Involvement of B cells in Non-Alcoholic Steatohepatitis (NASH)

Obesity leads to metabolic syndrome, type 2 diabetes, steatosis and steatohepatitis, making hepatocellular carcinoma (HCC) the fastest growing cancer in the U.S.A. and Europe. In a long-term diet inducing non-alcoholic steatohepatitis (NASH) with concomitant metabolic syndrome in mice we have demonstrated that CD8+ T and NKT cells interact with hepatocytes to induce non-alcoholic fatty liver disease (NAFLD), with its severe pathology (NASH) and eventually NASH-to-HCC transition. Recently, B cells have been considered important mediators in innate and adaptive immune responses associated with metabolic diseases. From our published studies it has become apparent that lymphocytes are crucial for NASH and NASH-induced HCC, however the exact role of B cells has remained unclear. We hypothesized that B cells might be important for CD8+ T cell-activation, either in the liver or in the periphery such as the lamina propria of the gastrointestinal tract. Here, our aim was to decipher the role of B cells in the development of NASH and to highlight potential new therapeutic avenues.

Long term CD-HFD diet was given to mice lacking mature B cells (JH-/-) and mice that are lacking mature B cells apart from the IgA+ B cells in the lamina propria (µMT-/-). Feeding experiments were performed in mice lacking immunoglobulins (AID-/-, IgA-/-, AIDg23 s, pIgR and IgMi) as well as in germ free mice. To deplete CD20+ B cells, C57BL/6 and µMT-/- CD-HFD were treated with anti-mouse CD20mAb (clone 5D2, GenTech) intraperitoneally. All Mice mice were analysed through immunohistochemistrical analysis (IHC), flow cytometry (FACS) and other methods (e.g. western blot, RT-qPCR, and ELISA).

Our data indicate that the gastrointestinal B cells contribute to hepatic and metabolomic changes under long-term CD-HFD driving NASH. Moreover, we identify immunoglobulins as important players for the development of the pathology.