Skip to main content
Top
Published in: BMC Gastroenterology 1/2012

Open Access 01-12-2012 | Research article

Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease

Authors: Dimitrios P Bogdanos, Dirk Roggenbuck, Dirk Reinhold, Thomas Wex, Polychronis Pavlidis, Ulrike von Arnim, Peter Malfertheiner, Alastair Forbes, Karsten Conrad, Martin W Laass

Published in: BMC Gastroenterology | Issue 1/2012

Login to get access

Abstract

Background

Glycoprotein 2 (GP2) was discovered as the major autoantigen of Crohn’s disease (CD)-specific pancreatic autoantibodies (PAB). We investigated anti-GP2 IgA and IgG antibodies as novel serological parameters in CD and assessed their association with distinct disease phenotypes.

Methods

Anti-GP2 and anti-Saccharomyces cerevisiae (ASCA) IgA and IgG were detected by ELISA employing recombinant human GP2 and phosphopeptidomannan, respectively and PAB by indirect immunofluorescence (IIF) in 271 sera, 169 with CD and 102 with ulcerative colitis (UC). As healthy controls 160 adult blood donors and 65 children were included.

Results

Anti-GP2 IgG and/or IgA were more prevalent in CD (51/169, 30.2%) than in UC (9/102, 8.9%) patients and in controls (9/225, 4%) (p < 0.001 respectively). ASCA IgG and/or IgA were present in 60/169 (35.5%) in CD and in 7/102 (6.9%) in UC patients (p < 0.001). CD patients with ileocolonic location (L3) showed a significantly higher prevalence of anti-GP2 and ASCA IgA and/or IgG (40/113 and 48/113, respectively; p < 0.05 for both comparisons), whereas CD patients with colonic location (L2) revealed a significantly diminished prevalence for these autoantibody specificities (2/32 and 5/32, respectively, p < 0.05 for both). Anti-GP2 IgG were significantly more prevalent in CD patients with stricturing behaviour (B2) and perianal disease (7/11, p < 0.02) and less prevalent in those with penetrating behaviour (B3) and perianal disease (4/31, p < 0.05). The occurrence of anti-GP2 IgA and/or IgG was significantly more prevalent in CD patients with age at diagnosis of ≤16 years (16/31, p < 0.009). Prevalence of one or more anti-GP2 or ASCA IgA and/or IgG was significantly higher in L3, B2, and A1 and lower in L2 (68/113, 27/41, 23/31, 6/32; p < 0.04, respectively).

