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

Background & Aims: Mice that express a dominant-negative form of transforming growth factor-beta receptor restricted to T cells (dnTGF-beta RII) develop anti-mitochonctrial 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 (Ig mu(-/-)) with dnTGF-beta RII mice, creating Ig mu(-/-) dnTGF-beta RII mice, and compared the resulting disease phenotype with that of dnTGF-beta RII mice (controls). We also performed adoptive transfer of dnTGF-beta RII 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 Ig mu(-/-)dnTGF-beta RII mice unexpectedly developed a more severe form of cholangitis than controls (dnTGF-beta RII 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 Ig mu-/-dnTGF-beta RII mice had increased levels of proinflammatory cytokines (tumor necrosis factor-a and interleukin-6) and developed a more severe form of colitis than controls. Adoptive transfer of CD8(+) splenocytes from dnTGF-beta RII 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-beta RII model of primary biliary cirrhosis.