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Ectopic CD40 Ligand Expression on B Cells Triggers Intestinal Inflammation ¹

Takahiro Kawamura^2,*, Takanori Kanai^2,*, Taeko Dohi, Koji Uraushihara^*, Teruji Totsuka^*, Ryoichi Iiyama^*, Chikara Taneda^*, Motomi Yamazaki^*, Tetsuya Nakamura^*, Tetsuya Higuchi, Yuichi Aiba, Takeshi Tsubata and Mamoru Watanabe^3,*

^* Department of Gastroenterology and Hepatology, Graduate School, and Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; and Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan

Several studies indicate that CD4⁺ T cells, macrophages, and dendritic cells initially mediate intestinal inflammation in murine models of human inflammatory bowel disease. However, the initial role of B cells in the development of intestinal inflammation remains unclear. In this study we present evidence that B cells can trigger intestinal inflammation using transgenic (Tg) mice expressing CD40 ligand (CD40L) ectopically on B cells (CD40L/B Tg). We demonstrated that CD40L/B Tg mice spontaneously developed severe transmural intestinal inflammation in both colon and ileum at 8–15 wk of age. In contrast, CD40L/B TgxCD40^–/– double-mutant mice did not develop colitis, indicating the direct involvement of CD40-CD40L interaction in the development of intestinal inflammation. The inflammatory infiltrates consisted predominantly of massive aggregated, IgM-positive B cells. These mice were also characterized by the presence of anti-colon autoantibodies and elevated IFN- production. Furthermore, although mice transferred with CD4⁺ T cells alone or with both CD4⁺ T and B220⁺ B cells, but not B220⁺ cells alone, from diseased CD40L/B Tg mice, develop colitis, mice transferred with B220⁺ B cells from diseased CD40L/B Tg mice and CD4⁺ T cells from wild-type mice also develop colitis, indicating that the Tg B cells should be a trigger for this colitis model, whereas T cells are involved as effectors. As it has been demonstrated that CD40L is ectopically expressed on B cells in some autoimmune diseases, the present study suggests the possible contribution of B cells in triggering intestinal inflammation in human inflammatory bowel disease.

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The JI 2004 172: 5811-5812. [Full Text]  

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