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1
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Xia CS, Krawczyk M, Di C, Krupa Ł, Kruk B, Krawczyk P, Milkiewicz P, Bao H, He X, Liu D, Fan C, Nasser A, Lopens S, Weiss FU, Frost F, Schierack P, Roggenbuck D, Liu Y. Loss of mucosal tolerance to glycoprotein 2 isoform 1 is a potential novel diagnostic biomarker for cholangiocarcinoma. Dig Liver Dis 2025; 57:14-22. [PMID: 38853092 DOI: 10.1016/j.dld.2024.05.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 04/17/2024] [Accepted: 05/23/2024] [Indexed: 06/11/2024]
Abstract
BACKGROUND Anti-glycoprotein 2 (anti-GP2) IgA and antineutrophil-cytoplasmic antibodies to proteinase 3 (PR3-ANCA) have been reported as predictive markers of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC), but their prevalence in CCA patients without PSC remains unclear. METHODS This study involved Asian discovery (n = 118) and European validation (n = 38) cohorts of CCA patients without PSC, alongside 49 Asian and 82 European pancreatic ductal adenocarcinoma (PDAC) patients, 21 with benign pancreatic neoplasms (BPN) and 45 with hepatocellular carcinoma (HCC), and 157 healthy controls (HC) from Asia and Europe. We analyzed the prevalence of PR3-ANCA, IgA and IgG against GP21 and GP24, and the CA19-9 levels. RESULTS Anti-GP21 IgA was the most prevalent in both CCA cohorts (discovery: 55.1 %; validation: 42.1 %) and significantly higher than in other groups except PDAC (all p < 0.05). It demonstrated the best diagnostic performance in distinguishing CCA from disease controls and HC, outperforming tumor markers. No significant correlation was found between anti-GP21 IgA levels and CA19-9 levels. CONCLUSION Our findings show that anti-GP21 IgA revealing the loss of mucosal tolerance is a potential novel diagnostic biomarker for CCA.
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Affiliation(s)
- Chang-Sheng Xia
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Chun Di
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Łukasz Krupa
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Medical Department, University of Rzeszów, Poland
| | - Beata Kruk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Huizhang Bao
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Xiao He
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Damin Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Chunhong Fan
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | | | - Steffi Lopens
- Medipan GmbH, R/D Department, Dahlewitz, Germany; Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Frank Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Fabian Frost
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Dirk Roggenbuck
- Medipan GmbH, R/D Department, Dahlewitz, Germany; Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Yudong Liu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing 100730, PR China.
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2
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Frost F, Weiss S, Hertel J, Rühlemann M, Bang C, Franke A, Nauck M, Dörr M, Völzke H, Roggenbuck D, Schierack P, Völker U, Homuth G, Aghdassi AA, Sendler M, Lerch MM, Weiss FU. Fecal glycoprotein 2 is a marker of gut microbiota dysbiosis and systemic inflammation. Gut Pathog 2024; 16:60. [PMID: 39427219 PMCID: PMC11490104 DOI: 10.1186/s13099-024-00657-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Antimicrobial autoantigenic glycoprotein 2 (GP2) is an important component of the innate immune system which originates from the exocrine pancreas as well as from the small intestines. The relationship of GP2 with the intestinal microbiome as well as the systemic implications of increased fecal GP2 levels are, however, still unclear. Therefore, fecal samples from 2,812 individuals of the Study of Health in Pomerania (SHIP) were collected to determine GP2 levels (enzyme-linked immunosorbent assay) and gut microbiota profiles (16 S rRNA gene sequencing). These data were correlated and associated with highly standardised and comprehensive phenotypic data of the study participants. RESULTS Fecal GP2 levels were increased in individuals with higher body mass index and smokers, whereas lower levels were found in case of preserved exocrine pancreatic function, female sex or a healthier diet. Moreover, higher GP2 levels were associated with increased serum levels of high-sensitivity C-reactive protein, loss of gut microbial diversity and an increase of potentially detrimental bacteria (Streptococcus, Haemophilus, Clostridium XIVa, or Collinsella). At the same time, predicted microbial pathways for the biosynthesis of beneficial short-chain fatty acids or lactic acid were depleted in individuals with high fecal GP2. Of note, GP2 exhibited a stronger association to overall microbiome variation than calprotectin. CONCLUSION Fecal GP2 is a biomarker of gut microbiota dysbiosis and associated with increased systemic inflammation. The intestines may be more important as origin for GP2 than pancreatic acinar cells. Future studies need to investigate the potential clinical value in disease specific patient cohorts.
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Affiliation(s)
- Fabian Frost
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany
| | - Stefan Weiss
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Johannes Hertel
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Malte Rühlemann
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Corinna Bang
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Marcus Dörr
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany
| | - Frank U Weiss
- Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruch- Straße, 17475, Greifswald, Germany.
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3
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Lopens S, Schierack P, Krause J, Piaszczyński M, Król R, Staroń R, Krupa Ł, Gutkowski K, Kruk B, Grąt M, Krawczyk M, Patkowski W, Glaser F, Rödiger S, Grossmann K, Pająk J, Milkiewicz P, Lammert F, Zieniewicz K, Schramm C, Roggenbuck D, Krawczyk M. Antimicrobial glycoprotein 2 (GP2) in gallstones, bile fluid and peribiliary glands of patients with primary sclerosing cholangitis. Clin Chim Acta 2024; 562:119841. [PMID: 38964568 DOI: 10.1016/j.cca.2024.119841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 05/28/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
BACKGROUND Glycoprotein-2 (GP2) IgA is a predictor of disease severity in primary sclerosing cholangitis (PSC). We examined GP2's occurrence in the biliary tract, the site of inflammation. METHODS GP2 was analyzed using ELISA, immunoblotting, mass spectrometry, and immunohistochemistry. The samples included: 20 bile and 30 serum samples from PSC patients, 23 bile and 11 serum samples from patients with gallstone disease (GD), 15 bile samples from healthy individuals undergoing liver-donation surgery (HILD), 20 extracts of gallstones (GE) obtained during cholecystectomy, and 101 blood-donor sera. RESULTS Biliary GP2 concentrations were significantly higher in patients with PSC and GD than in HILD (p < 0.0001). Serum GP2 levels were similar in PSC and GD patients, and controls, but lower than in bile (p < 0.0001). GP2 was detected in all 20 GEs. Mass spectrometry identified GP2 in the bile of 2 randomly selected GD and 2 PSC patients, and in none of 2 HILD samples. GP2 was found in peribiliary glands in 8 out of 12 PSC patients, showing morphological changes in acinar cells, but not in GD-gallbladders. CONCLUSIONS GP2 is present in bile of PSC and GD patients. It is synthesized in the peribiliary glands of PSC patients, supporting a pathogenic role for biliary GP2 in PSC.
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Affiliation(s)
- Steffi Lopens
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Medipan GmbH, Dahlewitz, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Jenny Krause
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michał Piaszczyński
- Department of General, Vascular and Transplant Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Robert Król
- Department of General, Vascular and Transplant Surgery, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Robert Staroń
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Rzeszów, Poland; Medical Department, University of Rzeszów, Rzeszów, Poland
| | - Łukasz Krupa
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Rzeszów, Poland; Medical Department, University of Rzeszów, Rzeszów, Poland
| | - Krzysztof Gutkowski
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Rzeszów, Poland; Medical Department, University of Rzeszów, Rzeszów, Poland
| | - Beata Kruk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Fabian Glaser
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Rödiger
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | | | - Jacek Pająk
- Department of Pathomorphology and Molecular Diagnostics, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Health Sciences, Hannover Medical School (MHH), Hannover, Germany
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany; Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany.
| | - Marcin Krawczyk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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4
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Preuß B, Frank A, Terjung B, Spengler U, Berg C, Klein R. Autoantibodies to beta tubulin in autoimmune liver diseases-Relation to pANCA and clinical relevance. Clin Exp Immunol 2024; 216:146-158. [PMID: 37823420 PMCID: PMC11036111 DOI: 10.1093/cei/uxad114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/30/2023] [Accepted: 10/10/2023] [Indexed: 10/13/2023] Open
Abstract
There was evidence that perinuclear antineutrophil cytoplasmic antibodies (pANCA) in autoimmune liver diseases react with human beta-tubulin-5 (TBB5). Here, we reevaluate the specificity and clinical relevance of anti-TBB5 antibodies. Patients with untreated autoimmune hepatitis (AIH; n = 53), AIH under immunosuppressive therapy (AIH-IS; n = 125), primary sclerosing cholangitis (PSC; n = 40), primary biliary cholangitis (PBC; n = 250), nonautoimmune liver diseases (n = 158), inflammatory bowel diseases (IBD; n = 30), and healthy individuals (n = 62) were tested by enzyme-linked immunosorbent assay for IgG- and IgA-antibodies against recombinant human TBB5. pANCA were detected by immunofluorescence test. Sera were absorbed with TBB5 coupled to cyanogen bromide-activated sepharose. Prevalence and reactivity of IgG anti-TBB5 were significantly higher in patients with untreated AIH (68%; arbitrary units [AU] median: 369) than in PSC (28%; AU median: 84, P < 0.001), other liver diseases (14%; AU median: 185, P < 0.0001), IBD (3%; AU median: 111, P < 0.0001), and healthy controls (3%; AU median: 135; P < 0.0001). Anti-TBB5 did not correlate with pANCA, and immunoprecipitation with TBB5 did not abolish pANCA reactivity. In untreated AIH, anti-TBB5-reactivity was significantly higher than in AIH-IS. Transaminases decreased under IS preferentially in anti-TBB5-negative patients. There was no correlation between anti-TBB5-reactivity and histological stages. IgA-anti-TBB5 was mainly found in alcohol-associated liver disease (ALD; 39%). Our data do not support TBB5 as an autoantigenic target of pANCA. However, IgG-anti-TBB5 showed high specificity for (untreated) AIH. While they did not correlate with histological and laboratory parameters, their presence may indicate a poor response to IS.
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Affiliation(s)
- Beate Preuß
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University of Tuebingen, Tuebingen, Germany
| | - Amelie Frank
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University of Tuebingen, Tuebingen, Germany
| | - Birgit Terjung
- Department of Gastroenterology, GFO Kliniken Bonn, St. Josef Hospital, Bonn, Germany
| | - Ulrich Spengler
- Department of Gastroenterology and Hepatology, Nephrology, Infectious Diseases, Endocrinology and Diabetology, University of Bonn, Bonn, Germany
| | - Christoph Berg
- Department of Gastroenterology and Infectiology, University of Tuebingen, Tuebingen, Germany
| | - Reinhild Klein
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University of Tuebingen, Tuebingen, Germany
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5
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Dudek P, Talar-Wojnarowska R. Current Approach to Risk Factors and Biomarkers of Intestinal Fibrosis in Inflammatory Bowel Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:305. [PMID: 38399592 PMCID: PMC10889938 DOI: 10.3390/medicina60020305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024]
Abstract
Inflammatory bowel disease (IBD), especially Crohn's disease (CD), characterized by a chronic inflammatory process and progressive intestinal tissue damage, leads to the unrestrained proliferation of mesenchymal cells and the development of bowel strictures. Complications induced by fibrosis are related to high rates of morbidity and mortality and lead to a substantial number of hospitalizations and surgical procedures, generating high healthcare costs. The development of easily obtained, reliable fibrogenesis biomarkers is essential to provide an important complementary tool to existing diagnostic and prognostic methods in IBD management, guiding decisions on the intensification of pharmacotherapy, proceeding to surgical methods of treatment and monitoring the efficacy of anti-fibrotic therapy in the future. The most promising potential markers of fibrosis include cartilage oligomeric matrix protein (COMP), hepatocyte growth factor activator (HGFA), and fibronectin isoform- extra domain A (ED-A), as well as antibodies against granulocyte macrophage colony-stimulating factor (GM-CSF Ab), cathelicidin (LL-37), or circulatory miRNAs: miR-19a-3p and miR-19b-3p. This review summarizes the role of genetic predisposition, and risk factors and serological markers potentially contributing to the pathophysiology of fibrotic strictures in the course of IBD.
