Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype
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 ) were found in patients with inflammatory bowel diseases but reactivity against specific GP2 e...
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| Published in | Frontiers in immunology Vol. 9; p. 1959 |
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| Main Authors | , , , , , , , , , , , , , , , |
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Frontiers Media S.A
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| Abstract | 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
) 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
and their association with the PSC phenotype for risk prediction were examined.
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
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.
Combined aGP2
and aGP2
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
IgA positivity is significantly associated with the presence of cirrhosis in PSC (
= 0.0056). Logistic regression revealed the occurrence of aGP2
IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03-1.86) and aGP2
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.
Combined aGP2
and aGP2
IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP2
and aGP2
IgA is associated with cirrhosis in PSC and could be used for risk stratification. |
|---|---|
| AbstractList | 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
) 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
and their association with the PSC phenotype for risk prediction were examined.
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
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.
Combined aGP2
and aGP2
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
IgA positivity is significantly associated with the presence of cirrhosis in PSC (
= 0.0056). Logistic regression revealed the occurrence of aGP2
IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03-1.86) and aGP2
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.
Combined aGP2
and aGP2
IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP2
and aGP2
IgA is associated with cirrhosis in PSC and could be used for risk stratification. Introduction: 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 1−4 ) 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 1−4 and their association with the PSC phenotype for risk prediction were examined. Methods: 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 1−4 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. Results: Combined aGP2 1 and aGP2 4 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 4 IgA positivity is significantly associated with the presence of cirrhosis in PSC ( p = 0.0056). Logistic regression revealed the occurrence of aGP2 1 IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03–1.86) and aGP2 4 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. Conclusions: Combined aGP2 1 and aGP2 4 IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP2 1 and aGP2 4 IgA is associated with cirrhosis in PSC and could be used for risk stratification. Introduction: 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 (aGP21−4) 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 aGP21−4 and their association with the PSC phenotype for risk prediction were examined.Methods: 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). aGP21−4 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.Results: Combined aGP21 and aGP24 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. aGP24 IgA positivity is significantly associated with the presence of cirrhosis in PSC (p = 0.0056). Logistic regression revealed the occurrence of aGP21 IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03–1.86) and aGP24 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.Conclusions: Combined aGP21 and aGP24 IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP21 and aGP24 IgA is associated with cirrhosis in PSC and could be used for risk stratification. Introduction: 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 (aGP21-4) 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 aGP21-4 and their association with the PSC phenotype for risk prediction were examined. Methods: 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). aGP21-4 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. Results: Combined aGP21 and aGP24 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. aGP24 IgA positivity is significantly associated with the presence of cirrhosis in PSC (p = 0.0056). Logistic regression revealed the occurrence of aGP21 IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03-1.86) and aGP24 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. Conclusions: Combined aGP21 and aGP24 IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP21 and aGP24 IgA is associated with cirrhosis in PSC and could be used for risk stratification.Introduction: 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 (aGP21-4) 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 aGP21-4 and their association with the PSC phenotype for risk prediction were examined. Methods: 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). aGP21-4 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. Results: Combined aGP21 and aGP24 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. aGP24 IgA positivity is significantly associated with the presence of cirrhosis in PSC (p = 0.0056). Logistic regression revealed the occurrence of aGP21 IgA (odds ratio [OR] 1.38, 95% confidence interval [CI]: 1.03-1.86) and aGP24 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. Conclusions: Combined aGP21 and aGP24 IgA analysis is preferred to single aGP2 isoform analysis for sensitive PSC autoantibody testing. Positivity for aGP21 and aGP24 IgA is associated with cirrhosis in PSC and could be used for risk stratification. |
| Author | Mytilinaiou, Maria G. Sowa, Mandy Suchanski, Jaroslaw Roggenbuck, Dirk Kolenda, Rafał Laass, Martin W. Schramm, Christoph Franke, Andre Papp, Maria Conrad, Karsten Pratschke, Johann Hammermann, Jutta Tornai, Tamas Bogdanos, Dimitrios P. Baumgart, Daniel C. Schierack, Peter |
| AuthorAffiliation | 9 Institute of Immunology, Technical University Dresden , Dresden , Germany 1 Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg , Senftenberg , Germany 8 Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden , Dresden , Germany 6 Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King‘s College Hospital , London , United Kingdom 12 GA Generic Assays GmbH , Berlin , Germany 2 Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences , Wroclaw , Poland 7 Department of Rheumatology and Clinical Immunology, School of Health Sciences, University of Thessaly , Larissa , Greece 4 Department of Surgery, Charité Medical School, Humboldt-University of Berlin , Berlin , Germany 5 Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of D |
| AuthorAffiliation_xml | – name: 1 Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg , Senftenberg , Germany – name: 2 Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences , Wroclaw , Poland – name: 7 Department of Rheumatology and Clinical Immunology, School of Health Sciences, University of Thessaly , Larissa , Greece – name: 4 Department of Surgery, Charité Medical School, Humboldt-University of Berlin , Berlin , Germany – name: 5 Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen , Debrecen , Hungary – name: 10 I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf , Hamburg , Germany – name: 8 Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden , Dresden , Germany – name: 11 Institute of Clinical Molecular Biology, Christian-Albrechts-University , Kiel , Germany – name: 9 Institute of Immunology, Technical University Dresden , Dresden , Germany – name: 3 Inflammatory Bowel Disease Center, Department of Gastroenterology and Hepatology, Charité Medical School, Humboldt-University of Berlin , Berlin , Germany – name: 6 Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King‘s College Hospital , London , United Kingdom – name: 12 GA Generic Assays GmbH , Berlin , Germany |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30233574$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2018 Sowa, Kolenda, Baumgart, Pratschke, Papp, Tornai, Suchanski, Bogdanos, Mytilinaiou, Hammermann, Laass, Conrad, Schramm, Franke, Roggenbuck and Schierack. 2018 Sowa, Kolenda, Baumgart, Pratschke, Papp, Tornai, Suchanski, Bogdanos, Mytilinaiou, Hammermann, Laass, Conrad, Schramm, Franke, Roggenbuck and Schierack |
| Copyright_xml | – notice: Copyright © 2018 Sowa, Kolenda, Baumgart, Pratschke, Papp, Tornai, Suchanski, Bogdanos, Mytilinaiou, Hammermann, Laass, Conrad, Schramm, Franke, Roggenbuck and Schierack. 2018 Sowa, Kolenda, Baumgart, Pratschke, Papp, Tornai, Suchanski, Bogdanos, Mytilinaiou, Hammermann, Laass, Conrad, Schramm, Franke, Roggenbuck and Schierack |
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| Keywords | immunoglobulin A zymogen granule glycoprotein 2 cholangiocarcinoma cirrhosis primary sclerosing cholangitis |
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| Snippet | Zymogen granule glycoprotein 2 (GP2) was demonstrated as first autoimmune mucosal target in primary sclerosing cholangitis (PSC) associated with disease... Introduction: Zymogen granule glycoprotein 2 (GP2) was demonstrated as first autoimmune mucosal target in primary sclerosing cholangitis (PSC) associated with... Introduction: Zymogen granule glycoprotein 2 (GP2) was demonstrated as first autoimmune mucosal target in primary sclerosing cholangitis (PSC) associated with... |
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| SubjectTerms | cholangiocarcinoma cirrhosis immunoglobulin A Immunology primary sclerosing cholangitis zymogen granule glycoprotein 2 |
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| Title | Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype |
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