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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 Mdr2\u2212\/\u2212 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 Mdr2\u2212\/\u2212 mice. Interestingly, the administration of anti-BAFF mAb in Mdr2\u2212\/\u2212 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, \u03b1-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.<\/jats:p>","DOI":"10.4049\/jimmunol.1900391","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T18:56:13Z","timestamp":1587754573000},"page":"3117-3128","source":"Crossref","is-referenced-by-count":20,"title":["Blockade of BAFF Reshapes the Hepatic B Cell Receptor Repertoire and Attenuates Autoantibody Production in Cholestatic Liver Disease"],"prefix":"10.1093","volume":"204","author":[{"given":"Manoj","family":"Thapa","sequence":"first","affiliation":[{"name":"Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-2066","authenticated-orcid":false,"given":"Dana","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev","family":"Gumber","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, Yerkes Research Primate Center, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J","family":"Elrod","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2442-8442","authenticated-orcid":false,"given":"Jin-Hwan","family":"Han","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7835-8393","authenticated-orcid":false,"given":"William H","family":"Kitchens","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-8456","authenticated-orcid":false,"given":"Joseph F","family":"Magliocca","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8925-9956","authenticated-orcid":false,"given":"Andrew B","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arash","family":"Grakoui","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine , Atlanta, GA 30329"},{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine , Atlanta, GA 30329"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,15]]},"reference":[{"key":"2025030417512076700_r1","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1046\/j.1365-2362.2001.00824.x","article-title":"The cryoglobulins: an overview","volume":"31","author":"Dammacco","year":"2001","journal-title":"Eur. 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