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Cutting Edge Issues in Primary Sclerosing Cholangitis

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Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium- to large-sized bile ducts and intense concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but the strong association between PSC and inflammatory bowel disease suggest causal links between the diseases. The male predominance in PSC, lack of a defined, pathogenic auto-antigen, and the potential role of the innate immune system suggest that PSC may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC shares several genetic susceptibility loci with other autoimmune diseases including the human leukocyte antigen DRB01*03 haplotype. The precise immune response of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease.

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Abbreviations

PSC:

Primary sclerosing cholangitis

IBD:

Inflammatory bowel disease

HLA:

Human leukocyte antigen

UC:

Ulcerative colitis

Mdr2:

Multi-drug resistance-2

NK:

Natural killer

KIRs:

Killer immunoglobulin-like receptors

MIC:

Major histocompatibility complex class I chain related

MAdCAM-1:

Mucosal addressin cell adhesion molecule-1

PBC:

Primary biliary cirrhosis

LIL:

Liver infiltrating lymphocytes

TGF:

Transforming growth factor

BEC:

Biliary epithelial cells

PAMPs:

Pathogen-associated molecular patterns

LPS:

Lipopolysaccharide

TLRs:

Toll-like receptors

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  1. Division of Gastroenterology and Hepatology, University of California Davis Medical Center, 4150 V Street, PSSB 3500, Sacramento, CA, 95817, USA

    Christopher L. Bowlus

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Bowlus, C.L. Cutting Edge Issues in Primary Sclerosing Cholangitis. Clinic Rev Allerg Immunol 41, 139–150 (2011). https://doi.org/10.1007/s12016-010-8221-3

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