Role of regulatory B cells in chronic intestinal inflammation: association with pathogenesis of Crohn's disease

• Project/Area Number: 23590942
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Shimane University
• Principal Investigator: ISHIHARA Shyunji 島根大学, 医学部, 准教授 (80263531)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 制御性B細胞 / 炎症性腸疾患 / 自然免疫 / IL-10 / クローン病モデルマウス

Research Abstract

The role of regulatory B cells (Bregs) producing IL-10 in the pathogenesis of Crohn's diseases (CD) remains unknown. We investigated IL-10 production in B cells from CD patients, as well as immunoregulatory functions of Bregs in experimental colitis mouse models. CpG DNA-induced IL-10 production was decreased in B cells from CD patients, as compared to those from healthy controls, while Bregs were found to be enriched in a population of CD19(hi)and CD1d(hi) B cells isolated from both human and mouse samples. The severity of intestinal inflammation was increased in the Breg-depleted mice, with similar results also found in adoptive transfer colitis model mice even after regulatory T cells (Tregs) depletion. Our findings show that Bregs 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.

Research Products

• [Journal Article] Role of regulatory B cells in chronic intestinal inflammation: association with pathogenesis of Crohn's disease (2014)
  • Author(s): Oka A, Ishihara S, Mishima Y, Tada Y, Kusunoki R, Fukuba N, Yuki T, Kawashima K, Matsumoto S, Kinoshita Y
  • Journal Title: Inflamm Bowel Dis Volume: 20 Issue: 2 Pages: 315-28
  • DOI: 10.1097/01.mib.0000437983.14544.d5
  • Peer Reviewed
• [Journal Article] Development of diffuse alopecia with psoriasis-like eruption during the administration of infliximab for Crohn’s disease (2013)
  • Author(s): Kawashima K, Ishihara S, Yamamoto A, Ohno Y, Fukuda K, Onishi K, Kinoshita Y
  • Journal Title: Inflamm Bowel Dis Volume: 19 Issue: 3 Pages: E33-E34
  • DOI: 10.1002/ibd.22922
  • Peer Reviewed
• [Journal Article] Pathogenesis of irritable bowel syndrome - review regarding associated infection and immune activation (2013)
  • Author(s): Ishihara S, Tada Y, Fukuba N, Oka A, Kusunoki R, Oshima N, Moriyama I, Yuki T, Kawashima K, Kinoshita Y
  • Journal Title: Digestion Volume: 87 Issue: 3 Pages: 204-11
  • DOI: 10.1159/000350054
  • Peer Reviewed
• [Journal Article] Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8 (2013)
  • Author(s): Mishiro T, Kusunoki R, Otani A, Ansary M, Tongu M, Harashima N, Yamada T, Sato S, Amano Y, Itoh K, Ishihara S, Kinoshita Y
  • Journal Title: Lab Invest Volume: 93 Issue: 7 Pages: 834-43
  • DOI: 10.1038/labinvest.2013.70
  • Peer Reviewed
• [Journal Article] Successful use of maintenance infliximab for nephropathy in a patient with secondary amyloidosis complicating Crohn's disease (2013)
  • Author(s): Tada Y, Ishihara S, Ito T, Matsui K, Sonoyama H, Oka A, Kusunoki R, Fukuba N, Mishima Y, Oshima N, Moriyama I, Yuki T, Kawashima K, Sato S, Adachi K, Ikeuchi H, Kinoshita Y
  • Journal Title: Intern Med Volume: 52 Pages: 1899-902
  • Peer Reviewed
• [Journal Article] Ulcerative colitis associated with isolated unilateral hypoglossal nerve palsy (2012)
  • Author(s): Kawashima K, Ishihara S, Doi K, Uemura Y, Ohno Y, Fukuda K, Onishi K, Tada Y, Oka A, Kusunoki R, Fukuba N, Yuki T, Kinoshita Y
  • Journal Title: Intern Med Volume: 51 Pages: 3135-7
  • Peer Reviewed
• [Journal Article] Roles of milk fat globule-epidermal growth factor 8 in intestinal inflammation (2012)
  • Author(s): Kusunoki R, Ishihara S, Aziz M, Oka A, Tada Y, Kinoshita Y
  • Journal Title: Digestion Volume: 85 Issue: 2 Pages: 103-7
  • DOI: 10.1159/000334679
  • Peer Reviewed
• [Journal Article] Intrarectal administration of milk fat globule epidermal growth factor-8 protein ameliorates murine experimental colitis (2012)
  • Author(s): Otani A, Ishihara S, Aziz MM, Oshima N, Mishima Y, Moriyama I, Yuki T, Amano Y, Ansary MM, Kinoshita Y
  • Journal Title: Int J Mol Med Volume: 29 Pages: 349-56
  • DOI: 10.3892/ijmm.2011.866
  • Peer Reviewed
• [Journal Article] 炎症性腸疾患における制御性B 細胞の役割 (2012)
  • Author(s): 岡 明彦, 石原俊治, 木下芳一
