title: Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients.
abstract: OBJECTIVE
  Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA.
  
  
  METHODS
  We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control).
  
  
  RESULTS
  Livers from rhesus rota virus-infected mice with BA had 7-fold more Il17a messenger RNA than control mice (P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 μmol/L vs 78 μmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues (P = .02).
  
  
  CONCLUSIONS
  In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Klemann
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Schröder
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Dreier
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Möhn
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dippel
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winterberg
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Wilde
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Thorenz
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.affiliation: Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Tolosa
authors.affiliation: Department of Pediatric Surgery, St Bernward Hospital, Hildesheim, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Leonhardt
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Jan D
authors.initials: JD
authors.lastname: Haas
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Immo
authors.initials: I
authors.lastname: Prinz
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Vieten
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Petersen
authors.affiliation: Department of Pediatric Surgery, Hannover Medical School, Hannover, Germany. Electronic address: Kuebler.joachim@mh-hannover.de.
authors.forename: Joachim F
authors.initials: JF
authors.lastname: Kuebler
mesh_terms: D000818:Animals; D001656:Biliary Atresia / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006505:Hepatitis / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D020381:Interleukin-17 / Q000378:metabolism*; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C098680:Il17a protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger
keywords: IL17−Producing γδ T Cells; Neonatal Immune System; Th17 Cell; Virus-Induced Autoimmunity