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

Graham, Jonathon J., Mukherjee, Sujit, Yuksel, Muhammad, Mateos, Rebeca Sanabria, Si, Tengfei, Huang, Zhenlin, Huang, Xiahong, Abu Arqoub, Hadil, Patel, Vishal, McPhail, Mark, Zen, Yoh, Heaton, Nigel, Longhi, Maria Serena, Heneghan, Michael A., Liberal, Rodrigo, Vergani, Diego, Mieli-Vergani, Giorgina, Ma, Yun and Hayee, Bu'Hussain 2022. Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis. Hepatology. 75 (3), pp. 518-530. https://doi.org/10.1002/hep.32193

TitleAberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis
TypeJournal article
AuthorsGraham, Jonathon J., Mukherjee, Sujit, Yuksel, Muhammad, Mateos, Rebeca Sanabria, Si, Tengfei, Huang, Zhenlin, Huang, Xiahong, Abu Arqoub, Hadil, Patel, Vishal, McPhail, Mark, Zen, Yoh, Heaton, Nigel, Longhi, Maria Serena, Heneghan, Michael A., Liberal, Rodrigo, Vergani, Diego, Mieli-Vergani, Giorgina, Ma, Yun and Hayee, Bu'Hussain
Abstract

Background and 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.

Approach and Results
Expression of MAdCAM‐1, CCL25, and E‐Cadherin were assessed histologically and using RT‐PCR on explanted liver tissue from patients with CLD undergoing OLT 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. Hepatic expression of MAdCAM‐1, CCL25 and E‐Cadherin was up‐regulated in all CLDs compared with 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, although 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 panetiological feature of CLD.

JournalHepatology
Journal citation75 (3), pp. 518-530
ISSN1527-3350
Year2022
PublisherWiley
American Association for the Study of Liver Diseases
Publisher's version
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1002/hep.32193
Publication dates
PublishedMar 2022
Published online11 Oct 2021

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