B Cells Suppress the Inflammatory Response in a Mouse Model of Primary Biliary Cirrhosis

Yuki Moritoki, Weici Zhang, Koichi Tsuneyama, Katsunori Yoshida, Kanji Wakabayashi, Guo Xiang Yang, Christopher Bowlus, William M. Ridgway, Yoshiyuki Ueno, Aftab A. Ansari, Ross L. Coppel, Ian R. Mackay, Richard A. Flavell, M. Eric Gershwin, Zhe Xiong Lian

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Mice that express a dominant-negative form of transforming growth factor-β receptor restricted to T cells (dnTGF-βRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis. Methods: To address the role of B cells in this model of primary biliary cirrhosis, we bred B cell-deficient mice (Igμ-/-) with dnTGF-βRII mice, creating Igμ-/-dnTGF-βRII mice, and compared the resulting disease phenotype with that of dnTGF-βRII mice (controls). We also performed adoptive transfer of dnTGF-βRII CD8+ splenocytes, with or without B cells, to 8-week-old female Rag-1-/- mice to assess the role of B cells in the inflammatory response. Results: The B cell-deficient Igμ-/-dnTGF-βRII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-βRII mice) and had a significantly greater frequency of activated CD4+ and CD8+ T cells in the liver. They also had reduced frequency of Foxp3+ regulatory T cells in the hepatic CD4+ T-cell population and natural killer (NK) T cells (NK1.1+ CD3+) in hepatic inflammatory cell infiltrates. The Igμ-/-dnTGF-βRII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8+ splenocytes from dnTGF-βRII mice and peritoneal cavity-derived, but not spleen-derived, CD19+ B cells into Rag-1-/- mice resulted in decreased amounts of liver inflammation and bile duct damage, compared with Rag-1-/- mice in which only CD8+ splenocytes were transferred. Conclusion: B cells have a suppressive effect on the inflammatory response in the dnTGF-βRII model of primary biliary cirrhosis.

Original languageEnglish (US)
Pages (from-to)1037-1047
Number of pages11
JournalGastroenterology
Volume136
Issue number3
DOIs
StatePublished - Mar 2009

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Biliary Liver Cirrhosis
B-Lymphocytes
Adoptive Transfer
Liver
T-Lymphocytes
Inflammation
Natural Killer T-Cells
Cholangitis
Growth Factor Receptors
Peritoneal Cavity
Transforming Growth Factors
Regulatory T-Lymphocytes
Colitis
Bile Ducts
Hepatocytes
Interleukin-6
Spleen
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Moritoki, Y., Zhang, W., Tsuneyama, K., Yoshida, K., Wakabayashi, K., Yang, G. X., ... Lian, Z. X. (2009). B Cells Suppress the Inflammatory Response in a Mouse Model of Primary Biliary Cirrhosis. Gastroenterology, 136(3), 1037-1047. https://doi.org/10.1053/j.gastro.2008.11.035

B Cells Suppress the Inflammatory Response in a Mouse Model of Primary Biliary Cirrhosis. / Moritoki, Yuki; Zhang, Weici; Tsuneyama, Koichi; Yoshida, Katsunori; Wakabayashi, Kanji; Yang, Guo Xiang; Bowlus, Christopher; Ridgway, William M.; Ueno, Yoshiyuki; Ansari, Aftab A.; Coppel, Ross L.; Mackay, Ian R.; Flavell, Richard A.; Gershwin, M. Eric; Lian, Zhe Xiong.

In: Gastroenterology, Vol. 136, No. 3, 03.2009, p. 1037-1047.