Conclusions

Anti-GP2 IgG and IgA, constituting novel CD specific autoantibodies, appear to be associated with distinct disease phenotypes identifying patients at a younger age, with ileocolonic location, and stricturing behaviour with perianal disease.
Appendix
Available only for authorised users
Literature
1.
go back to reference Walker DG, Williams HR, Kane SP, Mawdsley JE, Arnold J, McNeil I, Thomas HJ, Teare JP, Hart AL, Pitcher MC, Walters JR, Marshall SE, Orchard TR: Differences in inflammatory bowel disease phenotype between South Asians and Northern Europeans living in North West London, UK. Am J Gastroenterol. 2011, 106: 1281-1289. 10.1038/ajg.2011.85.CrossRefPubMed Walker DG, Williams HR, Kane SP, Mawdsley JE, Arnold J, McNeil I, Thomas HJ, Teare JP, Hart AL, Pitcher MC, Walters JR, Marshall SE, Orchard TR: Differences in inflammatory bowel disease phenotype between South Asians and Northern Europeans living in North West London, UK. Am J Gastroenterol. 2011, 106: 1281-1289. 10.1038/ajg.2011.85.CrossRefPubMed
2.
go back to reference Bogdanos DP, Rigopoulou EI, Smyk DS, Roggenbuck D, Reinhold D, Forbes A, Laass MW, Conrad K: Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn’s disease specific-pancreatic autoantibodies. Autoimmun Rev. 2011, 11: 143-148. 10.1016/j.autrev.2011.09.004.CrossRefPubMed Bogdanos DP, Rigopoulou EI, Smyk DS, Roggenbuck D, Reinhold D, Forbes A, Laass MW, Conrad K: Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn’s disease specific-pancreatic autoantibodies. Autoimmun Rev. 2011, 11: 143-148. 10.1016/j.autrev.2011.09.004.CrossRefPubMed
3.
go back to reference Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet. 2007, 369: 1627-1640. 10.1016/S0140-6736(07)60750-8.CrossRefPubMed Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet. 2007, 369: 1627-1640. 10.1016/S0140-6736(07)60750-8.CrossRefPubMed
4.
go back to reference Logan I, Bowlus CL: The geoepidemiology of autoimmune intestinal diseases. Autoimmun Rev. 2010, 9: A372-A378. 10.1016/j.autrev.2009.11.008.CrossRefPubMed Logan I, Bowlus CL: The geoepidemiology of autoimmune intestinal diseases. Autoimmun Rev. 2010, 9: A372-A378. 10.1016/j.autrev.2009.11.008.CrossRefPubMed
5.
go back to reference Wehkamp J, Koslowski M, Wang G, Stange EF: Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunol. 2008, S1: 67-74.CrossRef Wehkamp J, Koslowski M, Wang G, Stange EF: Barrier dysfunction due to distinct defensin deficiencies in small intestinal and colonic Crohn’s disease. Mucosal Immunol. 2008, S1: 67-74.CrossRef
6.
go back to reference Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Büttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Büning C, Feist E, Conrad K: Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut. 2009, 58: 1620-1628. 10.1136/gut.2008.162495.CrossRefPubMed Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Büttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Büning C, Feist E, Conrad K: Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut. 2009, 58: 1620-1628. 10.1136/gut.2008.162495.CrossRefPubMed
7.
go back to reference Seibold F, Weber P, Jenss H, Wiedmann KH: Antibodies to a trypsin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut. 1991, 32: 1192-1197. 10.1136/gut.32.10.1192.CrossRefPubMedPubMedCentral Seibold F, Weber P, Jenss H, Wiedmann KH: Antibodies to a trypsin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut. 1991, 32: 1192-1197. 10.1136/gut.32.10.1192.CrossRefPubMedPubMedCentral
8.
go back to reference Stöcker W, Otte M, Ulrich S, Normann D, Finkbeiner H, Stöcker K, Jantschek G, Scriba PC: Autoimmunity to pancreatic juice in Crohn’s disease. Results of an autoantibody screening in patients with chronic inflammatory bowel disease. Scand J Gastroenterol Suppl. 1987, 139: 41-52.CrossRefPubMed Stöcker W, Otte M, Ulrich S, Normann D, Finkbeiner H, Stöcker K, Jantschek G, Scriba PC: Autoimmunity to pancreatic juice in Crohn’s disease. Results of an autoantibody screening in patients with chronic inflammatory bowel disease. Scand J Gastroenterol Suppl. 1987, 139: 41-52.CrossRefPubMed
9.
go back to reference LeBel D, Beattie M: The major protein of pancreatic zymogen granule membranes (GP-2) is anchored via covalent bonds to phosphatidylinositol. Biochem Biophys Res Commun. 1988, 154: 818-823. 10.1016/0006-291X(88)90213-6.CrossRefPubMed LeBel D, Beattie M: The major protein of pancreatic zymogen granule membranes (GP-2) is anchored via covalent bonds to phosphatidylinositol. Biochem Biophys Res Commun. 1988, 154: 818-823. 10.1016/0006-291X(88)90213-6.CrossRefPubMed
10.
go back to reference Rindler MJ, Hoops TC: The pancreatic membrane protein GP-2 localizes specifically to secretory granules and is shed into the pancreatic juice as a protein aggregate. Eur J Cell Biol. 1990, 53: 154-163.PubMed Rindler MJ, Hoops TC: The pancreatic membrane protein GP-2 localizes specifically to secretory granules and is shed into the pancreatic juice as a protein aggregate. Eur J Cell Biol. 1990, 53: 154-163.PubMed
11.
go back to reference Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW, Itoh K, Kiyono H, Ohno H: Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009, 462: 226-230. 10.1038/nature08529.CrossRefPubMed Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Yabashi A, Waguri S, Nakato G, Kimura S, Murakami T, Iimura M, Hamura K, Fukuoka S, Lowe AW, Itoh K, Kiyono H, Ohno H: Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature. 2009, 462: 226-230. 10.1038/nature08529.CrossRefPubMed
12.
go back to reference Hölzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, Gärtner M, Steinberger P, Zlabinger GJ: The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell Immunol. 2011, 267: 88-93. 10.1016/j.cellimm.2010.12.001.CrossRefPubMedPubMedCentral Hölzl MA, Hofer J, Kovarik JJ, Roggenbuck D, Reinhold D, Goihl A, Gärtner M, Steinberger P, Zlabinger GJ: The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I). Cell Immunol. 2011, 267: 88-93. 10.1016/j.cellimm.2010.12.001.CrossRefPubMedPubMedCentral
13.
go back to reference Conrad K, Schmechta H, Klafki A, Lobeck G, Uhlig HH, Gerdi S, Henker J: Serological differentiation of inflammatory bowel diseases. Eur J Gastroenterol Hepatol. 2002, 14: 129-135. 10.1097/00042737-200202000-00006.CrossRefPubMed Conrad K, Schmechta H, Klafki A, Lobeck G, Uhlig HH, Gerdi S, Henker J: Serological differentiation of inflammatory bowel diseases. Eur J Gastroenterol Hepatol. 2002, 14: 129-135. 10.1097/00042737-200202000-00006.CrossRefPubMed
14.
15.
go back to reference Lakatos PL, Papp M, Rieder F: Serologic antiglycan antibodies in inflammatory bowel disease. Am J Gastroenterol. 2011, 106: 406-412. 10.1038/ajg.2010.505.CrossRefPubMed Lakatos PL, Papp M, Rieder F: Serologic antiglycan antibodies in inflammatory bowel disease. Am J Gastroenterol. 2011, 106: 406-412. 10.1038/ajg.2010.505.CrossRefPubMed
16.
go back to reference Ferrante M, Henckaerts L, Joossens M, Pierik M, Joossens S, Dotan N, Norman GL, Altstock RT, Van Steen K, Rutgeerts P, Van Assche G, Vermeire S: New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007, 56: 1394-1403. 10.1136/gut.2006.108043.CrossRefPubMedPubMedCentral Ferrante M, Henckaerts L, Joossens M, Pierik M, Joossens S, Dotan N, Norman GL, Altstock RT, Van Steen K, Rutgeerts P, Van Assche G, Vermeire S: New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut. 2007, 56: 1394-1403. 10.1136/gut.2006.108043.CrossRefPubMedPubMedCentral
17.
go back to reference Rieder F, Schleder S, Wolf A, Dirmeier A, Strauch U, Obermeier F, Lopez R, Spector L, Fire E, Yarden J, Rogler G, Dotan N, Klebl F: Serum anti-glycan antibodies predict complicated Crohn’s disease behavior: a cohort study. Inflamm Bowel Dis. 2010, 16: 1367-1375.CrossRefPubMed Rieder F, Schleder S, Wolf A, Dirmeier A, Strauch U, Obermeier F, Lopez R, Spector L, Fire E, Yarden J, Rogler G, Dotan N, Klebl F: Serum anti-glycan antibodies predict complicated Crohn’s disease behavior: a cohort study. Inflamm Bowel Dis. 2010, 16: 1367-1375.CrossRefPubMed
18.
go back to reference Roggenbuck D, Reinhold D, Wex T, Goihl A, von Arnim U, Malfertheiner P, Büttner T, Porstmann T, Porstmann S, Liedvogel B, Bogdanos DP, Laass MW, Conrad K: Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, are new markers in Crohn’s disease. Clin Chim Acta. 2011, 412: 718-724. 10.1016/j.cca.2010.12.029.CrossRefPubMed Roggenbuck D, Reinhold D, Wex T, Goihl A, von Arnim U, Malfertheiner P, Büttner T, Porstmann T, Porstmann S, Liedvogel B, Bogdanos DP, Laass MW, Conrad K: Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, are new markers in Crohn’s disease. Clin Chim Acta. 2011, 412: 718-724. 10.1016/j.cca.2010.12.029.CrossRefPubMed
19.
go back to reference Roggenbuck D, Reinhold D, Wex T, von Arnim U, Malfertheiner P, Sturm A, Werner L, Bogdanos DP, Laass MW, Conrad K: Authors’ response: antibodies to GP2, the major zymogen granule membrane glycoprotein, are specific for Crohn’s disease and may reflect treatment response. Gut. 2012, 61: 164-165. 10.1136/gut.2010.237214.CrossRef Roggenbuck D, Reinhold D, Wex T, von Arnim U, Malfertheiner P, Sturm A, Werner L, Bogdanos DP, Laass MW, Conrad K: Authors’ response: antibodies to GP2, the major zymogen granule membrane glycoprotein, are specific for Crohn’s disease and may reflect treatment response. Gut. 2012, 61: 164-165. 10.1136/gut.2010.237214.CrossRef
20.
go back to reference Pavlidis P, Forbes A, Bogdanos DP: Antibodies to glycoprotein 2 (GP2) in patients with inflammatory bowel diseases from UK. Clin Chim Acta. 2011, 412: 1163-1164. 10.1016/j.cca.2011.02.005.CrossRefPubMed Pavlidis P, Forbes A, Bogdanos DP: Antibodies to glycoprotein 2 (GP2) in patients with inflammatory bowel diseases from UK. Clin Chim Acta. 2011, 412: 1163-1164. 10.1016/j.cca.2011.02.005.CrossRefPubMed
21.
go back to reference Op De Beéck K, Vermeire S, Rutgeerts P, Bossuyt X: Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases. Gut. 2012, 61: 162-164.CrossRefPubMed Op De Beéck K, Vermeire S, Rutgeerts P, Bossuyt X: Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases. Gut. 2012, 61: 162-164.CrossRefPubMed
22.
go back to reference Lakatos PL, Altorjay I, Szamosi T, Palatka K, Vitalis Z, Tumpek J, Sipka S, Udvardy M, Dinya T, Lakatos L, Kovacs A, Molnar T, Tulassay Z, Miheller P, Barta Z, Stocker W, Papp J, Veres G, Papp M: Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a Hungarian IBD cohort. Inflamm Bowel Dis. 2009, 15: 365-374. 10.1002/ibd.20778.CrossRefPubMed Lakatos PL, Altorjay I, Szamosi T, Palatka K, Vitalis Z, Tumpek J, Sipka S, Udvardy M, Dinya T, Lakatos L, Kovacs A, Molnar T, Tulassay Z, Miheller P, Barta Z, Stocker W, Papp J, Veres G, Papp M: Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a Hungarian IBD cohort. Inflamm Bowel Dis. 2009, 15: 365-374. 10.1002/ibd.20778.CrossRefPubMed
23.
go back to reference Seibold F, Mörk H, Tanza S, Müller A, Holzhüter C, Weber P, Scheurlen M: Pancreatic autoantibodies in Crohn’s disease: a family study. Gut. 1997, 40: 481-484.CrossRefPubMedPubMedCentral Seibold F, Mörk H, Tanza S, Müller A, Holzhüter C, Weber P, Scheurlen M: Pancreatic autoantibodies in Crohn’s disease: a family study. Gut. 1997, 40: 481-484.CrossRefPubMedPubMedCentral
24.
go back to reference Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus EV, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF: Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005, 19 (Suppl A): 5-36.CrossRef Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus EV, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF: Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005, 19 (Suppl A): 5-36.CrossRef
25.
go back to reference IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition: Inflammatory bowel disease in children and adolescents: recommendations for diagnosis-the Porto criteria. J Pediatr Gastroenterol Nutr. 2005, 41: 1-7. 10.1097/01.MPG.0000163736.30261.82.CrossRef IBD Working Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition: Inflammatory bowel disease in children and adolescents: recommendations for diagnosis-the Porto criteria. J Pediatr Gastroenterol Nutr. 2005, 41: 1-7. 10.1097/01.MPG.0000163736.30261.82.CrossRef
26.
go back to reference Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, Barakauskiene A, Villanacci V, Von Herbay A, Warren BF, Gasche C, Tilg H, Schreiber SW, Schölmerich J, Reinisch W: European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. Gut. 2006, 55 (Suppl 1): i1-i15.CrossRefPubMedPubMedCentral Stange EF, Travis SP, Vermeire S, Beglinger C, Kupcinkas L, Geboes K, Barakauskiene A, Villanacci V, Von Herbay A, Warren BF, Gasche C, Tilg H, Schreiber SW, Schölmerich J, Reinisch W: European evidence based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. Gut. 2006, 55 (Suppl 1): i1-i15.CrossRefPubMedPubMedCentral
27.
go back to reference Wong SM, Lowe AW: Sequence of the cDNA encoding human GP-2, the major membrane protein in the secretory granule of the exocrine pancreas. Gene. 1996, 171: 311-312. 10.1016/0378-1119(96)00065-0.CrossRefPubMed Wong SM, Lowe AW: Sequence of the cDNA encoding human GP-2, the major membrane protein in the secretory granule of the exocrine pancreas. Gene. 1996, 171: 311-312. 10.1016/0378-1119(96)00065-0.CrossRefPubMed
28.
go back to reference Zöphel K, Wunderlich G, Kotzerke J, von Landenberg P, Roggenbuck D: M22 based (manual) ELISA for TSH-receptor antibody (TRAb) measurement is more sensitive than 2nd generation TRAb assays. Clin Chim Acta. 2009, 403: 266-10.1016/j.cca.2009.01.022.CrossRefPubMed Zöphel K, Wunderlich G, Kotzerke J, von Landenberg P, Roggenbuck D: M22 based (manual) ELISA for TSH-receptor antibody (TRAb) measurement is more sensitive than 2nd generation TRAb assays. Clin Chim Acta. 2009, 403: 266-10.1016/j.cca.2009.01.022.CrossRefPubMed
29.
go back to reference Egerer K, Roggenbuck D, Hiemann R, Weyer MG, Büttner T, Radau B, Krause R, Lehmann B, Feist E, Burmester GR: Automated evaluation of autoantibodies on human epithelial-2 cells as an approach to standardize cell-based immunofluorescence tests. Arthritis Res Ther. 2010, 12: R40-10.1186/ar2949.CrossRefPubMedPubMedCentral Egerer K, Roggenbuck D, Hiemann R, Weyer MG, Büttner T, Radau B, Krause R, Lehmann B, Feist E, Burmester GR: Automated evaluation of autoantibodies on human epithelial-2 cells as an approach to standardize cell-based immunofluorescence tests. Arthritis Res Ther. 2010, 12: R40-10.1186/ar2949.CrossRefPubMedPubMedCentral
Metadata
Title
Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease
Authors
Dimitrios P Bogdanos
Dirk Roggenbuck
Dirk Reinhold
Thomas Wex
Polychronis Pavlidis
Ulrike von Arnim
Peter Malfertheiner
Alastair Forbes
Karsten Conrad
Martin W Laass
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2012
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/1471-230X-12-102

Other articles of this Issue 1/2012

BMC Gastroenterology 1/2012 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.