Defining Tissue-Resident Immune Cell States in Early Primary Sclerosing Cholangitis

Patel, Meha (2026) Defining Tissue-Resident Immune Cell States in Early Primary Sclerosing Cholangitis. Doctoral thesis, University of East Anglia.

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Abstract

Primary sclerosing cholangitis (PSC) is a chronic fibro-inflammatory cholangiopathy characterised by progressive stricturing of the intra- and extrahepatic bile ducts, leading to cholestasis, recurrent cholangitis, and ultimately cirrhosis and liver failure. Despite its rarity, PSC accounts for a disproportionate burden of liver transplantation, representing 13% of UK transplants in 2024–2025, and is associated with significant morbidity. There are currently no medical therapies that improve transplant-free survival and liver transplantation remains the only definitive treatment. There have been drug trials for therapy targeting bile-acid modulation, the immune system, antimicrobials and anti-fibrotic therapies, with no trial demonstrating clinical benefit to date.

PSC is widely considered to arise from an interplay between genetic susceptibility and environmental triggers, resulting in a dysregulated immune response. Genome-wide association studies support a genetic contribution, with a strong association with inflammatory bowel disease, present in 60-80% of cases, the mechanisms of which remain incompletely understood. Despite decades of research, PSC has remained the “black box of hepatology”, reflecting uncertainty surrounding its pathogenesis and lack of effective targeted therapies. Human PSC research to date has largely been restricted to end-stage disease due to limited tissue accessibility, with explant tissue obtained during liver transplantation as the primary source of research samples. This may mean that confounding factors related to end-stage disease limit the conclusions about true disease pathophysiology.

This thesis has aimed to address the gap in transcriptomic research into early-stage PSC by integrating current clinical and immunological understanding of PSC and related autoimmune liver diseases with advanced transcriptomic approaches applied to liver, colon, and bile duct tissues. A proof-of-concept experimental pipeline from bedside to bench has been developed to generate high-quality single-cell and single-nuclei transcriptomic data from millimetre-scale clinical samples to explore the immunological landscape of early PSC, to identify novel mechanisms and therapeutic targets.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	27 Jul 2026 08:01
Last Modified:	27 Jul 2026 08:01
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103951
DOI:

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