Defects in biliary transport proteins, MDR3 in humans and Mdr2 in mice, can lead to a spectrum of cholestatic liver disorders. Although B cell disorders and the aberrant Ab production are the leading extrahepatic manifestations of cholestatic liver diseases, the mechanism underlying this phenomenon is incompletely understood. Using mice with deficiency of Mdr2 that progressively develop cholestatic liver disease, we investigated the contributions of BAFF to aberrant IgG autoantibody production and hepatic fibrosis. In Mdr22/2 mice, hepatic B lymphocytes constitutively produced IgG during fibrosis progression, which correlated with elevated serum levels of BAFF, antinuclear Abs (ANA) and immune complexes. The elevated BAFF and ANA titers were also detected in human patients with primary sclerosing cholangitis and hepatobiliary cholangiopathies. Consistent with the higher BAFF levels, liver-specific selection of the focused BCR IgH repertoire was found on hepatic B cells in Mdr22/2 mice. Interestingly, the administration of anti-BAFF mAb in Mdr22/2 mice altered the BCR repertoire on hepatic B lymphocytes and resulted in reduced ANA and immune complex titers. However, anti-BAFF treatment did not attenuate hepatic fibrosis as measured by collagen deposition, hepatic expressions of collagen-1a, a-smooth muscle actin, and mononuclear cell infiltration (CD11b+ Ly-6chi monocytes and CD11b+ Gr1+ neutrophils). Importantly, depletion of B cells by anti-CD20 mAb reduced both hepatic fibrosis and serum levels of ANA and immune complexes. Our findings implicate B cells as the potential therapeutic targets for hepatic fibrosis and targeting BAFF specifically for attenuating the autoantibody production associated with cholestatic liver disease.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health (NIH) Grants R01AI136533, R01AI124680, R01AI096882, and R01AI126890 (to A.G.), and ORIP/OD P51OD011132 (formerly NCRR P51RR000165) to the Yerkes National Primate Research Center. M.T. is supported by a National Institute of Diabetes and Digestive and Kidney Diseases Mentored Career Development Award (DK109025). This work was facilitated by the Immunology and Flow Cytometry Core of the Center for AIDS Research at Emory University (P30AI050409). This work was also supported by grants from the National Institute of Allergy and Infectious Diseases (AI136533, AI124680, AI096882, and AI126890). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
We are grateful to the patient donors who were undergoing liver transplantation at Emory University Hospital Transplant Center who kindly shared invaluable samples with us. We are thankful to the Emory Transplant Center team: surgeons and surgical staff, nursing staff, and coordinators for assistance and help during this study. We also thank Eduardo Salinas, Dan Chopyk, Patrick Speck, Dennis Jang, Sarah Chewing, and Fengzhi Jin for technical help and support. We are also grateful to the Flow Cytometry, Immunology, and Pathology Cores of Emory Vaccine Center and the veterinary and animal care staff of Yerkes National Primate Research Center, Emory University for assistance.
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