bims-nastce 2021-10-17 papers

Front Immunol. 2021 ;12 729143

The Role of B Cells in Adult and Paediatric Liver Injury.

Arzoo M Patel, Yuxin S Liu, Scott P Davies, Rachel M Brown, Deirdre A Kelly, Dagmar Scheel-Toellner, Gary M Reynolds, Zania Stamataki.

B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.

Keywords: B cell; biliary atresia; liver; liver diseases; liver fibrosis; paediatric liver disease

DOI: https://doi.org/10.3389/fimmu.2021.729143

Front Med (Lausanne). 2021 ;8 725390

Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases.

Alix Bruneau, Jana Hundertmark, Adrien Guillot, Frank Tacke.

The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.

Keywords: NAFLD (non-alcoholic fatty liver disease); NASH; PSC; TLRs (Toll-like receptors); gut-liver axis; immune cells; liver diseases; microbiota

DOI: https://doi.org/10.3389/fmed.2021.725390

Hepatology. 2021 Oct 11.

Aberrant hepatic trafficking of gut-derived T-cells is not specific to primary sclerosing cholangitis.

Jonathon J Graham, Sujit Mukherjee, Muhammad Yuksel, Rebeca Sanabria Mateos, Tengfei Si, Zenlin Huang, Xiahong Huang, Hadil Arbuq, Vishal Patel, Mark J McPhail, Yoh Zen, Nigel D Heaton, Maria Serena Longhi, Michael A Heneghan, Rodrigo Liberal, Diego Vergani, Giorgina Mieli-Vergani, Yun Ma, Bu'Hussain Hayee.

BACKGROUND & AIMS: The 'gut-homing' hypothesis suggests the pathogenesis of primary sclerosing cholangitis (PSC) is driven by aberrant hepatic expression of gut adhesion molecules and subsequent recruitment of gut-derived T-cells to the liver. However, inconsistencies lie within this theory including an absence of investigations and comparisons with other chronic liver diseases (CLD). Here we examine 'the gut-homing theory' in patients with PSC with associated inflammatory bowel disease (PSC-IBD) and across multiple inflammatory liver diseases.
METHODS: Expression of MAdCAM-1, CCL25 and E-Cadherin were assessed histologically and using RT-PCR on explanted liver tissue from CLD patients undergoing orthotopic liver transplantation and in normal liver. Liver mononuclear cells were isolated from explanted tissue samples and the expression of gut homing integrins and cytokines on hepatic infiltrating gut-derived T-cells was assessed using flow cytometry.
RESULTS: Hepatic expression of MAdCAM-1, CCL25 and E-Cadherin was upregulated in all CLDs compared to normal liver. There were no differences between disease groups. Frequencies of α4β7, αEβ7, CCR9 and GPR15 expressing hepatic T-cells was increased in PSC-IBD, but also in CLD controls, compared with normal liver. β7 expressing hepatic T-cells displayed an increased inflammatory phenotype compared with β7 negative cells, though this inflammatory cytokine profile was present in both the inflamed and normal liver.
CONCLUSIONS: These findings refute the widely accepted 'gut-homing' hypothesis as the primary driver of PSC and indicate that aberrant hepatic recruitment of gut-derived T-cells is not unique to PSC, but is a pan-aetiological feature of CLD.

Keywords: T helper cell; alpha 4 beta 7 integrin; liver mononuclear cells; chronic liver disease; inflammatory bowel disease; mucosal addressin cellular adhesion molecule 1; primary sclerosing cholangitis

DOI: https://doi.org/10.1002/hep.32193

Nature. 2021 Oct 13.

Convergent somatic mutations in metabolism genes in chronic liver disease.

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.

DOI: https://doi.org/10.1038/s41586-021-03974-6

Nat Metab. 2021 Oct 14.

Metabolic Messengers: tumour necrosis factor.

Jaswinder K Sethi, Gökhan S Hotamisligil.

Tumour necrosis factor (TNF) is a classical, pleiotropic pro-inflammatory cytokine. It is also the first 'adipokine' described to be produced from adipose tissue, regulated in obesity and proposed to contribute to obesity-associated metabolic disease. In this review, we provide an overview of TNF in the context of metabolic inflammation or metaflammation, its discovery as a metabolic messenger, its sites and mechanisms of action and some critical considerations for future research. Although we focus on TNF and the studies that elucidated its immunometabolic actions, we highlight a conceptual framework, generated by these studies, that is equally applicable to the complex network of pro-inflammatory signals, their biological activity and their integration with metabolic regulation, and to the field of immunometabolism more broadly.

DOI: https://doi.org/10.1038/s42255-021-00470-z