ORCID

Abstract

Bacterial translocation-induced inflammation and immune dysfunction are recognised factors contributing to the pathogenesis of primary biliary cholangitis (PBC). However, the specific involvement of interferons (IFNs) and soluble checkpoints (sol-CRs) in shaping the immune landscape in PBC patients remains unexplored. Furthermore, the influence of ursodeoxycholic acid (UDC) on these immune mediators is unknown. Twenty-eight cytokines and 14 sol-CRs were quantified by Luminex assays in plasma samples from 64 PBC patients and 10 healthy controls (HCs). D-lactate was measured as a marker of bacterial translocation. The PBC subgroups were: 24 UDC responders (UDCRs), 18 UDC non-responders (UDCNRs) and 22 patients with end-stage cirrhotic PBC (ESPBC). Soluble herpes virus entry mediator (HVEM) was upregulated in the UDCR subgroup compared to the HC group (p = 0.0404), with increased significance in the ESPBC subgroup (p < 0.0001). There was a progressive increase in several sol-CRs, particularly soluble CD80, LAG3 and CD137 in ESPBC patients. IFN-gamma was higher in the ESPBC subgroup compared to the UDCR subgroup. Elevated IFN-gamma in the UDCNR subgroup compared to UDCR was more significant on excluding patients with cirrhosis (p = 0.0056). Patients with ESPBC expressed several pro-inflammatory cytokines including IL-6, TNF-alpha and CXCL10 compared to the HC group. IFN-lambda-3, but not IFN-lambda-2, was elevated in the ESPBC subgroup compared to all other subgroups. D-lactate levels were equally elevated in all PBC subgroups compared to the HC group. This study provides valuable insights into the immune landscape of PBC, highlighting potential biomarkers and cytokine signatures associated with disease severity and treatment response. Further investigation into the mechanistic roles may pave the way for more targeted therapeutic interventions in PBC management.

Publication Date

2025-01-13

Publication Title

International Journal of Molecular Sciences

Volume

26

Issue

2

ISSN

1661-6596

Acceptance Date

2025-01-08

Deposit Date

2025-04-29

Funding

MAH is supported by the European Association for the Study of the Liver Registry Grant (Liver Disease in Pregnancy), The King\u2019s College Hospital NHS Trust Charity (Orpin Bequest), and The Kelly Group. The experimental work for this manuscript was funded by the Foundation for Liver Research and King\u2019s College Hospital (London, UK).

Keywords

Humans, Female, Male, Middle Aged, Liver Cirrhosis, Biliary/blood, Aged, Receptors, Tumor Necrosis Factor, Member 14/metabolism, Cytokines/blood, Adult, Interferons/metabolism, Biomarkers/blood, Ursodeoxycholic Acid/therapeutic use, Interferon Lambda, Up-Regulation, Case-Control Studies, interferon lambda, HVEM, bacterial translocation, soluble immune checkpoints, cirrhosis, primary biliary cholangitis

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