AUTHOR=Sowa Mandy , Kolenda Rafał , Baumgart Daniel C. , Pratschke Johann , Papp Maria , Tornai Tamas , Suchanski Jaroslaw , Bogdanos Dimitrios P. , Mytilinaiou Maria G. , Hammermann Jutta , Laass Martin W. , Conrad Karsten , Schramm Christoph , Franke Andre , Roggenbuck Dirk , Schierack Peter 

TITLE=Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01959

DOI=10.3389/fimmu.2018.01959

ISSN=1664-3224

ABSTRACT=<p><bold>Introduction:</bold> Zymogen granule glycoprotein 2 (GP2) was demonstrated as first autoimmune mucosal target in primary sclerosing cholangitis (PSC) associated with disease severity. Autoantibodies to four GP2 isoforms (aGP2<sub>1−4</sub>) were found in patients with inflammatory bowel diseases but reactivity against specific GP2 epitopes has not been investigated in PSC yet. Hence, the prevalence of aGP2<sub>1−4</sub> and their association with the PSC phenotype for risk prediction were examined.</p><p><bold>Methods:</bold> GP2 isoforms were stably expressed as glycosylphosphatidyl - inositol-anchored molecules in the membrane of HEp-2 cells and used as autoantigenic targets in indirect immunofluorescence assay (IFA). aGP2<sub>1−4</sub> IgA and IgG were detected by IFA in 212 PSC patients of four European university hospitals and 145 controls comprising 95 patients with cystic fibrosis and 50 healthy subjects.</p><p><bold>Results:</bold> Combined aGP2<sub>1</sub> and aGP2<sub>4</sub> IgA testing with a sensitivity of 66.0% and a specificity of 97.9% resulted in the best diagnostic performance (Youden index: 0.64) regarding all aGP2 and combinations thereof. aGP2<sub>4</sub> IgA positivity is significantly associated with the presence of cirrhosis in PSC (<italic>p</italic> = 0.0056). Logistic regression revealed the occurrence of aGP2<sub>1</sub> IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03–1.86) and aGP2<sub>4</sub> IgA (OR 1.52, 95%CI: 1.07–2.15) along with male gender (OR 0.51, 95%CI: 0.27–0.97) and older age (OR 1.03 95%CI: 1.01–1.05) as significant risks for the concomitant presence of cirrhosis in PSC.</p><p><bold>Conclusions:</bold> Combined aGP2<sub>1</sub> and aGP2<sub>4</sub> IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP2<sub>1</sub> and aGP2<sub>4</sub> IgA is associated with cirrhosis in PSC and could be used for risk stratification.</p>