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
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California, USA.
Gastroenterology. 2009 Mar;136(3):1037-47. doi: 10.1053/j.gastro.2008.11.035. Epub 2008 Nov 19.
BACKGROUND & AIMS: Mice that express a dominant-negative form of transforming growth factor-beta receptor restricted to T cells (dnTGF-betaRII) develop antimitochondrial antibodies and liver inflammation similar to human primary biliary cirrhosis.
To address the role of B cells in this model of primary biliary cirrhosis, we bred B cell-deficient mice (Igmu(-/-)) with dnTGF-betaRII mice, creating Igmu(-/-)dnTGF-betaRII mice, and compared the resulting disease phenotype with that of dnTGF-betaRII mice (controls). We also performed adoptive transfer of dnTGF-betaRII 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.
The B cell-deficient Igmu(-/-)dnTGF-betaRII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-betaRII 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 Igmu(-/-)dnTGF-betaRII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8(+) splenocytes from dnTGF-betaRII 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.
B cells have a suppressive effect on the inflammatory response in the dnTGF-betaRII model of primary biliary cirrhosis.
表达限于T细胞的转化生长因子β受体显性负性形式（dnTGF-βRII）的小鼠会产生抗线粒体抗体并出现肝脏炎症，类似于人类原发性胆汁性肝硬化。
为了研究B细胞在这种原发性胆汁性肝硬化模型中的作用，我们将B细胞缺陷小鼠（Igmu(-/-)）与dnTGF-βRII小鼠进行杂交，培育出Igmu(-/-)dnTGF-βRII小鼠，并将其产生的疾病表型与dnTGF-βRII小鼠（对照组）进行比较。我们还将dnTGF-βRII CD8(+)脾细胞（有或无B细胞）过继转移到8周龄雌性Rag-1(-/-)小鼠体内，以评估B细胞在炎症反应中的作用。
B细胞缺陷的Igmu(-/-)dnTGF-βRII小鼠意外地出现了比对照组（dnTGF-βRII小鼠）更严重的胆管炎形式，且肝脏中活化的CD4(+)和CD8(+) T细胞频率显著更高。它们肝脏CD4(+) T细胞群体中Foxp3(+)调节性T细胞的频率以及肝脏炎性细胞浸润中的自然杀伤（NK）T细胞（NK1.1(+) CD3(+)）频率也降低。Igmu(-/-)dnTGF-βRII小鼠促炎细胞因子（肿瘤坏死因子-α和白细胞介素-6）水平升高，且出现了比对照组更严重的结肠炎形式。与仅转移了CD8(+)脾细胞的Rag-1(-/-)小鼠相比，将dnTGF-βRII小鼠的CD8(+)脾细胞以及腹腔来源而非脾来源的CD19(+) B细胞过继转移到Rag-1(-/-)小鼠体内，导致肝脏炎症和胆管损伤减少。
在原发性胆汁性肝硬化的dnTGF-βRII模型中，B细胞对炎症反应具有抑制作用。
