th17 response, especially, may exacerbate the inflammatory processes leading to liver failure. IL-17-mediating liver neutrophil recruitment via induction of IL-8 may be one potential mechanism of liver injury in patients with hepatitis B. An improved understanding of the factors that influence the differentiation and function of these cell types in vivo will be of great importance to the future development of immune therapies in HBV-associated liver disease.
authors.affiliation: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Yufu
authors.initials: Y
authors.lastname: Ye
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xie
authors.forename: Jiwei
authors.initials: J
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.forename: Guoping
authors.initials: G
authors.lastname: Jiang
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Yu
authors.forename: Wenjin
authors.initials: W
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006509:Hepatitis B / Q000150:complications / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D014157:Transcription Factors
references.citation: Nat Immunol. 2005 Nov;6(11):1133-41
references.pmid: 16200068
references.citation: J Immunol. 1999 Feb 15;162(4):2347-52
references.pmid: 9973514
references.citation: Hepatology. 1997 Apr;25(4):1022-7
references.pmid: 9096614
references.citation: J Hepatol. 2009 May;50(5):980-9
references.pmid: 19329213
references.citation: Liver Int. 2006 Oct;26(8):912-9
references.pmid: 16953830
references.citation: Nat Med. 2007 Feb;13(2):139-45
references.pmid: 17290272
references.citation: J Autoimmun. 2009 Feb;32(1):43-51
references.pmid: 19101114
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Immunol Rev. 2008 Jun;223:87-113
references.pmid: 18613831
references.citation: Hepatology. 2009 May;49(5 Suppl):S45-55
references.pmid: 19399792
references.citation: Hepatology. 2010 Jan;51(1):81-91
references.pmid: 19842207
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070
references.citation: Nature. 2006 May 11;441(7090):235-8
references.pmid: 16648838
references.citation: Cancer Res. 2009 Mar 1;69(5):2010-7
references.pmid: 19244111
references.citation: J Clin Invest. 1997 Jun 15;99(12):3025-33
references.pmid: 9185527
references.citation: Gastroenterology. 1999 Sep;117(3):645-52
references.pmid: 10464141
references.citation: J Hepatol. 2007 Oct;47(4):598-607
references.pmid: 17692984
references.citation: Int Rev Immunol. 1998;16(5-6):541-51
references.pmid: 9646176
references.citation: Ann Surg Oncol. 2008 Dec;15(12):3494-502
references.pmid: 18830757
references.citation: Annu Rev Immunol. 1995;13:29-60
references.pmid: 7612225
references.citation: Int Arch Allergy Immunol. 2001 Nov;126(3):179-84
references.pmid: 11752873
references.citation: J Virol. 2005 Aug;79(15):9369-80
references.pmid: 16014900
references.citation: Annu Rev Immunol. 1995;13:251-76
references.pmid: 7612223
references.citation: Clin Microbiol Infect. 2005 Jan;11(1):52-6
references.pmid: 15649304
references.citation: Hepatology. 2009 May;49(5 Suppl):S13-21
references.pmid: 19399811
references.citation: J Immunol. 1999 Jun 1;162(11):6503-9
references.pmid: 10352265
references.citation: Annu Rev Immunol. 2009;27:147-63
references.pmid: 19302037
references.citation: Hepatology. 2009 Feb;49(2):646-57
references.pmid: 19177575
references.citation: Hepatol Res. 2007 Apr;37(4):248-54
references.pmid: 17397512
references.citation: Hepatology. 1995 Jul;22(1):61-8
references.pmid: 7601434
references.citation: J Med Virol. 2003 Nov;71(3):376-84
references.pmid: 12966542
references.citation: Clin Liver Dis. 2007 Nov;11(4):727-59, vii-viii
references.pmid: 17981227
references.citation: Antivir Ther. 1998;3(Suppl 3):13-24
references.pmid: 10726052
references.citation: Nat Rev Immunol. 2005 Mar;5(3):215-29
references.pmid: 15738952