Pathogenic role of B cells in anti-CD40-induced necroinflammatory liver disease.
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 (alphaCD40) 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 alphaCD40-induced liver disease unless they were reconstituted with normal B cells and that B cells as well as macrophages played key roles in alphaCD40-induced late phase of liver inflammation. Finally, liver disease and the recruitment of inflammatory cells into the liver were mediated by interferon-gamma and tumor necrosis factor-alpha, 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.
Kimura
Kiminori
K
First Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan. kkimura@cc.gifu-u.ac.jp
Moriwaki
Hisataka
H
Nagaki
Masahito
M
Saio
Masanao
M
Nakamoto
Yasunari
Y
Naito
Makoto
M
Kuwata
Kazuo
K
Chisari
Francis V
FV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma