Gene Expression by PBMC in Primary Sclerosing Cholangitis: Evidence for Dysregulation of Immune Mediated Genes

Christopher A Aoki,M Eric Gershwin,Christopher L Bowlus,Thomas P Kenny,Kevin Dawson

doi:10.1080/17402520600800085

Christopher A Aoki, M Eric Gershwin + Show 3 more

Open Access

https://doi.org/10.1080/17402520600800085

Copy DOI

Abstract

Primary sclerosing cholangitis (PSC) is a chronic disease of the bile ducts characterized by an inflammatory infiltrate and obliterative fibrosis. The precise role of the immune system in the pathogenesis of PSC remains unknown. We used RNA microarray analysis to identify immune-related genes and pathways that are differentially expressed in PSC. Messenger RNA (mRNA) from peripheral blood mononuclear cells (PBMC) was isolated from both patients with PSC and age and sex matched healthy controls. Samples from 5 PSC patients and 5 controls were analyzed by microarray and based upon rigorous statistical analysis of the data, relevant genes were chosen for confirmation by RT-PCR in 10 PSC patients and 10 controls. Using unsupervised hierarchical clustering, gene expression in PSC was statistically different from our control population. Interestingly, genes within the IL-2 receptor beta, IL-6 and MAP Kinase pathways were found to be differently expressed in patients with PSC compared to controls. Further, individual genes, TNF-α induced protein 6 (TNFaip6) and membrane-spanning 4-domains, subfamily A (ms4a) were found to be upregulated in PSC while similar to Mothers against decapentaplegic homolog 5 (SMAD 5) was downregulated. In conclusion, several immune-related pathways and genes were differentially expressed in PSC compared to control patients, giving further evidence that this disease is systemic and immune-mediated.

Highlights

Primary sclerosing cholangitis (PSC) is a rare liver disease of chronic inflammation affecting primarily medium and large sized bile ducts leading to fibrosis and eventually cirrhosis
We discovered in PSC peripheral blood mononuclear cells (PBMC) three genes expressed greater than 2-fold and 18 genes expressed less than 0.5-fold the median expression index of the controls (Tables III, IV and V)
We screened PBMC from PSC patients in search of genes that might lead to insights in the pathophysiology of PSC

Summary

Introduction

Primary sclerosing cholangitis (PSC) is a rare liver disease of chronic inflammation affecting primarily medium and large sized bile ducts leading to fibrosis and eventually cirrhosis. PSC is characterized by an inflammatory infiltrate and obliterative fibrosis, which leads to the pathognomic biliary strictures observed on cholangiographic imaging. Whether this immune response is autoimmune in nature or a response to bacterial or viral pathogens remains unresolved. The human leukocyte antigen (HLA) complex, the HLA B8-DR3 haplotype, has been positively associated with PSC (Schrumpf et al 1982; Chapman et al 1983; Spurkland et al 1999; Donaldson and Norris 2001; Wiencke et al 2001; Bittencourt et al 2002; Neri et al 2003).

Objectives

Methods

Results

Conclusion