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6
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Panic N, Marino M, Hauser G, Jacobsen S, Curcio F, Meroi F, Cifù A, Castagnaviz E, Pistis C, Terrosu G, Bulajic M, Vadalà di Prampero SF, Tarabar D, Krznaric-Zrnic I, Kovacevic G, Ranković I, Fabris M. A Multiparametric Method Improves the Serological Characterization of Inflammatory Bowel Diseases: Preliminary Results from a Multicenter Eastern Europe Study. GASTROINTESTINAL DISORDERS 2024; 6:152-163. [DOI: 10.3390/gidisord6010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2025] Open
Abstract
The serological support for early diagnosis and differential diagnosis of inflammatory bowel diseases (IBDs) is actually very limited. In this study, we evaluated the performance of a promising multiparametric method including either well-established and newly developed biomarkers. We conducted a multicenter cross-sectional study at the Gastroenterology Units of Udine (Italy), Rijeka (Croatia) and Belgrade (Serbia). Sera was collected from IBD patients, and autoantibody profiles were determined using a mosaic cell and tissue-based indirect immunofluorescence (IIF) method simultaneously investigating anti-saccharomyces cerevisiae antibodies (ASCAs), anti-atypical perinuclear neutrophilic antibodies (P-ANCAs), anti-pancreatic antigens antibodies (PABs) and anti-goblet cells antibodies (GAB). The study finally enrolled 156 patients with IBD: 100 affected by Crohn’s disease (CD) and 56 by ulcerative colitis (UC). Twenty age-sex matched blood donors (BDs) were included as controls. PAB (anti-CUZD1 and/or anti-GP2 antibodies) were present in 24 CD patients versus none of the UC patients or BDs (24% sensitivity, 100% specificity). As regards CD patients, combined positivity of PAB and ASCA (sensitivity 84%, specificity 71.4%) performed better than ASCA alone. Colon involvement (87.5% vs. 60.5%; p = 0.014), deep mucosal lesions (58.3% vs. 25.0%; p = 0.002) and need for biologic therapies (79.2% vs. 46.1%; p = 0.005) were significantly more prevalent in PAB-positive than in PAB-negative CD patients. Multivariate analysis identified PAB positivity (OR = 3.67; 95%CI = 1.29–10.46) and anti-CUZD1 in particular (OR = 3.54; 95%CI = 1.08–11.63) as significant risk factors for deep mucosal lesion development in CD. A multiparametric diagnostic approach appears very useful to better characterize IBD patients. PABs, whether isolated or combined with other autoantibodies, may support differential diagnosis but above all facilitate the selection of CD patients at risk for more severe disease.
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Affiliation(s)
- Nikola Panic
- Center for Digestive Endoscopy, University Clinic “Dr Dragisa Misovic”, 11000 Belgrade, Serbia
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Marco Marino
- Gastroenterology Unit, University Hospital of Udine, 33100 Udine, Italy
| | - Goran Hauser
- Department of Gastroenterology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia
- Faculty of Health Studies, 51000 Rijeka, Croatia
| | - Silvia Jacobsen
- Euroimmun—Medizinische Labordiagnostika AG, 23560 Lübeck, Germany
| | - Francesco Curcio
- Institute of Clinical Pathology, University Hospital of Udine, 33100 Udine, Italy
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Francesco Meroi
- Gastroenterology Unit, University Hospital of Udine, 33100 Udine, Italy
| | - Adriana Cifù
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | | | - Cinzia Pistis
- Institute of Clinical Pathology, University Hospital of Udine, 33100 Udine, Italy
| | - Giovanni Terrosu
- General Surgery and Transplantation Unit, University Hospital of Udine, 33100 Udine, Italy
| | - Milutin Bulajic
- Gastroenterology Unit, University Hospital of Udine, 33100 Udine, Italy
- Digestive Endoscopy Department, Isola Tiberina Hospital—Gemelli Isola, 00186 Rome, Italy
| | - Salvatore Francesco Vadalà di Prampero
- Gastroenterology Unit, University Hospital of Udine, 33100 Udine, Italy
- Digestive Endoscopy Department, Isola Tiberina Hospital—Gemelli Isola, 00186 Rome, Italy
| | - Dino Tarabar
- Center for Digestive Endoscopy, University Clinic “Dr Dragisa Misovic”, 11000 Belgrade, Serbia
| | - Irena Krznaric-Zrnic
- Department of Gastroenterology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia
| | - Gordana Kovacevic
- Center for Digestive Endoscopy, University Clinic “Dr Dragisa Misovic”, 11000 Belgrade, Serbia
| | - Ivan Ranković
- Department of Gastroenterology, Royal Cornwall Hospitals NHS Trust, Truro TR1 3LJ, UK
| | - Martina Fabris
- Institute of Clinical Pathology, University Hospital of Udine, 33100 Udine, Italy
- Department of Medicine, University of Udine, 33100 Udine, Italy
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7
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Zhang Z, Tanaka I, Nakahashi-Ouchida R, Ernst PB, Kiyono H, Kurashima Y. Glycoprotein 2 as a gut gate keeper for mucosal equilibrium between inflammation and immunity. Semin Immunopathol 2024; 45:493-507. [PMID: 38170255 PMCID: PMC11136868 DOI: 10.1007/s00281-023-00999-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024]
Abstract
Glycoprotein 2 (GP2) is a widely distributed protein in the digestive tract, contributing to mucosal barrier maintenance, immune homeostasis, and antigen-specific immune response, while also being linked to inflammatory bowel disease (IBD) pathogenesis. This review sheds light on the extensive distribution of GP2 within the gastrointestinal tract and its intricate interplay with the immune system. Furthermore, the significance of GP2 autoantibodies in diagnosing and categorizing IBD is underscored, alongside the promising therapeutic avenues for modulating GP2 to regulate immunity and maintain mucosal balance.
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Affiliation(s)
- Zhongwei Zhang
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Chiba University Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba, Japan
| | - Izumi Tanaka
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Chiba University Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba, Japan
| | - Rika Nakahashi-Ouchida
- Chiba University Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba, Japan
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Division of Mucosal Vaccines, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan
| | - Peter B Ernst
- Department of Medicine, School of Medicine, Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD cMAV), San Diego, CA, USA
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, CA, USA
- Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, CA, USA
- Future Medicine Education and Research Organization, Chiba University, Chiba, Japan
| | - Hiroshi Kiyono
- Chiba University Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba, Japan
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan
- Department of Medicine, School of Medicine, Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD cMAV), San Diego, CA, USA
- Future Medicine Education and Research Organization, Chiba University, Chiba, Japan
- HanaVax Inc., Tokyo, Japan
- Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Chiba University, Chiba, Japan
| | - Yosuke Kurashima
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
- Chiba University Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba, Japan.
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan.
- Department of Medicine, School of Medicine, Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD cMAV), San Diego, CA, USA.
- Division of Clinical Vaccinology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Institute for Advanced Academic Research, Chiba University, Chiba, Japan.
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8
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Grama A, Mititelu A, Sîrbe C, Benţa G, Pop TL. Immune-mediated cholangiopathies in children: the need to better understand the pathophysiology for finding the future possible treatment targets. Front Immunol 2023; 14:1206025. [PMID: 37928553 PMCID: PMC10623351 DOI: 10.3389/fimmu.2023.1206025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023] Open
Abstract
Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.
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Affiliation(s)
- Alina Grama
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Gabriel Benţa
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
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9
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Iwanaga T, Kimura S. GP2-expressing cells: a new guardian with divergent functions in the intestine, eyes, and nose. Biomed Res 2023; 44:233-243. [PMID: 38008422 DOI: 10.2220/biomedres.44.233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2023]
Abstract
GP (glycoprotein)-2, originally identified as a predominant membranous component of pancreatic acinar cells, has attracted the interest of researchers in mucosal immunology for its role as a functional molecule specific for antigen-sampling cells in the intestinal Peyer's patches. GP2 is involved in the detection of pathological bacteria and is also histologically useful for the identification of the M cell lineage and their differentiation in lymphoid tissues. Subsequent immunohistochemistry for GP2 has revealed a broad distribution of M cells and related cells in the nasopharyngeal lymphoid tissues, conjunctiva, tear duct, and airway. Especially, GP2 cells in the paranasal sinuses and tear duct have been identified as novel types of epithelial cells. The systematic administration of RANKL can induce extra-M cells in conventional epithelia of body. The production and release of GP2 by conjunctival goblet cells and several mucous glands suggests leading roles for mucous cells in protection, including the entrapment of microorganisms for infections. The ocular surface and conjunctiva are connected to the lacrimal sac, nasolacrimal duct, and further nasal cavity, comprising another canal that passes through the body. The broad distribution of GP2-expressingcells may indicate its function as a new guardian in the intestine, eyes, and nose, all of which are exposed to external milieu.
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Affiliation(s)
- Toshihiko Iwanaga
- Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Shunsuke Kimura
- Division of Biochemis- try, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo 105-8512, Japan
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10
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Luda KM, Da Silva C, Ahmadi F, Mowat AM, Ohno H, Kotarsky K, Agace WW. Identification and characterization of murine glycoprotein 2-expressing intestinal dendritic cells. Scand J Immunol 2022; 96:e13219. [PMID: 37807915 PMCID: PMC9786990 DOI: 10.1111/sji.13219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/18/2022] [Accepted: 09/23/2022] [Indexed: 11/30/2022]
Abstract
The intestinal lamina propria (LP) contains distinct subsets of classical dendritic cells (cDC), each playing key non-redundant roles in intestinal immune homeostasis. Here, we show that glycoprotein 2 (GP2), a GPI-anchored protein and receptor for bacterial type-I fimbriae, is selectively expressed by CD103+CD11b+ cDC in the murine small intestine (SI). GP2 expression was induced on CD103+CD11b+ cDC within the SI-LP and was regulated by IRF4, TGFβR1- and retinoic acid signalling. Mice selectively lacking Gp2 on CD103+CD11b+ cDC (huLang-Cre.gp2fl/fl mice) had normal numbers and proportions of innate and adaptive immune cells in the SI-LP suggesting that GP2 expression by CD103+CD11b+ cDC is not required for intestinal immune homoeostasis.
