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000276231 1001_ $$0P:(DE-HGF)0$$aKotsiliti, Elena$$b0$$eFirst author
000276231 245__ $$aIntestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.
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000276231 520__ $$aThe progression of nonalcoholic 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.C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet 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 CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.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 systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.
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000276231 650_7 $$2Other$$aB cells
000276231 650_7 $$2Other$$aHCC
000276231 650_7 $$2Other$$aNAFLD
000276231 650_7 $$2Other$$aNASH
000276231 650_7 $$2Other$$afibrosis
000276231 650_7 $$2Other$$agut-liver axis
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000276231 7001_ $$aGovaere, Olivier$$b3
000276231 7001_ $$aLi, Hai$$b4
000276231 7001_ $$aWolf, Monika J$$b5
000276231 7001_ $$aHorvatic, Helena$$b6
000276231 7001_ $$aBierwirth, Sandra$$b7
000276231 7001_ $$aHundertmark, Jana$$b8
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000276231 7001_ $$aGiannou, Anastasios D$$b14
000276231 7001_ $$aShiri, Ahmad Mustafa$$b15
000276231 7001_ $$aSchlesinger, Yehuda$$b16
000276231 7001_ $$0P:(DE-HGF)0$$aBeccaria, Maria Garcia$$b17
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000276231 7001_ $$aÖllinger, Rupert$$b20
000276231 7001_ $$aGadjalova, Iana$$b21
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000276231 7001_ $$aRahbari, Nuh$$b24
000276231 7001_ $$aHealy, Marc$$b25
000276231 7001_ $$0P:(DE-HGF)0$$aFernández-Vaquero, Mirian$$b26
000276231 7001_ $$0P:(DE-He78)241fe8af1e038118cd817048a65f803e$$aYahoo, Neda$$b27$$udkfz
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000276231 7001_ $$aLiu, Xinyuan$$b31
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000276231 7001_ $$aKho, Celia$$b39
000276231 7001_ $$aKendall, Timothy J$$b40
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000276231 7001_ $$aKeppler, Selina J$$b42
000276231 7001_ $$aBielecki, Piotr$$b43
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000276231 7001_ $$0P:(DE-He78)94de5f7413279464b6e738d91dfae1eb$$aRippe, Karsten$$b46$$udkfz
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000276231 7001_ $$aFlavell, Richard$$b53
000276231 7001_ $$aParnas, Oren$$b54
000276231 7001_ $$aRad, Roland$$b55
000276231 7001_ $$aPabst, Olivier$$b56
000276231 7001_ $$aHenderson, Neil C$$b57
000276231 7001_ $$aHuber, Samuel$$b58
000276231 7001_ $$aMacpherson, Andrew$$b59
000276231 7001_ $$aKnolle, Percy$$b60
000276231 7001_ $$aClaasen, Manfred$$b61
000276231 7001_ $$aGeier, Andreas$$b62
000276231 7001_ $$aTrautwein, Christoph$$b63
000276231 7001_ $$aUnger, Kristian$$b64
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000276231 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b71$$eLast author$$udkfz
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