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

作者：Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Olivier Govaere, Hai Li, Monika Julia Wolf, Helena Horvatic, Sandra Bierwirth, Jana Hundertmark, Donato Inverso, Laimdota Zizmare, Avital Sarusi-Portuguez, Revant Gupta, Tracy O’Connor, Anastasios D. Giannou, Ahmad Mustafa Shiri, Yehuda Schlesinger, María García‐Beccaria, Charlotte Rennert, Dominik Reinhard Pfister, Rupert Öllinger, Iana Gadjalova, Pierluigi Ramadori, Mohammad Rahbari, Nuh N. Rahbari, Marc Eammonn Healy, Mirian Fernández-Vaquero, Neda Yahoo, Jakob Janzen, Indrabahadur Singh, Chaofan Fan, Xinyuan Liu, Monika Rau, Martin Feuchtenberger, Eva Christina Schwaneck, Sebastian J. Wallace, Simon Cockell, John R. Wilson‐Kanamori, Prakash Ramachandran, Celia Kho, Timothy James Kendall, Anne‐Laure Leblond, Selina Jessica Keppler, Piotr Bielecki, Katja Steiger, Maike Hofmann, Karsten Rippe, Horst F. Zitzelsberger, Achim Weber, Nisar P. Malek, Tom Luedde, Mihael Vucur, Hellmut G. Augustin, Richard Anthony Flavell, Oren Parnas, Roland Rad, Olivier Pabst, Neil Cowan Henderson, Samuel J. Huber, Andrew J. Macpherson, Percy Alexander Knolle, Manfred Claassen, Andreas Geier, Christoph Trautwein, Kristian Unger, Eran Elinav, Ari Waisman, Zeinab Abdullah, Dirk Haller, Frank Tacke, Quentin Mark Anstee, Mathias F Heikenwälder · 发表于：Journal of Hepatology · 年份：2023 · DOI：10.1016/j.jhep.2023.04.037 · 被引用次数：105 · 研究领域：Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity、Gut microbiota and health

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of ...