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Affiliation(s)
- Katarzyna M Luda
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Clement Da Silva
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Fatemeh Ahmadi
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Allan Mcl Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hiroshi Ohno
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Knut Kotarsky
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - William W Agace
- Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden
- Mucosal Immunology Laboratory, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
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11
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Yu XT, Chen M, Guo J, Zhang J, Zeng T. Noninvasive detection and interpretation of gastrointestinal diseases by collaborative serum metabolite and magnetically controlled capsule endoscopy. Comput Struct Biotechnol J 2022; 20:5524-5534. [PMID: 36249561 PMCID: PMC9550535 DOI: 10.1016/j.csbj.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/15/2022] [Accepted: 10/02/2022] [Indexed: 11/16/2022] Open
Abstract
Gastrointestinal diseases are complex diseases that occur in the gastrointestinal tract. Common gastrointestinal diseases include chronic gastritis, peptic ulcers, inflammatory bowel disease, and gastrointestinal tumors. These diseases may manifest a long course, difficult treatment, and repeated attacks. Gastroscopy and mucosal biopsy are the gold standard methods for diagnosing gastric and duodenal diseases, but they are invasive procedures and carry risks due to the necessity of sedation and anesthesia. Recently, several new approaches have been developed, including serological examination and magnetically controlled capsule endoscopy (MGCE). However, serological markers lack lesion information, while MGCE images lack molecular information. This study proposes combining these two technologies in a collaborative noninvasive diagnostic scheme as an alternative to the standard procedures. We introduce an interpretable framework for the clinical diagnosis of gastrointestinal diseases. Based on collected blood samples and MGCE records of patients with gastrointestinal diseases and comparisons with normal individuals, we selected serum metabolite signatures by bioinformatic analysis, captured image embedding signatures by convolutional neural networks, and inferred the location-specific associations between these signatures. Our study successfully identified five key metabolite signatures with functional relevance to gastrointestinal disease. The combined signatures achieved discrimination AUC of 0.88. Meanwhile, the image embedding signatures showed different levels of validation and testing accuracy ranging from 0.7 to 0.9 according to different locations in the gastrointestinal tract as explained by their specific associations with metabolite signatures. Overall, our work provides a new collaborative noninvasive identification pipeline and candidate metabolite biomarkers for image auxiliary diagnosis. This method should be valuable for the noninvasive detection and interpretation of gastrointestinal and other complex diseases.
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Affiliation(s)
- Xiang-Tian Yu
- Clinical Research Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China,Corresponding authors at: Clinical Research Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Yishan Road 600, Shanghai, China (X.-T. Yu); Guangzhou Laboratory, Guangzhou, China (T. Zeng).
| | - Ming Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jingyi Guo
- Clinical Research Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Tao Zeng
- Guangzhou Laboratory, Guangzhou, China,Corresponding authors at: Clinical Research Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Yishan Road 600, Shanghai, China (X.-T. Yu); Guangzhou Laboratory, Guangzhou, China (T. Zeng).
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12
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Falloon K, Cohen BL, Ottichilo R, Grove D, Rieder F, Qazi T. Biomarkers for the Evaluation of Pouch Inflammation: A Systematic Review. CROHN'S & COLITIS 360 2022; 4:otac043. [PMID: 36778511 PMCID: PMC9802421 DOI: 10.1093/crocol/otac043] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Indexed: 11/25/2022] Open
Abstract
Background Ileal pouch inflammation is a common problem following ileal pouch-anal anastomosis (IPAA). Despite its prevalence, diagnosis remains multimodal and requires endoscopy. The use of biomarkers in the prediction of and/or association with pouchitis has not been well characterized. We performed a systematic review to summarize the available evidence. Method A search of Ovid, MEDLINE, Cochrane Library, EMBASE, and Web of Science was conducted. Inclusion criteria included studies evaluating biomarkers for the evaluation and prediction of inflammation in patients with IPAA utilizing pouchoscopy as the gold standard. Exclusion criteria included studies on the role of the microbiome or genetic markers. Results A total of 28 studies, 5 case-control studies, and 23 observational cohort studies were identified. Fecal biomarkers were assessed in 23 studies, of which fecal calprotectin was the most commonly studied with sensitivities ranging from 57% to 92% and specificities from 19% to 92%. Six studies examined serum biomarkers. None of the serum biomarkers demonstrated a high sensitivity or specificity in association with pouch inflammation. Six studies described the longitudinal assessment of biomarkers. Of these studies, only three reported a predictive role of biomarkers in diagnosing endoscopic inflammation. Conclusions Biomarkers have emerged as a potential option to improve the management of pouchitis given the relative ease of sampling compared to pouchoscopy. Unfortunately, the evaluated biomarkers have not consistently demonstrated accuracy in predicting inflammation. Moreover, these biomarkers have not been reliably shown to be sensitive or specific in association with endoscopic pouch inflammation to merit their widespread use in clinical practice.
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Affiliation(s)
- Katherine Falloon
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Benjamin L Cohen
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ronald Ottichilo
- Department of Inflammation and Immunity; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - David Grove
- Department of Inflammation and Immunity; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
- Department of Inflammation and Immunity; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Taha Qazi
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Uhlig R, Günther K, Bröker N, Gorbokon N, Lennartz M, Dwertmann Rico S, Reiswich V, Viehweger F, Büscheck F, Kluth M, Hube-Magg C, Hinsch A, Fraune C, Bernreuther C, Lebok P, Sauter G, Izbicki JR, Steurer S, Burandt E, Marx AH, Krech T, Simon R, Minner S, Clauditz TS, Jacobsen F. Diagnostic and prognostic role of pancreatic secretory granule membrane major glycoprotein 2 (GP2) immunohistochemistry: A TMA study on 27,681 tumors. Pathol Res Pract 2022; 238:154123. [PMID: 36137400 DOI: 10.1016/j.prp.2022.154123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/01/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
Abstract
Pancreatic secretory granule membrane major glycoprotein 2 (GP2) is a membrane component of zymogen granules which is abundantly secreted by pancreatic acinar cells. Because RNA based analyses suggest a strict limitation of GP2 expression to the pancreas in normal tissues, and a strong preference to pancreatic cancer among tumors, GP2 expression analysis might have diagnostic utility. To better understand the role of GP2 protein expression, GP2 was successfully analyzed in 27,965 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types by immunohistochemistry in a tissue microarray format (TMA). GP2 immunostaining was seen in 14 of 16 (87.5 %) acinar cell carcinomas, 6 of 507 (1.2 %) ductal adenocarcinomas, and 3 of 99 neuroendocrine neoplasms of the pancreas (3.0 %). GP2 was also found in 23 extra-pancreatic tumor entities including several types of neuroendocrine neoplasms (14.3-58.8 %), prostatic adenocarcinomas (8.2-18.8 %), various other adenocarcinomas (0.1-7.7 %), and several categories of benign and malignant salivary gland tumors (2.3-3.1 %). A strong GP2 positivity was only seen in 6 tumor categories including 50 % of 16 pancreatic acinus cell carcinomas, 11.8 % of 17 neuroendocrine tumors of the lung, 1.3 % of 80 primary Gleason 4 + 4 % and 0.6 % of 181 recurrent prostate cancers, as well as 0.8 % of 133 adenocarcinomas of the lung. In a cohort of 14,747 prostate cancers with follow up data, GP2 immunostaining was strongly linked to advanced pT stage, high Gleason grade, lymph node metastasis, and recurrence free survival (p < 0.0001 each). The prognostic impact of GP2 positivity was independent of established parameters in TMPRSS2:ERG fusion-negative cancers (p < 0.0001). In summary, our data show that GP2 is preferentially expressed in acinar cell carcinomas of the pancreas but the glycoprotein can - rarely - also be expressed in a variety of other tumor entities.
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Affiliation(s)
- Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karin Günther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nina Bröker
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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14
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Steiner CA, Berinstein JA, Louissaint J, Higgins PDR, Spence JR, Shannon C, Lu C, Stidham RW, Fletcher JG, Bruining DH, Feagan BG, Jairath V, Baker ME, Bettenworth D, Rieder F. Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review. Clin Gastroenterol Hepatol 2022; 20:817-846.e10. [PMID: 34089850 PMCID: PMC8636551 DOI: 10.1016/j.cgh.2021.05.054] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Jeffrey A Berinstein
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jeremy Louissaint
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Peter D R Higgins
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jason R Spence
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Carol Shannon
- Taubman Health Sciences Library, University of Michigan, Ann Arbor, Michigan
| | - Cathy Lu
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Ryan W Stidham
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | | | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian G Feagan
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Mark E Baker
- Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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15
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Adhesion of enteropathogenic, enterotoxigenic and commensal Escherichia coli to the Major Zymogen Granule Membrane Glycoprotein 2. Appl Environ Microbiol 2022; 88:e0227921. [PMID: 35020452 PMCID: PMC8904060 DOI: 10.1128/aem.02279-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Pathogenic bacteria, such as enteropathogenic Escherichia coli (EPEC) and enterotoxigenic E. coli (ETEC), cause diarrhea in mammals. In particular, E. coli colonizes and infects the gastrointestinal tract via type 1 fimbriae (T1F). Here, the major zymogen granule membrane glycoprotein 2 (GP2) acts as a host cell receptor. GP2 is also secreted by the pancreas and various mucous glands, interacting with luminal type 1 fimbriae-positive E. coli. It is unknown whether GP2 isoforms demonstrate specific E. coli pathotype binding. In this study, we investigated interactions of human, porcine, and bovine EPEC and ETEC, as well as commensal E. coli isolates with human, porcine, and bovine GP2. We first defined pathotype- and host-associated FimH variants. Second, we could prove that GP2 isoforms bound to FimH variants to various degrees. However, the GP2-FimH interactions did not seem to be influenced by the host specificity of E. coli. In contrast, soluble GP2 affected ETEC infection and phagocytosis rates of macrophages. Preincubation of the ETEC pathotype with GP2 reduced the infection of cell lines. Furthermore, preincubation of E. coli with GP2 improved the phagocytosis rate of macrophages. Our findings suggest that GP2 plays a role in the defense against E. coli infection and in the corresponding host immune response. IMPORTANCE Infection by pathogenic bacteria, such as certain Escherichia coli pathotypes, results in diarrhea in mammals. Pathogens, including zoonotic agents, can infect different hosts or show host specificity. There are Escherichia coli strains which are frequently transmitted between humans and animals, whereas other Escherichia coli strains tend to colonize only one host. This host specificity is still not fully understood. We show that glycoprotein 2 is a selective receptor for particular Escherichia coli strains or variants of the adhesin FimH but not a selector for a species-specific Escherichia coli group. We demonstrate that GP2 is involved in the regulation of colonization and infection and thus represents a molecule of interest for the prevention or treatment of disease.
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Lin Y, Nakatochi M, Sasahira N, Ueno M, Egawa N, Adachi Y, Kikuchi S. Glycoprotein 2 in health and disease: lifting the veil. Genes Environ 2021; 43:53. [PMID: 34861888 PMCID: PMC8641183 DOI: 10.1186/s41021-021-00229-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/16/2021] [Indexed: 11/10/2022] Open
Abstract
In 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).
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Affiliation(s)
- Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, 480-1195, Nagakute, Aichi, Japan.
| | - Masahiro Nakatochi
- Division of Public Health Informatics, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, 461-8673, Nagoya, Japan
| | - Naoki Sasahira
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 135-8550, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, 241-8515, Yokohama, Japan
| | - Naoto Egawa
- Department of Internal Medicine, Tokyo Metropolitan Matsuzawa Hospital, 156- 0057, Tokyo, Japan
| | - Yasushi Adachi
- Division of Gastroenterology, Department of Internal Medicine, Sapporo Shirakaba- dai Hospital, 062-0052, Sapporo, Japan
| | - Shogo Kikuchi
- Department of Public Health, Aichi Medical University School of Medicine, 480-1195, Nagakute, Aichi, Japan
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Antibodies Against Glycoprotein 2 Are Specific Biomarkers for Pediatric Crohn's Disease. Dig Dis Sci 2021; 66:2619-2626. [PMID: 32886311 DOI: 10.1007/s10620-020-06589-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/26/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND Serological markers can assist in accurate differentiation between Crohn's disease (CD) and ulcerative colitis (UC). One such marker is anti-glycoprotein 2 (anti-GP2) which was shown to be a specific marker for CD in adult patients. The aim of our study was to assess the utility of anti-GP2 and GP2 as biomarkers for pediatric CD, and determine whether they correlate with disease activity. METHODS Serum samples were tested by ELISA for anti-GP2 isoform 4 IgG and IgA, and also for GP2. Results were correlated with demographic and clinical data. RESULTS The cohort consisted of 53 pediatric patients with CD, 42 with UC, and 53 controls. Levels of anti-GP2 were significantly increased in pediatric patients with CD in comparison with patients with UC, and control subjects, with high positive predictive value for both IgG and IgA (97.9% and 82.6%, respectively). While specificity of anti-GP2 IgG and IgA was very high (98.7% and 90.0%, respectively), sensitivity was low (42.0% and 35.5% for IgG and IgA, respectively). In CD, anti-GP2 correlated with disease activity, and decreased in treatment-naïve patients following successful induction therapy. A higher IgA anti-GP2 was also demonstrated in patients with ileo-colonic involvement, and was associated with a younger age. Finally, positive GP2 level was identified in only 1/211 serum samples. CONCLUSIONS A positive anti-GP2 level is highly associated with CD, while a negative result does not exclude CD. Additional studies are required to determine whether these markers can be used in pediatric patients with CD for risk stratification.
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18
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Mizuochi T, Arai K, Kudo T, Nambu R, Tajiri H, Aomatsu T, Abe N, Kakiuchi T, Hashimoto K, Sogo T, Takahashi M, Etani Y, Takaki Y, Konishi KI, Ishihara J, Obara H, Kakuma T, Kurei S, Yamashita Y, Mitsuyama K. Diagnostic accuracy of serum proteinase 3 antineutrophil cytoplasmic antibodies in children with ulcerative colitis. J Gastroenterol Hepatol 2021; 36:1538-1544. [PMID: 33047817 DOI: 10.1111/jgh.15296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/15/2020] [Accepted: 10/07/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Serologic markers such as myeloperoxidase (MPO) antineutrophil cytoplasmic antibodies (ANCA) (MPO-ANCA) have been used to screen patients for ulcerative colitis (UC). However, MPO-ANCA shows limited accuracy in Asians. Proteinase 3 ANCA (PR3-ANCA) has performed better at UC diagnosis in Japanese adults than MPO-ANCA. The present study aimed to evaluate usefulness of PR3-ANCA for diagnosis of UC in Japanese pediatric practice. METHODS Patients under 17 years old undergoing assessment at 12 Japanese pediatric centers between November 2016 and February 2018 were prospectively enrolled and divided into groups with UC, Crohn's disease (CD), intestinal disease control (IC), and healthy control (HC). Serum PR3-ANCA and MPO-ANCA were analyzed using chemiluminescence enzyme immunoassay kits. RESULTS Sera from 367 patients (148 with UC at a median age of 12 years; 120 with CD, 13 years; 56 with IC, 10.5 years; and 43 with HC, 10 years) were examined. Median PR3-ANCA values in UC (1.6 U/mL) were greater than in CD (0.2; P < 0.001), IC (0.15; P < 0.001), and HC (0.1; P < 0.001). In receiver operating characteristic curve analyses, the area under the curve for PR3-ANCA was 0.79, significantly greater than for MPO-ANCA (0.58; P < 0.001). Using a cut-off value of 0.8 U/mL determined from the receiver operating characteristic analyses, PR3-ANCA showed significantly greater sensitivity (64.9%) than MPO-ANCA (cut-off, 0.2 U/mL; sensitivity, 19.6%; P < 0.001) and good specificity (83.6%). CONCLUSIONS In Japanese children and adolescents, PR3-ANCA performed better as a serologic marker for diagnosis of UC than MPO-ANCA. To our knowledge, this is the first report of such a comparison.
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Affiliation(s)
- Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Katsuhiro Arai
- Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Takahiro Kudo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Ryusuke Nambu
- Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan
| | - Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Tomoki Aomatsu
- Department of Pediatrics, Osaka Medical College, Osaka, Japan
| | - Naoki Abe
- Department of Infection and Immunology, Aichi Children's Health and Medical Center, Obu, Japan
| | - Toshihiko Kakiuchi
- Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan
| | - Kunio Hashimoto
- Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tsuyoshi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Michiko Takahashi
- Department of Pediatrics, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yuri Etani
- Department of Gastroenterology and Endocrinology, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Yugo Takaki
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Ken-Ichiro Konishi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Jun Ishihara
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Hitoshi Obara
- Biostatistics Center, Kurume University School of Medicine, Kurume, Japan
| | - Tatsuyuki Kakuma
- Biostatistics Center, Kurume University School of Medicine, Kurume, Japan
| | | | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Li QX, Guo YX, Hua RX, Shang HW, Li LS, Xu JD. New insight into function and dysfunction of gut microfold cells. Shijie Huaren Xiaohua Zazhi 2021; 29:197-203. [DOI: 10.11569/wcjd.v29.i4.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Microfold cells (M cells), derived from intestinal crypt Lgr5+ stem cells, are distributed in gut-associated lymphoid tissue (GALT), nasopharyngeal-associated lymphoid tissue (NALT), and bronchial-associated lymphoid tissue (BALT). The basement membrane of mature M cells protrudes upward, showing a "pocket-like" shape. M cell differentiation is mainly regulated by two pathways, one is the non-canonical NF-κB pathway, and the other is the canonical NF-κB pathway. The differentiation and maturation of M cells are closely related to RANKL and S100A4. M cells can not only transport antigens and trigger an immune response, but also are the gateway for various pathogens to invade the body. The occurrence and development of tuberculosis, prion disease, and Crohn's disease are closely related to M cells.
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Affiliation(s)
- Qiu-Xuan Li
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Yue-Xin Guo
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Rong-Xuan Hua
- Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Morphological Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Li-Sheng Li
- Functional Experiment Center, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
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20
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Mager R, Roda G, Shalaby MK, Vetrano S. Fibrotic Strictures in Crohn's Disease: Mechanisms and Predictive Factors. Curr Drug Targets 2021; 22:241-251. [PMID: 33081672 DOI: 10.2174/1389450121666201020160803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/13/2020] [Accepted: 08/27/2020] [Indexed: 11/22/2022]
Abstract
Fibrotic strictures are one of the most severe complications of Crohn's Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.
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Affiliation(s)
- Riccardo Mager
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
| | - Giulia Roda
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Mohammad Khaled Shalaby
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Milan, Italy
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21
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Derer S, Brethack AK, Pietsch C, Jendrek ST, Nitzsche T, Bokemeyer A, Hov JR, Schäffler H, Bettenworth D, Grassl GA, Sina C. Inflammatory Bowel Disease-associated GP2 Autoantibodies Inhibit Mucosal Immune Response to Adherent-invasive Bacteria. Inflamm Bowel Dis 2020; 26:1856-1868. [PMID: 32304568 DOI: 10.1093/ibd/izaa069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Indexed: 02/06/2023]
Abstract
Adherent-invasive Escherichia coli have been suggested to play a pivotal role within the pathophysiology of inflammatory bowel disease (IBD). Autoantibodies against distinct splicing variants of glycoprotein 2 (GP2), an intestinal receptor of the bacterial adhesin FimH, frequently occur in IBD patients. Hence, we aimed to functionally characterize GP2-directed autoantibodies as a putative part of IBD's pathophysiology. Ex vivo, GP2-splicing variant 4 (GP2#4) but not variant 2 was expressed on intestinal M or L cells with elevated expression patterns in IBD patients. The GP2#4 expression was induced in vitro by tumor necrosis factor (TNF)-α. The IBD-associated GP2 autoantibodies inhibited FimH binding to GP2#4 and were decreased in anti-TNFα-treated Crohn's disease patients with ileocolonic disease manifestation. In vivo, mice immunized against GP2 before infection with adherent-invasive bacteria displayed exacerbated intestinal inflammation. In summary, autoimmunity against intestinal expressed GP2#4 results in enhanced attachment of flagellated bacteria to the intestinal epithelium and thereby may drive IBD's pathophysiology.
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Affiliation(s)
- Stefanie Derer
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Ann-Kathrin Brethack
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Carlotta Pietsch
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany
| | - Sebastian T Jendrek
- Department of Rheumatology, University of Schleswig-Holstein, Lübeck, Germany
| | - Thomas Nitzsche
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany.,Institute for Experimental Immunology, Euroimmun Corp., Lübeck, Germany
| | - Arne Bokemeyer
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Johannes R Hov
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Norwegian PSC Research Center, Section of Gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Holger Schäffler
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Guntram A Grassl
- Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover Medical School, Hannover, Germany
| | - Christian Sina
- Institute of Nutritional Medicine, Molecular Gastroenterology, University Hospital Schleswig- Holstein, Campus Lübeck, Lübeck, Germany.,1st Department of Medicine, Section of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
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22
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Cohen JD, Bermudez JG, Good MC, Sundaram MV. A C. elegans Zona Pellucida domain protein functions via its ZPc domain. PLoS Genet 2020; 16:e1009188. [PMID: 33141826 PMCID: PMC7665627 DOI: 10.1371/journal.pgen.1009188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 11/13/2020] [Accepted: 10/12/2020] [Indexed: 01/24/2023] Open
Abstract
Zona Pellucida domain (ZP) proteins are critical components of the body's external-most protective layers, apical extracellular matrices (aECMs). Although their loss or dysfunction is associated with many diseases, it remains unclear how ZP proteins assemble in aECMs. Current models suggest that ZP proteins polymerize via their ZPn subdomains, while ZPc subdomains modulate ZPn behavior. Using the model organism C. elegans, we investigated the aECM assembly of one ZP protein, LET-653, which shapes several tubes. Contrary to prevailing models, we find that LET-653 localizes and functions via its ZPc domain. Furthermore, we show that ZPc domain function requires cleavage at the LET-653 C-terminus, likely in part to relieve inhibition of the ZPc by the ZPn domain, but also to promote some other aspect of ZPc domain function. In vitro, the ZPc, but not ZPn, domain bound crystalline aggregates. These data offer a new model for ZP function whereby the ZPc domain is primarily responsible for matrix incorporation and tissue shaping.
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Affiliation(s)
- Jennifer D. Cohen
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Jessica G. Bermudez
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Matthew C. Good
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Meera V. Sundaram
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
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23
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Cohen JD, Sundaram MV. C. elegans Apical Extracellular Matrices Shape Epithelia. J Dev Biol 2020; 8:E23. [PMID: 33036165 PMCID: PMC7712855 DOI: 10.3390/jdb8040023] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023] Open
Abstract
Apical extracellular matrices (aECMs) coat exposed surfaces of epithelia to shape developing tissues and protect them from environmental insults. Despite their widespread importance for human health, aECMs are poorly understood compared to basal and stromal ECMs. The nematode Caenorhabditis elegans contains a variety of distinct aECMs, some of which share many of the same types of components (lipids, lipoproteins, collagens, zona pellucida domain proteins, chondroitin glycosaminoglycans and proteoglycans) with mammalian aECMs. These aECMs include the eggshell, a glycocalyx-like pre-cuticle, both collagenous and chitin-based cuticles, and other understudied aECMs of internal epithelia. C. elegans allows rapid genetic manipulations and live imaging of fluorescently-tagged aECM components, and is therefore providing new insights into aECM structure, trafficking, assembly, and functions in tissue shaping.
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Affiliation(s)
| | - Meera V. Sundaram
- Department of Genetics, University of Pennsylvania Perelman School of Medicine 415 Curie Blvd, Philadelphia, PA 19104-6145, USA;
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24
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Liaskos C, Gkoutzourelas A, Spyrou V, Koutsoumpas A, Athanasiou LV, Amiridis GS, Billinis C, Bogdanos DP. Pancreatic anti-GP2 and anti-Saccharomyces cerevisiae antibodies in ruminants with paratuberculosis: A better understanding of the immunopathogenesis of Crohn's disease. Clin Res Hepatol Gastroenterol 2020; 44:778-785. [PMID: 32035824 DOI: 10.1016/j.clinre.2019.12.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/12/2019] [Accepted: 12/27/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Ruminants (cattle and sheep) with Mycobacterium avium (MAP)-induced paratuberculosis (ptb), the ruminant model of Crohn's disease (CD), exhibit pancreatic specific autoantibodies (PAB) against GP2 but not against CUZD1. Since anti-Saccharomyces cerevisiae antibodies (ASCAs) is a CD marker, we tested MAP-infected ptb ruminants for ASCA, and compared them with ruminants lacking evidence of anti-MAP serology or with ruminants, which were positive for anti-GP2 antibodies. MATERIAL AND METHODS A total of 98 samples from ruminants (48 cattle and 50 sheep) were studied. IgG anti-MAP antibodies, and CD-related ASCA and anti-GP2 antibodies were tested by modified ELISAs. RESULTS Nine cattle (18.75%) and 20 sheep (40%) were suffered from ptb. ASCA antibodies were present in 21/48 (43.7%) cattle and 10/50 (20%) sheep while anti-GP2 antibodies were present in 14/48 (29.2%) cattle, and 8/50 (16%) sheep. ASCA antibodies were more prevalent in anti-MAP antibody positive (14/29, 48.3%) than in anti-MAP negative ruminants (17/69, 24.6%, P=0.022) and also in anti-GP2 antibody positive (13/23, 56.5%) than in anti-GP2 negative ruminants (18/75, 24%, P=0.003). No association between ASCA and anti-MAP antibody concentrations were found (r=0.159, P=0.117). A significant association between ASCA and anti-GP2 antibody concentration were observed (r=0.211 and P=0.037). CONCLUSION ASCA are present in a significant proportion of ruminants with ptb and correlate with anti-GP2 antibody positivity, a finding further supporting the notion that Crohn's disease and ptb share common immunological mechanisms of antigen-driven loss of self-tolerance.
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Affiliation(s)
- Christos Liaskos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece.
| | - Athanasios Gkoutzourelas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece
| | - Vasiliki Spyrou
- Department of Animal Production, University of Thessaly, 41110 Larissa, Greece
| | - Andreas Koutsoumpas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece
| | - Labrini V Athanasiou
- Department of Medicine, Faculty of Veterinary Medicine, University of Thessaly, Karditsa, Greece
| | - Georgios S Amiridis
- Department of Reproduction and Obstetrics, Faculty of Veterinary Medicine, University of Thessaly, Karditsa, Greece
| | - Charalambos Billinis
- Department of Microbiology and Parasitology, Faculty of Veterinary Medicine, University of Thessaly, Karditsa, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41110 Larissa, Greece
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Antibodies to Crohn's disease peptide 353 as a diagnostic marker for pediatric Crohn's disease: a prospective multicenter study in Japan. J Gastroenterol 2020; 55:515-522. [PMID: 31980893 DOI: 10.1007/s00535-019-01661-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 12/29/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Various serologic markers such as anti-glycoprotein 2 antibodies and anti-Saccharomyces cerevisiae antibodies have been reported to be diagnostically useful in Crohn's disease. Mitsuyama et al. reported that antibodies to Crohn's disease peptide 353, a newly proposed serologic marker, were more useful in Japanese adults than anti-Saccharomyces. We addressed the same issue in Japanese children and adolescents. METHODS Prospectively enrolled subjects under 17 years old assessed and treated at 12 pediatric centers in Japan included groups with Crohn's disease, ulcerative colitis, other intestinal diseases, or good health. The 3 serum markers were analyzed by enzyme-linked immunosorbent assays. RESULTS Enrolled subjects, numbering 367, included 120 with Crohn's disease, 148 with ulcerative colitis, 56 with other intestinal diseases, and 43 healthy subjects. In Crohn's disease, anti-Crohn's disease peptide 353, anti-glycoprotein 2, and anti-Saccharomyces concentrations (median, 2.25, 3.0, and 8.9 U/mL) were significantly greater than in ulcerative colitis (1.1, 1.9, and 3.4; all P < 0.001), other intestinal diseases (1.1, 1.85, and 2.95; all P < 0.001), and healthy controls (1.1, 1.7, and 2.8; all P < 0.001), respectively. At 95% specificity, sensitivity of anti-Crohn's disease peptide (45.0%) was significantly higher than for anti-glycoprotein 2 (30.8%; P < 0.05) or anti-Saccharomyces (26.7%; P < 0.01). CONCLUSIONS Anti-Crohn's disease peptide 353 proved more useful for diagnosis of Crohn's disease in Japanese children than the other 2 markers. To our knowledge, this is the first pediatric report to that effect.
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Lopens S, Krawczyk M, Papp M, Milkiewicz P, Schierack P, Liu Y, Wunsch E, Conrad K, Roggenbuck D. The search for the Holy Grail: autoantigenic targets in primary sclerosing cholangitis associated with disease phenotype and neoplasia. AUTO- IMMUNITY HIGHLIGHTS 2020; 11:6. [PMID: 32178720 PMCID: PMC7077156 DOI: 10.1186/s13317-020-00129-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022]
Abstract
Unlike in other autoimmune liver diseases such as autoimmune hepatitis and primary biliary cholangitis, the role and nature of autoantigenic targets in primary sclerosing cholangitis (PSC), a progressive, chronic, immune-mediated, life threatening, genetically predisposed, cholestatic liver illness, is poorly elucidated. Although anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with the occurrence of PSC, their corresponding targets have not yet been identified entirely. Genome-wide association studies revealed a significant number of immune-related and even disease-modifying susceptibility loci for PSC. However, these loci did not allow discerning a clear autoimmune pattern nor do the therapy options and the male gender preponderance in PSC support a pathogenic role of autoimmune responses. Nevertheless, PSC is characterized by the co-occurrence of inflammatory bowel diseases (IBD) demonstrating autoimmune responses. The identification of novel autoantigenic targets in IBD such as the major zymogen granule membrane glycoprotein 2 (GP2) or the appearance of proteinase 3 (PR3) autoantibodies (autoAbs) have refocused the interest on a putative association of loss of tolerance with the IBD phenotype and consequently with the PSC phenotype. Not surprisingly, the report of an association between GP2 IgA autoAbs and disease severity in patients with PSC gave a new impetus to autoAb research for autoimmune liver diseases. It might usher in a new era of serological research in this field. The mucosal loss of tolerance against the microbiota-sensing GP2 modulating innate and adaptive intestinal immunity and its putative role in the pathogenesis of PSC will be elaborated in this review. Furthermore, other potential PSC-related autoantigenic targets such as the neutrophil PR3 will be discussed. GP2 IgA may represent a group of new pathogenic antibodies, which share characteristics of both type 2 and 3 of antibody-mediated hypersensitive reactions according to Coombs and Gell.
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Affiliation(s)
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Hospital, Saarland University, Homburg/Saar, Germany
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Yudong Liu
- Department of Laboratory Medicine, Peking University People's Hospital, Beijing, China
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Karsten Conrad
- Institute of Immunology, Technical University Dresden, Dresden, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany.
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, the Brandenburg Medical School Theodor Fontane and the University of Potsdam, Universitätsplatz 1, 01968, Senftenberg, Germany.
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27
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Gkiouras K, Grammatikopoulou MG, Theodoridis X, Pagkalidou E, Chatzikyriakou E, Apostolidou AG, Rigopoulou EI, Sakkas LI, Bogdanos DP. Diagnostic and clinical significance of antigen-specific pancreatic antibodies in inflammatory bowel diseases: A meta-analysis. World J Gastroenterol 2020; 26:246-265. [PMID: 31988587 PMCID: PMC6962435 DOI: 10.3748/wjg.v26.i2.246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/19/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-invasive criteria are needed for Crohn's disease (CD) diagnosis, with several biomarkers being tested. Results of individual diagnostic test accuracy studies assessing the diagnostic value of pancreatic autoantibodies-to-glycoprotein-2 (anti-GP2) tests for the diagnosis of CD appear promising. AIM To systematically review and meta-analyze evidence on the diagnostic accuracy of anti-GP2 tests in patients with suspected/confirmed CD. METHODS An electronic search was conducted on PubMed, Cochrane-CENTRAL and grey literature (CRD42019125947). The structured research question in PICPTR format was "Population" including patients with symptoms akin to CD, the "Index test" being anti-GP2 testing, the "Comparator" involved standard CD diagnosis, the "Purpose of test" being diagnostic, "Target disorder" was CD, and the "Reference standard" included standard clinical, radiological, endoscopical, and histological CD diagnostic criteria. Quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool and hierarchical models were employed to synthesize the data. RESULTS Out of 722 studies retrieved, 15 were meta-analyzed. Thirteen studies had industry-related conflicts-of-interest, and most included healthy donors as controls (spectrum bias). For the combination of IgA and/or IgG anti-GP2 test, the summary sensitivity was 20% (95% confidence interval: 10%-29%) at a median specificity of 97%. If the test was applied in 10000 suspected patients, 9669 would be true negatives and in 26, the diagnosis would be missed. In this hypothetical cohort, the anti-GP2 would fail to produce a diagnosis for 81.3% of the positive cases. Low summary points of sensitivity and high specificity were estimated for the IgG or IgA anti-GP2 test. Analogous results were observed when the analyses were restricted using specific cut-offs, or when ulcerative colitis patients were used as comparators. CONCLUSION Anti-GP2 tests demonstrate low sensitivity and high specificity. These results indicate that caution is required before relying on its diagnostic value. Additionally, the need for improving the methodology of diagnostic test accuracy studies is evident.
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Affiliation(s)
- Konstantinos Gkiouras
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Maria G Grammatikopoulou
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Sindos Campus, Thessaloniki GR57400, Greece
| | - Xenophon Theodoridis
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Eirini Pagkalidou
- Laboratory of Hygiene, Social and Preventive Medicine and Medical Statistics, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Evangelia Chatzikyriakou
- Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
- Laboratory of Clinical Neurophysiology, AHEPA University Hospital, Faculty of Medicine, Aristotle University of Thessaloniki, University Campus, Thessaloniki GR54124, Greece
| | - Anna G Apostolidou
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Sindos Campus, Thessaloniki GR57400, Greece
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Biopolis, Larissa GR41110, Greece
| | - Lazaros I Sakkas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
| | - Dimitrios Petrou Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa GR41110, Greece
- Division of Transplantation, Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London Medical School, London GR41110, United Kingdom
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Kanaya T, Williams IR, Ohno H. Intestinal M cells: Tireless samplers of enteric microbiota. Traffic 2019; 21:34-44. [DOI: 10.1111/tra.12707] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/12/2019] [Accepted: 10/14/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Takashi Kanaya
- Department of PathologyEmory University School of Medicine Atlanta Georgia
| | - Ifor R. Williams
- Laboratory for Intestinal EcosystemRIKEN Center for Integrative Medical Sciences Yokohama Japan
| | - Hiroshi Ohno
- Department of PathologyEmory University School of Medicine Atlanta Georgia
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Kobayashi N, Takahashi D, Takano S, Kimura S, Hase K. The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases. Front Immunol 2019; 10:2345. [PMID: 31649668 PMCID: PMC6794464 DOI: 10.3389/fimmu.2019.02345] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023] Open
Abstract
Microfold (M) cells are located in the epithelium covering mucosa-associated lymphoid tissues, such as the Peyer's patches (PPs) of the small intestine. M cells actively transport luminal antigens to the underlying lymphoid follicles to initiate an immune response. The molecular machinery of M-cell differentiation and function has been vigorously investigated over the last decade. Studies have shed light on the role of M cells in the mucosal immune system and have revealed that antigen uptake by M cells contributes to not only mucosal but also systemic immune responses. However, M-cell studies usually focus on infectious diseases; the contribution of M cells to autoimmune diseases has remained largely unexplored. Accumulating evidence suggests that dysbiosis of the intestinal microbiota is implicated in multiple systemic diseases, including autoimmune diseases. This implies that the uptake of microorganisms by M cells in PPs may play a role in the pathogenesis of autoimmune diseases. We provide an outline of the current understanding of M-cell biology and subsequently discuss the potential contribution of M cells and PPs to the induction of systemic autoimmunity, beyond the mucosal immune response.
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Affiliation(s)
- Nobuhide Kobayashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,Department of Bacteriology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daisuke Takahashi
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Takano
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy and Graduate School of Pharmaceutical Science, Keio University, Tokyo, Japan.,International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo (IMSUT), Tokyo, Japan
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30
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Deutschmann C, Sowa M, Murugaiyan J, Roesler U, Röber N, Conrad K, Laass MW, Bogdanos D, Sipeki N, Papp M, Rödiger S, Roggenbuck D, Schierack P. Identification of Chitinase-3-Like Protein 1 as a Novel Neutrophil Antigenic Target in Crohn's Disease. J Crohns Colitis 2019; 13:894-904. [PMID: 30753386 PMCID: PMC6657965 DOI: 10.1093/ecco-jcc/jjz012] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS There is an increasing incidence of inflammatory bowel disease [IBD]. Autoimmune responses are involved in the pathophysiology of IBD, but their underlying pathways and target antigens have not yet been fully elucidated. METHODS Autoantigenic targets in IBD were identified after separation of whole cell proteins isolated from neutrophils using two-dimensional electrophoresis and matrix assisted laser desorption ionization - time of flight mass spectrometry-based protein identification of the spots that displayed Western blotting signals with anti-neutrophil cytoplasmic antibody-positive sera. The prevalence of IgG, IgA and secretory IgA [sIgA] to chitinase 3-like protein 1 [CHI3L1] was analysed by enzyme-linked immunosorbent assays using recombinant CHI3L1 in 110 patients with Crohn's disease [CD], 95 with ulcerative colitis [UC], 126 with coeliac disease [CeD] and 86 healthy controls [HCs]. RESULTS The 18-glycosylhydrolase family member CHI3L1 was identified as a neutrophil autoantigenic target. CD patients displayed significantly higher levels of IgG to CHI3L1 than patients with UC and CeD (p < 0.0001, respectively). IgA and sIgA to CHI3L1 was significantly higher in CD than in UC, CeD and HCs [p < 0.0001, respectively]. IgA and sIgA to CHI3L1 demonstrated the highest prevalence in CD [25.5%, 28/110; and 41.8%%, 46/110] compared to HCs [2.3%, 2/86; and 4.7%%, 4/86; p = 0.0015 and p < 0.0001] and are associated with a more complicated progression of CD. CONCLUSION CHI3L1 is a novel neutrophil autoantigenic target in CD. IgA and sIgA to CHI3L1 may serve as novel markers for CD and may facilitate the serological diagnosis of IBD.
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Affiliation(s)
- Claudia Deutschmann
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany
| | - Mandy Sowa
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Medipan/GA Generic Assays GmbH, Ludwig-Erhard-Ring, Dahlewitz, Berlin, Germany
| | - Jayaseelan Murugaiyan
- Institute for Animal Hygiene and Environmental Health, Freie Universität Berlin, Centre for Infectious Medicine, Robert-von-Ostertag-Str., Berlin, Germany,Department of Biotechnology, SRM University-AP, Amaravati, India
| | - Uwe Roesler
- Institute for Animal Hygiene and Environmental Health, Freie Universität Berlin, Centre for Infectious Medicine, Robert-von-Ostertag-Str., Berlin, Germany
| | - Nadja Röber
- Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Karsten Conrad
- Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Martin W Laass
- Children’s Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Dimitrios Bogdanos
- Department of Rheumatology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Nora Sipeki
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Nagyerdei krt., Debrecen, Hungary
| | - Maria Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Nagyerdei krt., Debrecen, Hungary
| | - Stefan Rödiger
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Medipan/GA Generic Assays GmbH, Ludwig-Erhard-Ring, Dahlewitz, Berlin, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Corresponding author: Prof. Dr Peter Schierack, Faculty Environment and Natural Sciences, Brandenburg University of Technology, Universitätsplatz 1, 01968 Senftenberg, Germany. Tel: +49 (0) 3573 85 932; Fax: +49 (0) 3573 85 909;
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Deutschmann C, Roggenbuck D, Schierack P. The loss of tolerance to CHI3L1 – A putative role in inflammatory bowel disease? Clin Immunol 2019; 199:12-17. [DOI: 10.1016/j.clim.2018.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Duman AE, Hülagü S, Çelebi A, Korkmaz U, Musul MM, Şentürk Ö, Şirin G, Yılmaz H, Koç DÖ, Dindar G, Öztürkler M, Bozkurt N, Kır HM. Differential diagnosis of Crohn's disease using antibodies to glycoprotein 2 and Saccharomyces cerevisiae. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2019; 30:21-27. [PMID: 30465525 PMCID: PMC6389294 DOI: 10.5152/tjg.2018.18135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/19/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS Glycoprotein 2 (GP2), the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies, is reportedly correlated with several characteristics of CD. We investigated this serological marker in Turkish patients with CD and assessed its utility in combination with anti-Saccharomyces cerevisiae antibodies (ASCAs) for differential diagnosis of CD. MATERIALS AND METHODS A total of 60 patients with CD, 62 patients with ulcerative colitis (UC), and 46 healthy controls with a definite diagnosis who were similar in age and sex were enrolled in the study conducted from November 2011 to October 2012. ASCA and anti-GP2 levels were measured using commercially available kits. RESULTS Anti-GP2 IgA and IgG levels were higher in patients with CD (25%) than in those with UC (5%) and controls (2%). The seroprevalence of anti-GP2 IgA was markedly higher than that of IgG in patients with CD in contrast to previous studies. The specificity and positive predictive value of seropositivity for both ASCA and anti-GP2 were 100%. ASCA IgA seropositivity was correlated with a complicated disease course and a history of surgery. There was no correlation between anti-GP2 seropositivity and disease location, disease behavior, or a history of surgery. CONCLUSION The combination of ASCA and anti-GP2 may enable differentiation of CD from UC. As ASCA seropositivity is associated with a more complicated disease course, patients seropositive for ASCA at the initial diagnosis should undergo more intense therapy.
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Affiliation(s)
- Ali Erkan Duman
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Sadettin Hülagü
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Altay Çelebi
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Uğur Korkmaz
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Mahmut Mert Musul
- Department of Biochemistry, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Ömer Şentürk
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Göktuğ Şirin
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Hasan Yılmaz
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Deniz Öğütmen Koç
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Gökhan Dindar
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Murat Öztürkler
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Neslihan Bozkurt
- Department of Gastroenterology, Kocaeli University School of Medicine, Kocaeli, Turkey
| | - Hale Maral Kır
- Department of Biochemistry, Kocaeli University School of Medicine, Kocaeli, Turkey
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Cummings D, Cruise M, Lopez R, Roggenbuck D, Jairath V, Wang Y, Shen B, Rieder F. Loss of tolerance to glycoprotein 2 isoforms 1 and 4 is associated with Crohn's disease of the pouch. Aliment Pharmacol Ther 2018; 48:1251-1259. [PMID: 30411391 DOI: 10.1111/apt.15034] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 08/30/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Zymogen granule glycoprotein 2 (GP2) is a major autoantigen of Crohn's disease-specific pancreatic autoantibodies. AIM To test a link between loss of tolerance to isoforms of GP2 and pouch disorders in a cross-sectional study in ulcerative colitis patients with ileal pouch-anal anastomosis (IPAA). METHODS Serum samples of 117 consecutive ulcerative colitis patients after IPAA were tested for presence of Anti-GP2 isoforms 1 (GP21 ) & 4 (GP24 ) IgG and IgA as well as anti-Saccaromyces cervisiae (ASCA) IgG and IgA antibodies in a blinded fashion via enzyme-linked immunosorbent assay. Pouch disorders were diagnosed based on clinical, endoscopic, histological and radiographic criteria. Crohn's disease of the pouch was defined as involvement of the small bowel mucosa proximal to the ileal pouch with Crohn's disease, development of perianal complications or pouch fistula more than 3 months after ileostomy closure. RESULTS Positivity and level of Anti-GP21 IgG (AUC 0.77; P < 0.001 & P = 0.02, respectively), Anti-GP24 IgG (AUC 0.74; P < 0.001 & P = 0.025, respectively) and Anti-GP24 IgA (AUC 0.77; P < 0.001 to P = 0.018, respectively) were specifically associated with Crohn's disease of the pouch. Anti-GP2 was not associated with endoscopic or histological pouch disease activity index. Neither positivity nor levels of ASCA IgG (AUC 0.63; P = 0.12 & P = 0.35, respectively) or ASCA IgA (AUC 0.67; P = 0.38 & P = 0.53) were associated with pouch phenotypes. CONCLUSIONS The novel anti-GP21 and GP24 antibodies are associated with Crohn's disease of the pouch in ulcerative colitis patients after IPAA. Serological anti-GP2 antibodies could aid in diagnosis of Crohn's disease of the pouch.
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Affiliation(s)
- Donelle Cummings
- Department of Internal Medicine, Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio.,Division of Gastroenterology and Hepatology, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York
| | - Michael Cruise
- Department of Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Rocio Lopez
- Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Dirk Roggenbuck
- Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Vipul Jairath
- Department of Medicine, University of Western Ontario, London, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.,University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bo Shen
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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Schlör A, Holzlöhner P, Listek M, Grieß C, Butze M, Micheel B, Hentschel C, Sowa M, Roggenbuck D, Schierack P, Füner J, Schliebs E, Goihl A, Reinhold D, Hanack K. Generation and validation of murine monoclonal and camelid recombinant single domain antibodies specific for human pancreatic glycoprotein 2. N Biotechnol 2018; 45:60-68. [DOI: 10.1016/j.nbt.2018.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 02/28/2018] [Accepted: 03/29/2018] [Indexed: 12/24/2022]
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35
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Sowa M, Kolenda R, Baumgart DC, Pratschke J, Papp M, Tornai T, Suchanski J, Bogdanos DP, Mytilinaiou MG, Hammermann J, Laass MW, Conrad K, Schramm C, Franke A, Roggenbuck D, Schierack P. Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype. Front Immunol 2018; 9:1959. [PMID: 30233574 PMCID: PMC6127632 DOI: 10.3389/fimmu.2018.01959] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Mandy Sowa
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg, Senftenberg, Germany
| | - Rafał Kolenda
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg, Senftenberg, Germany
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Wroclaw, Poland
| | - Daniel C. Baumgart
- Inflammatory Bowel Disease Center, Department of Gastroenterology and Hepatology, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| | - Maria Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamas Tornai
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Jaroslaw Suchanski
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Wroclaw, Poland
| | - Dimitrios P. Bogdanos
- Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King‘s College Hospital, London, United Kingdom
- Department of Rheumatology and Clinical Immunology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Maria G. Mytilinaiou
- Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at King‘s College Hospital, London, United Kingdom
- Department of Rheumatology and Clinical Immunology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Jutta Hammermann
- Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Martin W. Laass
- Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Karsten Conrad
- Institute of Immunology, Technical University Dresden, Dresden, Germany
| | - Christoph Schramm
- I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg, Senftenberg, Germany
- GA Generic Assays GmbH, Berlin, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus–Senftenberg, Senftenberg, Germany
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Kolenda R, Burdukiewicz M, Schiebel J, Rödiger S, Sauer L, Szabo I, Orłowska A, Weinreich J, Nitschke J, Böhm A, Gerber U, Roggenbuck D, Schierack P. Adhesion of Salmonella to Pancreatic Secretory Granule Membrane Major Glycoprotein GP2 of Human and Porcine Origin Depends on FimH Sequence Variation. Front Microbiol 2018; 9:1905. [PMID: 30186250 PMCID: PMC6113376 DOI: 10.3389/fmicb.2018.01905] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/30/2018] [Indexed: 12/25/2022] Open
Abstract
Bacterial host tropism is a primary determinant of the range of host organisms they can infect. Salmonella serotypes are differentiated into host-restricted and host-adapted specialists, and host-unrestricted generalists. In order to elucidate the underlying molecular mechanisms of host specificity in Salmonella infection, we investigated the role of the intestinal host cell receptor zymogen granule membrane glycoprotein 2 (GP2), which is recognized by FimH adhesin of type 1 fimbriae found in Enterobacteriaceae. We compared four human and two porcine GP2 isoforms. Isoforms were expressed in Sf9 cells as well as in one human (HEp-2) and one porcine (IPEC-J2) cell line. FimH genes of 128 Salmonella isolates were sequenced and the 10 identified FimH variants were compared regarding adhesion (static adhesion assay) and infection (cell line assay) using an isogenic model. We expressed and characterized two functional porcine GP2 isoforms differing in their amino acid sequence to human isoforms by approximately 25%. By comparing all isoforms in the static adhesion assay, FimH variants were assigned to high, low or no-binding phenotypes. This FimH variant-dependent binding was neither specific for one GP2 isoform nor for GP2 in general. However, cell line infection assays revealed fundamental differences: using HEp-2 cells, infection was also FimH variant-specific but mainly independent of human GP2. In contrast, this FimH variant dependency was not obvious using IPEC-J2 cells. Here, we propose an alternative GP2 adhesion/infection mechanism whereby porcine GP2 is not a receptor that determined host-specificity of Salmonella. Salmonella specialists as well as generalists demonstrated similar binding to GP2. Future studies should focus on spatial distribution of GP2 isoforms in the human and porcine intestine, especially comparing health and disease.
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Affiliation(s)
- Rafał Kolenda
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- Department of Biochemistry and Molecular Biology, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Michał Burdukiewicz
- Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
| | - Juliane Schiebel
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Stefan Rödiger
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Lysann Sauer
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Istvan Szabo
- National Salmonella Reference Laboratory, Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Aleksandra Orłowska
- Department of Biochemistry and Molecular Biology, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Jörg Weinreich
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Jörg Nitschke
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Alexander Böhm
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Ulrike Gerber
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- GA Generic Assays GmbH, Berlin, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
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Antibodies against glycoprotein 2 display diagnostic advantages over ASCA in distinguishing CD from intestinal tuberculosis and intestinal Behçet's disease. Clin Transl Gastroenterol 2018; 9:e133. [PMID: 29446764 PMCID: PMC5830545 DOI: 10.1038/ctg.2018.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/16/2017] [Indexed: 02/07/2023] Open
Abstract
Objectives: There is an increasing need to identify reliable biomarkers for distinguishing Crohn’s disease (CD) from other gastrointestinal disorders sharing similar clinical and pathological features. This study aimed at evaluating the diagnostic potential of antibodies to zymogen granule glycoprotein GP2 (aGP2) in a large, well-defined Chinese cohort with a special focus on their role in discriminating CD from intestinal Behçet's disease (BD) and intestinal tubercolosis (ITB). Methods: A total of 577 subjects were prospectively enrolled, including 171 patients with CD, 208 patients with ulcerative colitis (UC), 71 with BD, 57 with ITB and 70 healthy controls (HC). aGP2 and anti-Saccharomyces cerevisiae antibodies (ASCA) were determined by ELISA. Perinuclear antineutrophil cytoplasmic antibodies were tested by indirect immunofluorescent assay. Results: aGP2 IgG and IgA levels were significantly elevated in patients with CD compared with those in patients with UC, intestinal BD, and ITB and HC. Conversely, ASCA IgG levels were not different between CD and intestinal BD patients, whereas ASCA IgA levels did not discriminate CD from intestinal BD and ITB patients. aGP2 IgA and IgG displayed a better assay performance (larger areas under the curve) over ASCA IgA and IgG in differentiating CD from disease controls (P<0.05). ASCA IgA did not discriminate CD from disease controls. aGP2 IgA and/or IgG was significantly associated with penetrating disease (B3) and ileal CD (L1) (P<0.05), whereas ASCA IgA and/or IgG was not. Conclusions: In comparison with ASCA, aGP2 distinguishes CD from intestinal BD or ITB as disease controls more efficiently, aiding in the differential diagnosis of IBD.
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Tornai T, Tornai D, Sipeki N, Tornai I, Alsulaimani R, Fechner K, Roggenbuck D, Norman GL, Veres G, Par G, Par A, Szalay F, Lakatos PL, Antal-Szalmas P, Papp M. Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis. Sci Rep 2018; 8:399. [PMID: 29321484 PMCID: PMC5762861 DOI: 10.1038/s41598-017-18622-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 12/14/2017] [Indexed: 02/08/2023] Open
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.
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Affiliation(s)
- Tamas Tornai
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - David Tornai
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Nora Sipeki
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Istvan Tornai
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Rayan Alsulaimani
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kai Fechner
- Institute of Experimental Immunology, Euroimmun AG, Lübeck, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- GA Generic Assays GmbH, Dahlewitz, Germany
| | | | - Gabor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Gabriella Par
- 1st Department of Medicine, University of Pecs, Pecs, Hungary
| | - Alajos Par
- 1st Department of Medicine, University of Pecs, Pecs, Hungary
| | - Ferenc Szalay
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | | | - Peter Antal-Szalmas
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Maria Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Autoantibodies Against Glycoprotein 2 Isoforms in Pediatric Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23:1624-1636. [PMID: 28691939 DOI: 10.1097/mib.0000000000001159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Anti-Glycoprotein 2 (GP2) antibodies are associated with a more complicated course of Crohn's disease (CD) in adults. Four different GP2 isoforms with different length and antibody-binding sites have been identified so far but not been explored in serological studies. We aimed to investigate the diagnostic utility of autoantibodies against all 4 isoforms of GP2 in an exclusively pediatric population for the first time. METHODS We included 278 children and adolescents with inflammatory bowel disease: 164 with CD, 114 with ulcerative colitis, 83 disease controls (acute gastrointestinal infection, nonspecific gastrointestinal functional disorders), and 219 healthy controls. Sera were tested for anti-GP2 antibodies using 4 different isoforms of GP2 for anti-Saccharomyces cerevisiae antibodies, antineutrophil cytoplasmic antibodies, and pancreatic antibodies. RESULTS Anti-GP2 antibodies were significantly more prevalent in patients with CD than in ulcerative colitis and controls. We found a sensitivity of 38% (with a specificity of 95%) for anti-GP2 IgG against isoform 4 in CD. Anti-GP2 IgA against isoform 1 and anti-GP2 IgG against isoform 4 possessed the best diagnostic values for identification of CD. For the differentiation of CD from ulcerative colitis anti-GP2 IgG against isoforms 3 and 4 proved to be most accurate markers. Anti-GP2 antibodies were associated with a more complicated disease behavior and bowel surgery in CD. In a subgroup of patients with CD, anti-GP2 IgG against isoform 4 proved to be a relatively stable marker over time independent of disease activity. CONCLUSIONS Anti-GP2 antibodies against different isoforms are specific markers for CD and for different phenotypes in pediatric inflammatory bowel disease.
