Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

Non-alcoholic steatohepatitis (NASH), which is increasing in incidence due to the obesity epidemic, is a T-cell mediated, auto-aggressive condition that can result in progressive liver disease and hepatocellular carcinoma (HCC). The gut-liver axis contributes to NASH, yet mechanisms underlying metabolic T-cell activation and NASH-related fibrosis have largely remained elusive. We found that gastrointestinal B-cells are activated and increased in number in mouse/human NASH, allowing metabolic T-cell activation to induce NASH antigen- and microbiota-independently. Genetic/therapeutic depletion of B-cells systemically or of gastrointestinal B-cells specifically, prevented or reverted NASH and fibrosis. Secretion of immunoglobulins was essential for NASH and fibrosis development. IgA secretion was necessary for fibrosis-induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR? signaling-axis. Furthermore, clinical/molecular analyses from NASH-patients demonstrated IgA and activated FcR?+ hepatic myeloid cells to correlate with the degree of liver-fibrosis. Thus, gastrointestinal B-cells and the IgA-FcR? signaling-axis on hepatic myeloid cells represent potential therapeutic targets to treat NASH. Overall design: Single-cell transcriptomic data are presented from sorted CD45+ cells of small intestines (after removal of Peyer's patches) of one WT normal diet fed mouse used as control, and one WT CD-HFD (choline-deficient high fat diet) mouse as model for NASH.