Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis

Tamas Tornai,Gary L Norman,Gabriella Par,Ferenc Szalay,Dirk Roggenbuck,Istvan Tornai,Alajos Par,Peter Laszlo Lakatos,Nora Sipeki,Peter Antal-Szalmas,Gabor Veres,Rayan Alsulaimani,Kai Fechner,Maria Papp,David Tornai

doi:10.1038/s41598-017-18622-1

Abstract

Glycoprotein 2[GP2] is a specific target of pancreatic autoantibodies[PAbs] in Crohn’s disease(CD) and is involved in gut innate immunity processes. Our aim was to evaluate the prevalence and prognostic potential of PAbs in primary sclerosing cholangitis(PSC). Sixty-five PSC patients were tested for PAbs by indirect immunofluorescence and compared with healthy (n = 100) and chronic liver disease controls(CLD, n = 488). Additionally, a panel of anti-microbial antibodies and secretory (s)IgA levels were measured, as markers of bacterial translocation and immune dysregulation. PAbs were more frequent in PSC(46.2%) compared to controls(healthy:0% and CLD:4.5%), [P < 0.001, for each]. Occurrence of anti-GP2 antibody was 30.8% (20/65) and was exclusively of IgA isotype. Anti-GP2 IgA positive patients had higher sIgA levels (P = 0.021). With flow-cytometry, 68.4% (13/19) of anti-GP2 IgA antibodies were bound with secretory component, suggesting an active retro-transportation of anti-GP2 from the gut lumen to the mucosa. Anti-GP2 IgA was associated with shorter transplant-free survival [PLogRank < 0.01] during the prospective follow-up (median, IQR: 87 [9–99] months) and remained an independent predictor after adjusting for Mayo risk score(HR: 4.69 [1.05–21.04], P = 0.043). These results highlight the significance of gut-liver interactions in PSC. Anti-GP2 IgA might be a valuable tool for risk stratification in PSC and considered as a potential therapeutic target.

Highlights

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by persistent, progressive biliary inflammation and fibrosis
We demonstrated in a large cohort of patients with IBD10, that the presence of pancreatic autoantibodies (PAbs) was associated with concomitant PSC and with faster disease progression in patients with Crohn’s disease (CD)
The aims of this study were to investigate1: the prevalence and type of target specific PAbs in a mixed cohort of pediatric and adult PSC patients with and without IBD2; the association between PAbs and both clinical and laboratory characteristics of the disease3; whether the presence of PAbs is associated with a progressive disease course in PSC; and4 the possible mechanisms related to the formation of PSC-associated PAbs

Summary

Introduction

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by persistent, progressive biliary inflammation and fibrosis. The gut-associated lymphoid tissue (GALT) plays a central role in the IgA antibody formation. Association between serological antibodies linked to enteric bacteria and the progressive disease course in PSC is a reasonable hypothesis. It plays a role in neutralizing microbial antigens and in preventing interaction with the intestinal epithelium, a mechanism called immune exclusion. The aims of this study were to investigate: the prevalence and type of target specific PAbs in a mixed cohort of pediatric and adult PSC patients with and without IBD2; the association between PAbs and both clinical and laboratory characteristics of the disease; whether the presence of PAbs is associated with a progressive disease course in PSC; and the possible mechanisms related to the formation of PSC-associated PAbs

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