Gastrointestinal B-cells license metabolic T-cell activation in NASH microbiota anigen-independently and contribute to fibrosis by IgA-FcRy signalling

Non-alcoholic steatohepatitis (NASH) is a T-cell mediated, auto-aggressive condition that can result in progressive liver disease and hepatocellular carcinoma. Gastrointestinal B-cells are activated and increased in number in mouse and human NASH, licensing metabolic-cell activation to induce NASH antigen- and microbiota-independently. Genetic or therapeutic depletion of B-cells systemically or gastrointestinal B-cells specifically prevented or reverted NASH and fibrosis. Clinical and molecular analyses from NASH patients demonstrated IgA-levels and activated FcRy+ hepatic myeloid cells to correlate with liver fibrosis degree. Single, live cells were isolated from a NAFLD liver explant and FACS-sorted for CD45+ cells, taking a 70-30 HLADR- to HLADR+ split to correct for lymphocyte preponderance.