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(American Journal of Pathology. 2007;170:981-989.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060474

Thymic Stromal Lymphopoietin Transgenic Mice Develop Cryoglobulinemia and Hepatitis with Similarities to Human Hepatitis C Liver Disease

Jolanta Kowalewska*, Anja S. Mühlfeld*, Kelly L. Hudkins*, Matthew M. Yeh*, Andrew G. Farr{dagger}, Jeffrey V. Ravetch{ddagger} and Charles E. Alpers*

From the Department of Pathology,* University of Washington, Seattle, Washington; and the Division of Nephrology and Immunology{dagger} and Laboratory of Molecular Genetics and Immunology,{ddagger} The Rockefeller University, New York, New York

Essential mixed cryoglobulinemia in humans is strongly associated with chronic hepatitis C virus infection. It remains controversial whether liver injury in hepatitis C is primarily attributable to direct viral cytopathic effect or to an immune-mediated response. We characterized the role of cryoglobulinemia in the development of liver disease in thymic stromal lymphopoietin (TSLP) transgenic mice that produce mixed cryoglobulinemia and develop hepatitis. The role of immune complexes in this animal model was evaluated using techniques of light, immunofluorescence, and electron microscopy. To assess the role of Fc receptor engagement in mediation of the disease, TSLP transgenic mice were crossbred with mice deficient for immunoglobulin-binding receptor {gamma} IIb (Fc{gamma}RIIb). Livers from the TSLP transgenic animals showed mild to moderate liver injury, minimal to mild fibrosis, and deposition of immunoglobulin around the portal tracts. TSLP transgenic mice deficient in inhibitory Fc{gamma}RIIb had more severe hepatitis and accelerated mortality. TSLP-associated hepatitis bears strong similarity to hepatitis C virus-related hepatitis as it occurs in humans, making this a valuable model system of chronic hepatitis and fibrosis to study therapies aimed at manipulating immune responses. Periportal immune complex deposition may play an important role in the pathogenesis of hepatitis occurring in the setting of systemic cryoglobulinemia.




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[Abstract] [Full Text] [PDF]


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