Premium
CD4 + T cells use IFN‐γ, not IL‐17, to drive neutrophil‐mediated liver damage in murine autoimmune hepatitis
Author(s) -
Wang Jing,
Cripps James G,
Robinson Richard T,
Gorham James D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.668.1
Subject(s) - neutrophilia , autoimmune hepatitis , immunology , cytokine , monoclonal antibody , immune system , biology , hepatitis , antibody
Autoimmune hepatitis (AIH) is a poorly understood disease caused by an immune‐mediated attack on hepatocytes. BALB/c‐TGF‐β1 −/− mice spontaneously develop fulminant AIH that recapitulates important features of the human disease. Liver disease is dependent upon both CD 4+ T cells and IFN‐γ. Intracellular cytokine analysis as well as cell subset depletion showed that CD 4+ T cells, but not CD 8+ T cells or NK cells, are the relevant source of IFN‐γ in this model system. Histological examination of TGF‐β1 −/− livers revealed an abundance of neutrophils, supported by microarray analysis showing increased expression of neutrophil‐associated gene products. Liver neutrophilia was dependent upon the CD 4+ T cell subset as well as on the Th1 cytokine IFN‐γ. Interestingly, TGF‐β1−/− liver CD 4+ T cells produced abundant IFN‐γ, but no detectable IL‐17. The relevance of the neutrophil subset for pathology was confirmed directly, as depletion of neutrophils using a subsetspecific monoclonal antibody protected TGF‐β1 −/− mice from liver disease. Thus AIH in TGF‐β1 −/− mice is driven by a CD 4+ Th1 – IFN‐γ – neutrophil pathway, with no role for IL‐17.