Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis.
Autoimmune hepatitis (AIH) in humans arises spontaneously in genetically susceptible individuals and is associated with the presence of Th1 cells in the liver. The understanding of AIH has advanced more slowly than that of other organ-specific autoimmune diseases, however, largely because of the lack of an appropriate animal model. We now describe a new mouse model characterized by spontaneous development of necroinflammatory hepatitis that is restricted by genetic background. Mice deficient in the immunomodulatory cytokine TGF-beta1 were extensively back-bred to the BALB/c background. The BALB/c background dramatically modified the phenotype of TGF-beta1(-/-) mice: specifically, BALB/c-TGF-beta1(-/-) mice developed a lethal necroinflammatory hepatitis that was not observed in TGF-beta1(-/-) mice on a different genetic background. BALB/c background TGF-beta1(-/-) livers contained large numbers of activated CD4(+) T cells that produced large quantities of IFN-gamma, but little IL-4, identifying them as Th1 cells. BALB/c background TGF-beta1(-/-)/IFN-gamma(-/-) double knockout mice, generated by cross-breeding, did not develop necroinflammatory hepatitis, demonstrating that IFN-gamma is mechanistically required for its pathogenesis. This represents the first murine model of hepatitis that develops spontaneously, is restricted by genetic background, and is dependent upon the Th1 cytokine IFN-gamma, and that thus recapitulates these important aspects of AIH.
Gorham
J D
JD
Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA. James.D.Gorham@Dartmouth.edu
Lin
J T
JT
Sung
J L
JL
Rudner
L A
LA
French
M A
MA
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D003433:Crosses, Genetic; D020022:Genetic Predisposition to Disease; D006520:Hepatitis, Animal / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics* / Q000276:immunology; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009336:Necrosis; D015996:Survival Rate; D018417:Th1 Cells / Q000473:pathology; D018418:Th2 Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma