☆ 4.8 Article

Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease

GUT (2009)

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GUT

卷 58, 期 12, 页码 1620-1628

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BMJ PUBLISHING GROUP

DOI: 10.1136/gut.2008.162495

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Gastroenterology & Hepatology

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Backround and aims: The aetiopathogenesis of Crohn's disease, an inflammatory bowel disease (IBD), is not yet fully understood. Autoimmune mechanisms are thought to play a role in the development of Crohn's disease, but the target antigens and the underlying pathways have not been sufficiently identified. Methods: Based on data from immunoblotting and matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry, the major antigenic target of pancreatic autoantibodies (PABs), which are specific for Crohn's disease, was identified. Specificity of autoantibody reactivity was confirmed by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) using purified rat and human recombinant GP2 synthesised in transiently transfected mammalian HEK 293 cells. Real-time polymerase chain reaction (rt-PCR) and IIF were used to detect mRNA and antigen localisation in human colon biopsies. Results: The major zymogen granule membrane glycoprotein 2 (GP2) was identified as the autoantigen of PABs in Crohn's disease. PAB-positive sera from patients with Crohn's disease (n = 42) displayed significantly higher IgG reactivity to rat GP2 in ELISA than either PAB-negative sera (n = 31), or sera from patients with ulcerative colitis (n = 49), or sera from blood donors (n = 69) (p < 0.0001, respectively). Twenty-eight (66%) and 18 (43%) of 42 PAB-positive sera demonstrated IgG and IgA reactivity to human recombinant GP2 in IIF, respectively. Patients with PAB-negative Crohn's disease (n = 31) were not reactive. GP2 mRNA transcription was significantly higher in colon biopsies from patients with Crohn's disease (n = 4) compared to patients with ulcerative colitis (n = 4) (p = 0.0286). Immunochemical staining confirmed GP2 expression in human colon biopsies from patients with Crohn's disease. Conclusion: Anti-GP2 autoantibodies constitute novel Crohn's disease-specific markers, the quantification of which could significantly improve the serological diagnosis of IBD. The expression of GP2 in human enterocytes suggests an important role for anti-GP2 response in the pathogenesis of Crohn's disease.

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Human glycoprotein-2 expressed in Brunner glands-A putative autoimmune target and link between Crohn's and coeliac disease

Dirk Roggenbuck, Alexander Goihl, Mandy Sowa, Steffi Lopens, Stefan Roediger, Peter Schierack, Karsten Conrad, Ulrich Sommer, Korinna Joehrens, Robert Gruetzmann, Dirk Reinhold, Martin W. Laass

Summary: This study examined the expression of GP2-isoform (GP21-4) in intestinal biopsies of pediatric patients with Crohn's disease (CD), coeliac disease (CeD), ulcerative colitis (UC), and healthy children (HC). The results showed that transcription of GP21-4 was elevated in the proximal small intestine in CeD and CD patients, and CeD patients had higher levels of duodenal GP22/4-mRNA compared to HC/UC patients. Duodenal synthesis of small GP2 isoforms was demonstrated in epithelial cells and Brunner glands, with a more frequent apical location in CD/CeD patients. All four GP2 isoforms interacted with gliadin and phosphopeptidomannan. Gliadin digestion improved binding to GP2 isoforms. The findings suggest an autoimmune link between CeD/CD and GP2.

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