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-betaRII) 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 (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. RESULTS 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. CONCLUSION B cells have a suppressive effect on the inflammatory response in the dnTGF-betaRII model of primary biliary cirrhosis.

[1]  M. Fujimoto,et al.  Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. , 2008, The Journal of clinical investigation.

[2]  T. Tedder,et al.  Regulatory B cells as inhibitors of immune responses and inflammation , 2008, Immunological reviews.

[3]  Y. Benno,et al.  Regulatory role of B-1 B cells in chronic colitis. , 2008, International immunology.

[4]  M. Fujimoto,et al.  A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. , 2008, Immunity.

[5]  R. Flavell,et al.  Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. , 2008, Hepatology.

[6]  R. Flavell,et al.  Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant‐negative mouse model of primary biliary cirrhosis , 2007 .

[7]  S. Ansell,et al.  CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. , 2007, Blood.

[8]  I. Maričić,et al.  Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. , 2007, The Journal of clinical investigation.

[9]  Yanping Tan,et al.  B Cell Regulation of CD4+CD25+ T Regulatory Cells and IL-10 Via B7 is Essential for Recovery From Experimental Autoimmune Encephalomyelitis1 , 2007, The Journal of Immunology.

[10]  S. Ansell,et al.  CD 70 non-Hodgkin lymphoma B cells induce Foxp 3 expression and regulatory function in intratumoral CD 4 CD 25 T cells , 2007 .

[11]  M. Harada,et al.  Autoreactive T‐cell responses in primary biliary cirrhosis are proinflammatory whereas those of controls are regulatory , 2007, Gastroenterology.

[12]  A. Bhan,et al.  A Case for Regulatory B Cells1 , 2006, The Journal of Immunology.

[13]  R. Coppel,et al.  New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. , 2006, Cellular immunology.

[14]  M. Kaplan,et al.  Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. , 2005, Gastroenterology.

[15]  M. Harada,et al.  Biliary epithelial cells regulate autoreactive T cells: Implications for biliary‐specific diseases , 2005, Hepatology.

[16]  M. Kaplan,et al.  medical progress Primary Biliary Cirrhosis , 2005 .

[17]  G. Gores,et al.  Caspase induction by IgA antimitochondrial antibody: IgA‐mediated biliary injury in primary biliary cirrhosis , 2004, Hepatology.

[18]  上平 幸史.  Distinct costimulation dependent and independent autoreactive T cell clones in primary biliary cirrhosis , 2004 .

[19]  J. Neuberger,et al.  Liver transplantation for primary biliary cirrhosis. , 2003, Clinics in liver disease.

[20]  S. Matsushita,et al.  Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. , 2003, Gastroenterology.

[21]  K. Tsuneyama,et al.  Accumulating CD57 + CD3 +  natural killer T cells are related to intrahepatic bile duct lesions in primary biliary cirrhosis , 2003, Liver international : official journal of the International Association for the Study of the Liver.

[22]  M. Kaplan,et al.  Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. , 2002, Gastroenterology.

[23]  M. Kaplan,et al.  Identification of HLA-A2–restricted CD8+ Cytotoxic T Cell Responses in Primary Biliary Cirrhosis , 2002, The Journal of Experimental Medicine.

[24]  J. Neuberger,et al.  Anti-mitochondrial antibodies in primary biliary cirrhosis. , 2002, Journal of hepatology.

[25]  S. Matsushita,et al.  Fine specificity of T cells reactive to human PDC‐E2 163‐176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: Implications for molecular mimicry and cross‐recognition among mitochondrial autoantigens , 2000, Hepatology.

[26]  M. Gershwin,et al.  Mimicry peptides of human PDC‐E2 163‐176 peptide, the immunodominant T‐cell epitope of primary biliary cirrhosis , 2000, Hepatology.

[27]  M. Rowley,et al.  Primary biliary cirrhosis: an orchestrated immune response against epithelial cells , 2000, Immunological reviews.

[28]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[29]  M. Kaplan,et al.  Primary Biliary Cirrhosis , 1987, The New England journal of medicine.

[30]  F. Preffer,et al.  Suppressive Role of B Cells in Chronic Colitis of  T Cell Receptor α Mutant Mice , 1997, The Journal of experimental medicine.

[31]  Y. Nakanuma.  Distribution of B lymphocytes in nonsuppurative cholangitis in primary biliary cirrhosis , 1993, Hepatology.

[32]  M. Kaplan,et al.  Inhibition of α‐ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis , 1990 .

[33]  R. Coppel,et al.  Primary biliary cirrhosis. Inhibition of pyruvate dehydrogenase complex activity by autoantibodies specific for E1 alpha, a non-lipoic acid containing mitochondrial enzyme. , 1990, Journal of immunology.

[34]  M. Kaplan,et al.  Inhibition of alpha-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis. , 1990, Hepatology.

[35]  K. Rajewsky,et al.  Expansion and functional activity of Ly‐1+ B cells upon transfer of peritoneal cells into allotype‐congenic, newborn mice , 1987, European journal of immunology.

[36]  R. Hardy,et al.  Progenitors for Ly-1 B cells are distinct from progenitors for other B cells , 1985, The Journal of experimental medicine.