  • Journal Title: G.I.Research Volume: 20 Pages: 479-485
• [Journal Article] 炎症性腸疾患における制御性B細胞の役割 (2012)
  • Author(s): 岡 明彦、石原俊治、木下芳一
  • Journal Title: G.I.Research Volume: 20 Pages: 479-485
• [Journal Article] Rare case of Takayasu's arteritis associated with Crohn's disease (2011)
  • Author(s): Kusunoki R, Ishihara S, Sato M, Sumita Y, Mishima Y, Okada M, Tada Y, Oka A, Fukuba N, Oshima N, Moriyama I, Yuki T, Sato S, Amano Y, Murakawa Y, Kinoshita Y
  • Journal Title: Intern Med Volume: 50 Pages: 1581-5
• [Journal Article] Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells (2011)
  • Author(s): Li YY, Ishihara S, Aziz MM, Oka A, Kusunoki R, Tada Y, Yuki T, Amano Y, Ansary MU, Kinoshita Y
  • Journal Title: Int J Mol Med Volume: 27 Issue: 3 Pages: 337-44
  • DOI: 10.3892/ijmm.2011.596
• [Journal Article] 制御性B 細胞からみたIBD 治療へのアプローチ (2011)
  • Author(s): 岡明彦, 石原俊治, 木下芳一
  • Journal Title: IBD Research Volume: 5 Pages: 259-64
• [Presentation] Susceptibility for colitis-associated cancer development in SAMP1/Yit mice (2013)
  • Author(s): Ishihara S Tada Y, Fukuba N, Sonoyama H, Oka A, Kusunoki R, Oshima N, Moriyama I, Yuki T, Kawashima K, Kushiyama Y, Fujishiro H, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Berlin (International Congress Centrum (ICC Berlin)), Germany
  • Year and Date: 2013-10-16
• [Presentation] Eelevated matrix metalloproteinase-3 Levels in serum correlated with Crohn's disease severity: efficacy as clinical biomarker (2013)
  • Author(s): Kawashima K, Ishihara S, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuba N, Oshima N, Moriyama I, Yuki T, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Berlin (International Congress Centrum (ICC Berlin)), Germany
  • Year and Date: 2013-10-15
• [Presentation] Down-regulation of serotonin reuptake transporter gene expression in colonic mucosa during inflammation and healing phases of inflammatory bowel disease (2012)
  • Author(s): Tada Y, Ishihara S, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam (Amsterdam RAI), Netherlands
  • Year and Date: 2012-10-23
• [Presentation] Effects of pH-dependent release formulation of mesalazine on active ulcerative colitis resistant to time-dependent release formulation of mesalazine (2012)
  • Author(s): Kawashima K, Ishihara S, Oka A, Fukuba N, Ryusaku K, Tada Y, Tamagawa Y, Yuki T, Moriyama I, Yuki T, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam (Amsterdam RAI), Netherlands
  • Year and Date: 2012-10-23
• [Presentation] Regulatory role of CD19highCD1dhigh B cells in intestinal inflammation: association with pathogenesis of Crohn's disease (2012)
  • Author(s): Oka A, Ishihara S, Sonoyama H, Tada Y, A.U. Mesbah, Fukuba N, Moriyama I, Yuki T, Kawashima K, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam (Amsterdam RAI), Netherlands
  • Year and Date: 2012-10-22
• [Presentation] 制御性Ｂ細胞による腸管免疫抑制機構とその破綻による腸炎発症機序の解明-クローン病モデルマウスの病態解析からの知見とその応用- (2011)
  • Author(s): ○岡明彦、石原俊治、木下芳一
  • Organizer: 第53回日本消化器病学会大会:シンポジウム"消化器疾患と免疫"
  • Place of Presentation: 福岡国際センター他（福岡市）
• [Presentation] クローン病モデルマウスのＴ細胞に対する制御性Ｂ細胞の影響 (2011)
  • Author(s): ○岡明彦、石原俊治、多田育賢、楠龍策、福庭暢彦、森山一郎、結城崇史、天野祐二、木下芳一
  • Organizer: 第53回日本消化器病学会大会
  • Place of Presentation: 福岡国際センター他（福岡市）
• [Presentation] Elevated serum pancreatic enzymes in inflammatory bowel disease associated with clinical parameters
  • Author(s): Sonoyama H, Kawashima K, Ishihara S, Tada Y, Oka A, Kusunoki R, Fukuba N, Oshima N, Moriyama I, Yuki T, Kinoshita Y
  • Organizer: The 1 st Annual Meeting of Asian Organization for Crohn’s & Colitis
  • Place of Presentation: Hotel Laforet Tokyo（Tokyo, Japan）
• [Presentation] Milk fat globule-epidermal growth factor 8 accelerates angiogenesis-related gene expression in colonic mucosa during regenerating phase of colitis
  • Author(s): Tada Y, Ishihara S, Kusunoki R, Fukuba N, Sonoyama H, Oka A, Moriyama I, Yuki T, Kawashima K, Ansary MM, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Messe Berlin (Berlin, Germany)
• [Presentation] Televated matrix metalloproteinase-3 Levels in serum correlated with Crohn’s disease severity: efficacy as clinical biomarker
