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

Kotsiliti, Eleni; Leone, Valentina; Schuehle, Svenja; Govaere, Olivier; Li, Hai; Wolf, Monika; Horvatic, Helena; Bierwirth, Sandra; Hundertmark, Jana; Inverso, Donato; Zizmare, Laimdota; Sarusi-Portuguez, Avital; Gupta, Revant; O’Connor, Tracy; Giannou, Anastasios D.; Shiri, Ahmad Mustafa; Schlesinger, Y.; García‐Beccaria, María; Rennert, Charlotte; Pfister, Dominik; Öllinger, Rupert; Gadjalova, Iana; Ramadori, Pierluigi; Rahbari, Mohammad; Rahbari, Nuh N.; Healy, Marc E.; Fernández-Vaquero, Mirian; Yahoo, Neda; Janzen, Jakob; Singh, Indrabahadur; Fan, Chaofan; Liu, Xinyuan; Rau, Monika; Feuchtenberger, Martin; Schwaneck, Eva Christina; Wallace, Sebastian J.; Cockell, Simon; Wilson-Kanamori, John; Ramachandran, Prakash; Kho, Celia; Kendall, Timothy J.; Leblond, Anne-Laure; Keppler, Selina J.; Bielecki, Piotr; Steiger, Katja; Hofmann, Maike; Rippe, Karsten; Zitzelsberger, Horst; Weber, Achim; Malek, Nisar P.; Lüdde, Tom; Vucur, Mihael; Augustin, Hellmut G.; Flavell, Richard A.; Parnas, Oren; Rad, Roland; Pabst, Oliver; Henderson, Neil C.; Huber, Samuel; Knolle, Percy A.; Claasen, M.; Geier, Andreas; Trautwein, Christoph; Unger, Kristian; Elinav, Eran; Waisman, Ari; Abdullah, Zeinab; Haller, Dirk; Tacke, Frank; Anstee, Quentin M.; Heikenwälder, M

doi:10.1016/j.jhep.2023.04.037

Cited by 35 publications

(19 citation statements)

References 67 publications

(85 reference statements)

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“…Many studies indicate that B cells that produce IgA antibodies can also play a role in promoting liver fibrosis and HCC development, particularly in non-alcoholic steatohepatitis (NASH)-driven HCC [ 91 ]. IgA + B cells upregulate the expression of PD-L1 and inhibit the activation and cytotoxicity of T cells by secreting IL-10, and genetic or therapeutic depletion of IgA + B cells is beneficial in alleviating liver fibrosis [ 92 ] and reducing liver carcinogenesis [ 93 ]. Regulatory B cells (Bregs), as a novel subset of B cells characterized by their secretion of IL-10, not only inhibit T cell function but also directly promote the progression and vascular invasion of HCC through the CD40/CD154 axis [ 94 ].…”

Section: Immunosuppressive Microenvironment Of Hccmentioning

confidence: 99%

Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives

Shen,

Zhu,

Xie

et al. 2024

J Hematol Oncol

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Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.

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Section: Immunosuppressive Microenvironment Of Hccmentioning

confidence: 99%

Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives

Shen,

Zhu,

Xie

et al. 2024

J Hematol Oncol

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“…Together, these data suggest that primed T cells homing to the liver are responsible for the liver damage and MASH. Metabolic activation of T cells is further promoted by B cells independent of TCR signaling ( 62 ). B cells become activated within the lamina propria independent of microbiota and home to the liver where they affect CD8 T cells and further promote damage and fibrosis via their IgA secretion ( 62 ).…”

Section: Mash and The Adaptive Arm Of The Immune Responsementioning

confidence: 99%

“…Metabolic activation of T cells is further promoted by B cells independent of TCR signaling ( 62 ). B cells become activated within the lamina propria independent of microbiota and home to the liver where they affect CD8 T cells and further promote damage and fibrosis via their IgA secretion ( 62 ). This phenomenon is accompanied by the increased presence of autoantibodies targeting oxidative stress-derived epitopes in approximately 40% of adults and in 60% of children with MASH ( 63 ).…”

Section: Mash and The Adaptive Arm Of The Immune Responsementioning

confidence: 99%

The role of dendritic cells in MASH: friends or foes?

Pinto,

Lukacs-Kornek

2024

Front. Immunol.

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Dendritic cells (DCs) are major antigen-presenting cells that connect innate and adaptive immunity. Hepatic DCs are less activated and contribute to maintain the tolerogenic environment of the liver under steady state. Several studies indicated DCs in metabolic dysfunction-associated steatohepatitis (MASH), representing a substantial burden on healthcare systems due to its association with liver-related morbidity and mortality. Studies highlighted the potential disease-promoting role of liver DCs in the development of MASH while other experimental systems suggested their protective role. This review discusses this controversy and the current understanding of how DCs affect the pathogenesis of MASH.

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“…1C). Next, we assessed how MASH affects antibody-producing B cells, previously shown to participate in the pathogenesis of MASH 9,24 . There were no alterations in the number of plasmablasts and plasma cells within the MASH liver (Fig.…”

Section: Mash Induces a Shift In Intrahepatic B Cell Populationsmentioning

confidence: 99%

“…Inflammation plays a pivotal role in the progression of steatosis to the more severe MASH. Although the underlying mechanisms are poorly understood, several immune cells, including macrophages [5][6][7][8] , B cells [9][10][11] , CD4 T cells 12,13 , CD8 T cells 14,15 , neutrophils 16,17 , and dendritic cells (DCs) 18 have been shown to in promote inflammation and fibrosis during MASH.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH

Barrow,

Wang,

Fredrickson

et al. 2023

Preprint

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B cells play a crucial role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease that if persistent can lead to cirrhosis, liver failure, and cancer. Chronic inflammation and fibrosis are key features of MASH that determine disease progression and outcomes. Recent advances have revealed that pathogenic B cell-derived cytokines and antibodies promote the development of MASH. However, the mechanisms through which B cells promote fibrosis and the metabolic adaptations underlying their pathogenic responses remain unclear. Here, we report that a subset of mature B cells with heightened cytokine responses accumulate in the liver and promote inflammation in MASH. To meet the increased energetic demand of effector responses, B cells increase their ATP production via oxidative phosphorylation (OXPHOS) fueled by pyruvate oxidation in a B cell receptor (BCR)-specific manner. Blocking pyruvate oxidation completely abrogated the inflammatory capacity of MASH B cells. Accordingly, the restriction of the BCR led to MASH attenuation, including reductions in steatosis, hepatic inflammation, and fibrosis. Mechanistically, BCR restriction decreased B cell maturation, activation, and effector responses in the liver, accompanied by decreased T cell- and macrophage-mediated inflammation. Notably, attenuated liver fibrosis in BCR-restricted mice was associated with lower IgG production and decreased expression of Fc-gamma receptors on hepatic stellate cells. Together, these findings indicate a key role for B cell antigen-specific responses in promoting steatosis, inflammation, and fibrosis during MASH.

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

Cited by 35 publications

References 67 publications

Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives

Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: current status and prospectives

The role of dendritic cells in MASH: friends or foes?

Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH

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