CTLA-4 Expression Plays a Role in PSC and PBC Progression

Phil Meister; Christian Steinke-Ramming; Mechthild Beste; Henrike Lenzen; Guido Gerken; Ali Canbay; Christoph Jochum

doi:10.3390/diseases8020021

CTLA-4 Expression Plays a Role in PSC and PBC Progression

Diseases. 2020 Jun 12;8(2):21. doi: 10.3390/diseases8020021.

Authors

Phil Meister^{1

2}, Christian Steinke-Ramming¹, Mechthild Beste¹, Henrike Lenzen¹, Guido Gerken¹, Ali Canbay^{1

3}, Christoph Jochum^{1

4}

Affiliations

¹ Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany.
² Department of General-, Visceral-, and Transplantsurgery, University Hospital Essen, 45147 Essen, Germany.
³ Medical Clinic, University Hospital Bochum, 44892 Bochum, Germany.
⁴ Department of Hepatology and Gastroenterology, Charite Berlin, 10117 Berlin, Germany.

Abstract

Background & aims: The pathogenesis of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) remains unclear. The aim of this study was to reveal certain single nucleotide polymorphisms (SNP) in genes for regulatory proteins in the immunologic pathway possibly going along with susceptibility of attaining PBC or PSC.

Methods: 126 patients with either PBC or PSC with clinical and laboratory data were enrolled in the study. SNPs in three genes (CTLA-4, ICOS, and FOX-P3) which are suspected to play a key role in the autoimmune pathway were analyzed to determine allele variants. Gene expression was measured by RealTime PCR using mRNA.

Results: Patients with cirrhosis had a lower number of CTLA-4 copies than patients without cirrhosis (p = 0.04). Accordingly, patients with lower CTLA-4 copies had a poorer recovery of gamma-glutamyltransferase (GGT) in course of their disease (-69.8 U/l vs. -176.1 U/l p = 0.04). Two SNP allele variants (CTLA4 rs733618 and FOXP3 rs2280883) associated with low CTLA-4 expression could be determined. Patients having both variants showed worsening of GGT (-61.7 U/l vs. -132.6 U/l, p = 0.04) and a trend towards a more progressive disease in terms of cirrhosis. (24% vs. 13% p = ns).

Conclusions: Low expression of CTLA-4 is associated with a more advanced disease in patients with PBC and PSC. Furthermore, we identified two SNP allele variants (CTLA4-SNP rs733618 and FOXP3-SNP rs2280883) associated with a lower CTLA-4 expression and possibly a more severe course of the diseases. Taken together, these results provide further evidence for the involvement of the immune system in the pathogenesis of these two cholestatic liver diseases. Lay summary: Primary biliary cholangitis and primary sclerosing cholangitis are chronic diseases of the bile ducts. Their cause remains widely unclear, but evidence suggests the immune system plays a central role. This study shows that gene alterations connected to the immune system might play a role in the course of the disease.

Keywords: CTLA-4; PBC; PSC; cirrhosis; immunogenetics.