Chronic liver fibrosis triggers autoantibody production by B cells in a MyD88-dependent pathway (BA4P.126)

Our recent finding suggests that B cells contribute to liver fibrosis through hepatic stellate cells (HSCs) activation. While antibodies produced by the activated intrahepatic B cells contribute to autoimmunity is not known, mixed cryoglobulinemia and other B cell disorders are the leading extrahepatic manifestations of advanced liver diseases in humans. Here, our aim was to determine whether increased antibody production during liver fibrosis could potentially lead to systemic autoimmunity by production of autoantibodies and immune complexes (IC). We studied the role of B cells in autoimmunity using a carbon tetrachloride (CCl4)-induced mouse model of fibrosis and a genetically engineered multidrug resistance gene 2 knock out (Mdr2 -/- ) mice, which constitutively develop progressive liver fibrosis. In both fibrosis models, the frequency of B cells in the liver was elevated and B cells exhibited increased state of activation as measured by CD44 and CD86 expressions, constitutive IgG production and elevated TNF-a production. By using antinuclear antibody (ANA) staining with HEp-2 stabilized substrate and C1q standard ELISA, we detected the presence of antinuclear antibodies (ANA) and IC respectively in the serum of C57BL/6 mice treated with CCl4 for six weeks and Mdr2 -/- mice at 25 week. Interestingly, the targeted deletion of MyD88 signaling in B cells during liver fibrosis resulted in reduced ANA in the serum suggesting the critical role of MyD88 in systemic autoimmunity.