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Role of Regulatory B Cells in Chronic Intestinal Inflammation: Association with Pathogenesis of Crohn's Disease

Oka, Akihiko MD*; Ishihara, Shunji MD, PhD*; Mishima, Yoshiyuki MD, PhD*; Tada, Yasumasa MD*; Kusunoki, Ryusaku MD*; Fukuba, Nobuhiko MD*; Yuki, Takafumi MD, PhD; Kawashima, Kousaku MD, PhD*; Matsumoto, Satoshi PhD; Kinoshita, Yoshikazu MD, PhD*

doi: 10.1097/01.MIB.0000437983.14544.d5
Original Basic Science Articles

Abstract: The role of regulatory B cells (Bregs) producing interleukin (IL)-10 in the pathogenesis of inflammatory bowel diseases remains unknown. We investigated IL-10 production in B cells from patients with inflammatory bowel diseases and immunoregulatory functions of Bregs in experimental colitis mouse models. CpG DNA-induced IL-10 production in peripheral blood B cells isolated from patients with inflammatory bowel diseases and control subjects was examined. CD19 and CD1d were used for evaluating possible cell surface markers of Bregs. Colitis models of severe combined immunodeficiency mice were established by adoptive transfer of whole CD4+ T cells or regulatory T cell (Treg)-depleted T cells (CD4+CD25) isolated from SAMP1/Yit mice and the function of Bregs in intestinal inflammation was elucidated by evaluating the effects of cotransfer of whole or Breg-depleted B cells. CpG DNA-induced IL-10 production was significantly decreased in B cells from patients with Crohn's disease (CD), as compared with those from healthy controls, whereas Bregs were found to be enriched in a population of CD19hi and CD1dhi B cells isolated from both human and mouse samples. The severity of intestinal inflammation was significantly increased in the Breg-depleted mice, with similar results also found in adoptive transfer colitis model mice even after Treg depletion. Our findings show that Bregs, characterized by the cell surface markers CD19hi and CD1dhi, significantly reduced experimental colitis regardless of the presence or absence of Tregs. These results suggest that a deficiency or decrease of Bregs function exacerbates intestinal inflammation, which may be associated with the pathogenesis of CD.

Article first published online 2 January 2014Supplemental Digital Content is Available in the Text.

*Department of Internal Medicine II, Shimane University School of Medicine, Shimane, Japan;

Division of Gastrointestinal Endoscopy, Shimane University Hospital, Shimane, Japan; and

Yakult Central Institute for Microbiological Research, Tokyo, Japan.

Reprints: Shunji Ishihara, MD, PhD, Department of Internal Medicine II, Shimane Medical University, 89-1, Enya-cho, Izumo, 693-8501, Shimane, Japan (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Supported in part by Health and Labour Sciences Research Grants for research of intractable diseases from the Ministry of Health, Labour, and Welfare of Japan.

The authors have no conflicts of interest to disclose.

Received October 07, 2013

Accepted October 29, 2013

© Crohn's & Colitis Foundation of America, Inc.
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