  • Author(s): Kawashima K, Ishihara S, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuba N, Oshima N, Moriyama I, Yuki T, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Messe Berlin (Berlin, Germany)
• [Presentation] Prevalence of irritable bowel syndrome-like symptoms in ulcerative colitis patients with clinical and endoscopic evidence of remission: prospective multicenter study
  • Author(s): Fukuba N, Ishihara S Tada Y, Sonoyama H, Oka A, Kusunoki R, Oshima N, Moriyama I, Yuki T, Kawashima K, Kushiyama Y, Fujishiro H, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Messe Berlin (Berlin, Germany)
• [Presentation] Role of milk fat globule-epidermal growth factor 8 during Citrobacter rodentium-induced colitis in mice
  • Author(s): Oshima N, Ishihara S, Sonoyama H, Tada Y, Oka A, Kusunoki R, Fukuba N, Moriyama I, Yuki T, Kawashima K, Ansary MM, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Messe Berlin (Berlin, Germany)
• [Presentation] Susceptibility for colitis-associated cancer development in SAMP1/Yit mice
  • Author(s): Ishihara S Tada Y, Fukuba N, Sonoyama H, Oka A, Kusunoki R, Oshima N, Moriyama I, Yuki T, Kawashima K, Kushiyama Y, Fujishiro H, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Messe Berlin (Berlin, Germany)
• [Presentation] 潰瘍性大腸炎患者における血清マトリックスメタロプロテイナーゼ-3の疾患活動性マーカーとしての有用性の検討
  • Author(s): 川島耕作，石原俊治，園山浩紀，多田育賢，岡 明彦，楠 龍策，福庭暢彦，大嶋直樹，結城崇史，木下芳一
  • Organizer: 第21回日本消化器関連学会週間 JDD 2013
  • Place of Presentation: ｸﾞﾗﾝﾄﾞプリンスホテル新高輪（東京）
• [Presentation] 炎症性腸疾患の膵酵素異常についての臨床的検討
  • Author(s): 園山浩紀，川島耕作，石原俊治，多田育賢，岡 明彦，楠 龍策，福庭暢彦，大嶋直樹，森山一郎，結城崇史，木下芳一
  • Organizer: 第21回日本消化器関連学会週間（JDD 2013）
  • Place of Presentation: ｸﾞﾗﾝﾄﾞプリンスホテル新高輪（東京）
• [Presentation] Down-regulation of serotonin reuptake transporter gene expression in colonic mucosa during inflammation and healing phases of inflammatory bowel disease
  • Author(s): Tada Y, Ishihara S, Kinoshita Y
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] Role of milk fat globule-epidermal growth factor 8 in intestinal inflammation and carcinogenesis
  • Author(s): Kusunoki R, Ishihara S, Sonoyama H, et al
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] Regulatory role of CD19highCD1dhigh B cells in intestinal inflammation: association with pathogenesis of Crohn’s disease
  • Author(s): Oka A, Ishihara S, Sonoyama H, et al
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] Expression profiles of angiogenesis- and inflammation-related genes in colonic mucosa of ulcerative colitis in remission - comparison with narrow-band imaging magnifying colonoscopy findings
  • Author(s): Yuki T, Ishihara S, Sonoyama H, et al
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] Effects of pH-dependent release formulation of mesalazine on active ulcerative colitis resistant to time-dependent release formulation of mesalazine.
  • Author(s): Kawashima K, Ishihara S, Oka A, et al
  • Organizer: United European Gastroenterology Week (UEGW)
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] 活動期潰瘍性大腸炎に対するpH依存性メサラジン製剤の治療効果
  • Author(s): 川島耕作，石原俊治，結城崇史，他
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] 緩解期潰瘍性大腸炎粘膜におけるNBI拡大所見と局所炎症所見および血管新生因子の対比
  • Author(s): 結城崇史，石原俊治，多田育賢，他
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] 寛解期潰瘍性大腸炎患者IBS様症状と内視鏡像についての多施設共同研究
  • Author(s): 福庭暢彦，石原俊治，多田育賢，他
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] 潰瘍性大腸炎の大腸粘膜におけるセロトニン取り込みトランスポーターの発現に関する検討
  • Author(s): 多田育賢，石原俊治，楠 龍策，他
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都）
• [Presentation] MFG-E8の大腸炎症および発癌への関与
  • Author(s): 楠 龍策，石原俊治，多田育賢，他
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸国際展示場（神戸市）
• [Presentation] 難治性潰瘍性大腸炎に対するタクロリムスによる寛解導入治療症例の経過
  • Author(s): 結城崇史，石原俊治，多田育賢，他
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸国際展示場（神戸市）
• [Presentation] 制御性B細胞による腸炎抑制効果 制御生T細胞非依存的な抑制機構の検討
  • Author(s): 岡 明彦，石原俊治，多田育賢，他
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸国際展示場（神戸市）
• [Presentation] シンポジウム14 腸管炎症におけるserotonin reuptake transporterの遺伝子発現と機能性消化管障害の病態への関与
  • Author(s): 多田育賢，石原俊治，木下芳一
  • Organizer: 54回日本消化器病学会大会
  • Place of Presentation: 神戸国際展示場（神戸市）