title: Dysregulated intrahepatic CD4+T-cell activation drives liver inflammation in ileitis-prone SAMP1/YitFc mice.
abstract: OBJECTIVE
  Liver inflammation is a common extraintestinal manifestation of inflammatory bowel disease (IBD); however, whether liver involvement is a consequence of a primary intestinal defect or results from alternative pathogenic processes remains unclear. Therefore, we sought to determine the potential pathogenic mechanism(s) of concomitant liver inflammation in an established murine model of IBD.
  
  
  METHODS
  Liver inflammation and immune cell subsets were characterized in ileitis-prone SAMP1/YitFc (SAMP) and AKR/J (AKR) control mice, lymphocyte-depleted SAMP (SAMPxRag-1-/-), and immunodeficient SCID recipient mice receiving SAMP or AKR donor CD4+T-cells. Proliferation and suppressive capacity of CD4+T-effector (Teff) and T-regulatory (Treg) cells from gut-associated lymphoid tissue (GALT) and livers of SAMP and AKR mice were measured.
  
  
  RESULTS
  Surprisingly, prominent inflammation was detected in 4-wk-old SAMP livers, prior to histologic evidence of ileitis, while both disease phenotypes were absent in age-matched AKRs. SAMP liver disease was characterized by abundant infiltration of lymphocytes, required for hepatic inflammation to occur, a Th1-skewed environment, and phenotypically-activated CD4+T-cells. SAMP intrahepatic CD4+T-cells also had the ability to induce liver and ileal inflammation when adoptively transferred into SCID recipients, whereas GALT-derived CD4+T-cells produced milder ileitis, but not liver inflammation. Interestingly, SAMP intrahepatic CD4+Teff cells showed increased proliferation compared to both SAMP GALT- and AKR liver-derived CD4+Teff cells, while SAMP intrahepatic Tregs were decreased among CD4+T-cells and impaired inin vitrosuppressive function compared to AKR.
  
  
  CONCLUSIONS
  Activated intrahepatic CD4+T-cells induce liver inflammation and contribute to experimental ileitis via locally-impaired hepatic immunosuppressive function.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Omenetti
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Brogi
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Goodman
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Saada
authors.initials: S
authors.lastname: Eid
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: "DENOThe" Center, University of Florence, Florence, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Laffi
authors.affiliation: Department of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy ; UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
keywords: IBD-associated liver inflammation; SAMP1/YitFc mice; hepatic CD4+ T-cells; liver sinusoidal endothelial cells; regulatory T-cells