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(American Journal of Pathology. 2006;168:786-795.)
© 2006 American Society for Investigative Pathology

Pathogenic Role of B Cells in Anti-CD40-Induced Necroinflammatory Liver Disease

Kiminori Kimura^*, Hisataka Moriwaki^*, Masahito Nagaki^*, Masanao Saio, Yasunari Nakamoto^¶, Makoto Naito^||, Kazuo Kuwata and Francis V. Chisari

From the First Department of Internal Medicine,^* Gifu University School of Medicine, Gifu, Japan; the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California; the Center for Emerging Infectious Diseases, Gifu University, Gifu, Japan; the Department of Immunopathology, Gifu University Graduate School of Medicine, Gifu, Japan; the Department of Gastroenterology,^¶ Kanazawa University Graduate School of Medicine, Kanazawa, Japan; the Department of Cellular Function,^|| Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Activated B cells function in antibody production and antigen presentation, but whether they perform any pathophysiological functions at sites of inflammation is not fully understood. Here, we report that intravenous injection of an agonistic anti-CD40 monoclonal antibody (CD40) causes a biphasic inflammatory liver disease in inbred mice. The late phase of disease was suppressed in B-cell-deficient mice and by the depletion of macrophages, but not T cells or natural killer cells. We also report that SCID mice were not susceptible to CD40-induced liver disease unless they were reconstituted with normal B cells and that B cells as well as macrophages played key roles in CD40-induced late phase of liver inflammation. Finally, liver disease and the recruitment of inflammatory cells into the liver were mediated by interferon- and tumor necrosis factor-, but not by Fas. In conclusion, these results indicate that CD40 ligation can trigger a B-cell-mediated inflammatory response that can have pathogenic consequences for the liver.

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