Research output: Contribution to journalArticle

Moritoki, Y, Zhang, W, Tsuneyama, K, Yoshida, K, Wakabayashi, K, Yang, GX, Bowlus, C, Ridgway, WM, Ueno, Y, Ansari, AA, Coppel, RL, Mackay, IR, Flavell, RA, Gershwin, ME & Lian, ZX 2009, 'B Cells Suppress the Inflammatory Response in a Mouse Model of Primary Biliary Cirrhosis', Gastroenterology, vol. 136, no. 3, pp. 1037-1047. https://doi.org/10.1053/j.gastro.2008.11.035
Moritoki, Yuki ; Zhang, Weici ; Tsuneyama, Koichi ; Yoshida, Katsunori ; Wakabayashi, Kanji ; Yang, Guo Xiang ; Bowlus, Christopher ; Ridgway, William M. ; Ueno, Yoshiyuki ; Ansari, Aftab A. ; Coppel, Ross L. ; Mackay, Ian R. ; Flavell, Richard A. ; Gershwin, M. Eric ; Lian, Zhe Xiong. / B Cells Suppress the Inflammatory Response in a Mouse Model of Primary Biliary Cirrhosis. In: Gastroenterology. 2009 ; Vol. 136, No. 3. pp. 1037-1047.
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abstract = "Background & Aims: Mice that express a dominant-negative form of transforming growth factor-β receptor restricted to T cells (dnTGF-βRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis. Methods: To address the role of B cells in this model of primary biliary cirrhosis, we bred B cell-deficient mice (Igμ-/-) with dnTGF-βRII mice, creating Igμ-/-dnTGF-βRII mice, and compared the resulting disease phenotype with that of dnTGF-βRII mice (controls). We also performed adoptive transfer of dnTGF-βRII CD8+ splenocytes, with or without B cells, to 8-week-old female Rag-1-/- mice to assess the role of B cells in the inflammatory response. Results: The B cell-deficient Igμ-/-dnTGF-βRII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-βRII mice) and had a significantly greater frequency of activated CD4+ and CD8+ T cells in the liver. They also had reduced frequency of Foxp3+ regulatory T cells in the hepatic CD4+ T-cell population and natural killer (NK) T cells (NK1.1+ CD3+) in hepatic inflammatory cell infiltrates. The Igμ-/-dnTGF-βRII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8+ splenocytes from dnTGF-βRII mice and peritoneal cavity-derived, but not spleen-derived, CD19+ B cells into Rag-1-/- mice resulted in decreased amounts of liver inflammation and bile duct damage, compared with Rag-1-/- mice in which only CD8+ splenocytes were transferred. Conclusion: B cells have a suppressive effect on the inflammatory response in the dnTGF-βRII model of primary biliary cirrhosis.",
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AU - Moritoki, Yuki

AU - Zhang, Weici

AU - Tsuneyama, Koichi

AU - Yoshida, Katsunori

AU - Wakabayashi, Kanji

AU - Yang, Guo Xiang

AU - Bowlus, Christopher

AU - Ridgway, William M.

AU - Ueno, Yoshiyuki

AU - Ansari, Aftab A.

AU - Coppel, Ross L.

AU - Mackay, Ian R.

AU - Flavell, Richard A.

AU - Gershwin, M. Eric

AU - Lian, Zhe Xiong

PY - 2009/3

Y1 - 2009/3

N2 - Background & Aims: Mice that express a dominant-negative form of transforming growth factor-β receptor restricted to T cells (dnTGF-βRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis. Methods: To address the role of B cells in this model of primary biliary cirrhosis, we bred B cell-deficient mice (Igμ-/-) with dnTGF-βRII mice, creating Igμ-/-dnTGF-βRII mice, and compared the resulting disease phenotype with that of dnTGF-βRII mice (controls). We also performed adoptive transfer of dnTGF-βRII CD8+ splenocytes, with or without B cells, to 8-week-old female Rag-1-/- mice to assess the role of B cells in the inflammatory response. Results: The B cell-deficient Igμ-/-dnTGF-βRII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-βRII mice) and had a significantly greater frequency of activated CD4+ and CD8+ T cells in the liver. They also had reduced frequency of Foxp3+ regulatory T cells in the hepatic CD4+ T-cell population and natural killer (NK) T cells (NK1.1+ CD3+) in hepatic inflammatory cell infiltrates. The Igμ-/-dnTGF-βRII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8+ splenocytes from dnTGF-βRII mice and peritoneal cavity-derived, but not spleen-derived, CD19+ B cells into Rag-1-/- mice resulted in decreased amounts of liver inflammation and bile duct damage, compared with Rag-1-/- mice in which only CD8+ splenocytes were transferred. Conclusion: B cells have a suppressive effect on the inflammatory response in the dnTGF-βRII model of primary biliary cirrhosis.

AB - Background & Aims: Mice that express a dominant-negative form of transforming growth factor-β receptor restricted to T cells (dnTGF-βRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis. Methods: To address the role of B cells in this model of primary biliary cirrhosis, we bred B cell-deficient mice (Igμ-/-) with dnTGF-βRII mice, creating Igμ-/-dnTGF-βRII mice, and compared the resulting disease phenotype with that of dnTGF-βRII mice (controls). We also performed adoptive transfer of dnTGF-βRII CD8+ splenocytes, with or without B cells, to 8-week-old female Rag-1-/- mice to assess the role of B cells in the inflammatory response. Results: The B cell-deficient Igμ-/-dnTGF-βRII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-βRII mice) and had a significantly greater frequency of activated CD4+ and CD8+ T cells in the liver. They also had reduced frequency of Foxp3+ regulatory T cells in the hepatic CD4+ T-cell population and natural killer (NK) T cells (NK1.1+ CD3+) in hepatic inflammatory cell infiltrates. The Igμ-/-dnTGF-βRII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8+ splenocytes from dnTGF-βRII mice and peritoneal cavity-derived, but not spleen-derived, CD19+ B cells into Rag-1-/- mice resulted in decreased amounts of liver inflammation and bile duct damage, compared with Rag-1-/- mice in which only CD8+ splenocytes were transferred. Conclusion: B cells have a suppressive effect on the inflammatory response in the dnTGF-βRII model of primary biliary cirrhosis.

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