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Wang H, Demirkan G, Bian X, Wallstrom G, Barker K, Karthikeyan K, Tang Y, Pasha SF, Leighton JA, Qiu J, LaBaer J. Identification of Antibody Against SNRPB, Small Nuclear Ribonucleoprotein-Associated Proteins B and B', as an Autoantibody Marker in Crohn's Disease using an Immunoproteomics Approach. J Crohns Colitis 2017; 11:848-856. [PMID: 28204086 DOI: 10.1093/ecco-jcc/jjx019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Current non-invasive biomarkers for Crohn's disease are limited in their utility. Progress in identifying individual autoantigens and autoantibodies in Crohn's disease has been challenging due to limitations of available immunoassays. AIMS Our aim was to identify autoantibodies associated with Crohn's disease that may be useful in diagnosis and management using an innovative protein array technology, namely nucleic acid programmable protein arrays [NAPPA]. METHODS Serum samples of 96 patients with established Crohn's disease and 96 healthy controls were included and evenly split into discovery and validation sets randomly. Autoantibodies of both IgG and IgA classes were profiled against ~1900 human proteins in the discovery set on NAPPA. Autoantibodies discovered to be Crohn's disease-specific were further validated in the independent validation set by enzyme-linked immunosorbent assay. RESULTS Overall, reactivity of IgG autoantibodies was stronger than that of IgA autoantibodies; however, IgA autoantibodies showed greater differential reactivity between cases and controls. Four IgA autoantibodies against SNRPB, PRPH, PTTG1 and SNAI1 were newly identified with sensitivities above 15% at 95% specificity, among which anti-SNRPB-IgA had the highest sensitivity of 24.0%. Autoantibodies associated with specific disease subtypes were also found. CONCLUSIONS As one of the first studies to use immunoproteomics for the identification of autoantibodies in Crohn's disease, our results support the utility of NAPPA in implementing future expanded studies with better coverage of the human proteome and microbial proteomes relevant to Crohn's disease and identifying antibody markers that may have clinical impact in diagnosis and management.
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Affiliation(s)
- Haoyu Wang
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Gokhan Demirkan
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Xiaofang Bian
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Garrick Wallstrom
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Kristi Barker
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Kailash Karthikeyan
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Yanyang Tang
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Shabana F Pasha
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Jonathan A Leighton
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Ji Qiu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Joshua LaBaer
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA
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Deng C, Li W, Li J, Zhang S, Li Y. Diagnostic value of the antiglycoprotein-2 antibody for Crohn's disease: a PRISMA-compliant systematic review and meta-analysis. BMJ Open 2017; 7:e014843. [PMID: 28601823 PMCID: PMC5734552 DOI: 10.1136/bmjopen-2016-014843] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES To perform a meta-analysis to evaluate the diagnostic performance of the antiglycoprotein-2 (GP2) antibody for Crohn's disease (CD). METHODS Three databases (EMBASE, ISI Web of Knowledge and PubMed) were systematically searched. There were 17 eligible studies included in the meta-analysis. A total of 2439 patients with CD and 3184 controls were involved in these studies. STATA V.11.2 and Meta-DiSc V.1.4 were used to perform the meta-analysis. RESULTS The area under the summary receiver operating characteristic curve was 0.68-0.72. The pooled diagnostic sensitivity of the anti-GP2 antibody ranged from 14% to 24%, and the specificity was 96%-98%. CONCLUSIONS The anti-GP2 antibody is a specific biomarker for CD, and further exploration of its prevalence among different clinical phenotypes of CD will provide a better understanding of its diagnostic performance.
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Affiliation(s)
- Chuiwen Deng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Wenli Li
- Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Jing Li
- Clinical Laboratory, Peking University International Hospital, Beijing, China
| | - Shulan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Yongzhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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Roggenbuck D, Goihl A, Hanack K, Holzlöhner P, Hentschel C, Veiczi M, Schierack P, Reinhold D, Schulz HU. Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2. Clin Chem Lab Med 2017; 55:854-864. [PMID: 27837595 DOI: 10.1515/cclm-2016-0797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 10/10/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Glycoprotein 2 (GP2), the pancreatic major zymogen granule membrane glycoprotein, was reported to be elevated in acute pancreatitis in animal models. METHODS Enzyme-linked immunosorbent assays (ELISAs) were developed to evaluate human glycoprotein 2 isoform alpha (GP2a) and total GP2 (GP2t) as specific markers for acute pancreatitis in sera of 153 patients with acute pancreatitis, 26 with chronic pancreatitis, 125 with pancreatic neoplasms, 324 with non-pancreatic neoplasms, 109 patients with liver/biliary disease, 67 with gastrointestinal disease, and 101 healthy subjects. GP2a and GP2t levels were correlated with procalcitonin and C-reactive protein in 152 and 146 follow-up samples of acute pancreatitis patients, respectively. RESULTS The GP2a ELISA revealed a significantly higher assay accuracy in contrast to the GP2t assay (sensitivity ≤3 disease days: 91.7%, specificity: 96.7%, positive likelihood ratio [LR+]: 24.6, LR-: 0.09). GP2a and GP2t levels as well as prevalences were significantly elevated in early acute pancreatitis (≤3 disease days) compared to all control cohorts (p<0.05, respectively). GP2a and GP2t levels were significantly higher in patients with severe acute pancreatitis at admission compared with mild cases (p<0.05, respectively). Odds ratio for GP2a regarding mild vs. severe acute pancreatitis with lethal outcome was 7.8 on admission (p=0.0222). GP2a and GP2t levels were significantly correlated with procalcitonin [Spearman's rank coefficient of correlation (ρ)=0.21, 0.26; p=0.0110, 0.0012; respectively] and C-reactive protein (ρ=0.37, 0.40; p<0.0001; respectively). CONCLUSIONS Serum GP2a is a specific marker of acute pancreatitis and analysis of GP2a can aid in the differential diagnosis of acute upper abdominal pain and prognosis of severe acute pancreatitis.
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Affiliation(s)
- Dirk Roggenbuck
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg
| | - Alexander Goihl
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg
| | - Katja Hanack
- Chair of Immunotechnology, Department of Biochemistry and Biology, University of Potsdam, Potsdam
| | - Pamela Holzlöhner
- Chair of Immunotechnology, Department of Biochemistry and Biology, University of Potsdam, Potsdam
| | | | | | - Peter Schierack
- Institute of Biotechnology, Faculty of Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg
| | - Dirk Reinhold
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg
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Schultz BM, Paduro CA, Salazar GA, Salazar-Echegarai FJ, Sebastián VP, Riedel CA, Kalergis AM, Alvarez-Lobos M, Bueno SM. A Potential Role of Salmonella Infection in the Onset of Inflammatory Bowel Diseases. Front Immunol 2017; 8:191. [PMID: 28293241 PMCID: PMC5329042 DOI: 10.3389/fimmu.2017.00191] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 02/09/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) includes a set of pathologies that result from a deregulated immune response that may affect any portion of the gastrointestinal tract. The most prevalent and defined forms of IBD are Crohn’s disease and ulcerative colitis. Although the etiology of IBD is not well defined, it has been suggested that environmental and genetic factors contribute to disease development and that the interaction between these two factors can trigger the pathology. Diet, medication use, vitamin D status, smoking, and bacterial infections have been proposed to influence or contribute to the onset or development of the disease in susceptible individuals. The infection with pathogenic bacteria is a key factor that can influence the development and severity of this disease. Here, we present a comprehensive review of studies performed in human and mice susceptible to IBD, which supports the notion that infection with bacterial pathogens, such as Salmonella, could promote the onset of IBD due to permanent changes in the intestinal microbiota, disruption of the epithelial barrier and alterations of the intestinal immune response after infection.
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Affiliation(s)
- Bárbara M Schultz
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Carolina A Paduro
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Geraldyne A Salazar
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Francisco J Salazar-Echegarai
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Valentina P Sebastián
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Claudia A Riedel
- Facultad de Ciencias Biológicas y Facultad de Medicina, Departamento de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Universidad Andrés Bello , Santiago , Chile
| | - Alexis M Kalergis
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile; Facultad de Medicina, Departamento de Endocrinología, Pontificia Universidad Católica de Chile, Santiago, Chile; INSERM, UMR 1064, Nantes, France
| | - Manuel Alvarez-Lobos
- Facultad de Medicina, Departamento de Gastroenterología, Pontificia Universidad Católica de Chile , Santiago , Chile
| | - Susan M Bueno
- Facultad de Ciencias Biológicas, Departamento de Genética Molecular y Microbiología, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile; INSERM, UMR 1064, Nantes, France
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Farkona S, Soosaipillai A, Filippou P, Liaskos C, Bogdanos DP, Diamandis EP, Blasutig IM. Novel immunoassays for detection of CUZD1 autoantibodies in serum of patients with inflammatory bowel diseases. ACTA ACUST UNITED AC 2017; 55:1574-1581. [DOI: 10.1515/cclm-2016-1120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 02/21/2017] [Indexed: 02/07/2023]
Abstract
AbstractBackground:Pancreatic autoantibodies (PABs) are detected in patients with inflammatory bowel disease (IBD). Their prevalence is higher in Crohn’s disease (CrD) than in ulcerative colitis (UC). Glycoprotein 2 (GP2) and, more recently, CUB and zona pellucida-like domain-containing protein 1 (CUZD1) have been identified as target autoantigens of PAB. The clinical utility of CUZD1 autoantibodies has only recently been assessed by indirect immunofluorescence (IIF) assays. In this study, we developed and validated novel immunoassays for the detection of CUZD1 autoantibodies.Methods:Recombinant CUZD1 protein was utilized as a solid-phase antigen for the development of two immunoassays for the detection of IgG and IgA CUZD1 autoantibodies. Serum samples from 100 patients with CrD, 100 patients with UC, 129 patients assessed for various autoimmune diseases (vADs) and 50 control individuals were analyzed.Results:Two immunofluorometric assays for the detection of IgG and IgA CUZD1-specific antibodies were developed. CUZD1 autoantibodies were detected in 12.5% (25/200) IBD patients, including 16% of patients with CrD and in 9% of patients with UC (CrD vs. UC, p<0.05), compared with 3.1% (4/129) patients suspected of having vADs (CrD vs. ADs, p<0.05; UC vs. ADs, p=0.08). CUZD1 autoantibody positivity was not found to be related to disease location, age of disease onset or disease phenotype.Conclusions:This is the first study to describe novel IgA and IgG CUZD1 autoantibody enzyme-linked immunosorbent assay. These immunoassays agree well with standard IIF techniques and can be utilized in multicenter studies to investigate the diagnostic and clinical utility of CUZD1 autoantibodies.
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Kimura S, Nio-Kobayashi J, Kishimoto A, Iwanaga T. The broad distribution of GP2 in mucous glands and secretory products. Biomed Res 2017; 37:351-358. [PMID: 28003582 DOI: 10.2220/biomedres.37.351] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
GP2, a GPI-anchored glycoprotein that is a useful marker for M cells of Peyer's patches, is functionally related to the uptake of pathogenic bacteria in the gut lumen. Our immunostaining throughout the whole body of mice detected a broader localization than previously found of GP2 in various mucous glands and secretory cells. In the oral cavity, the palatine gland and lingual gland intensely expressed GP2 with immunolabeling along the basolateral membrane of acini and in luminal secretions of ducts. Secretory portions of the duodenal gland as well as the pancreas were immunoreactive for GP2 in the digestive tract. Luminal contents in the small intestine contained aggregations of GP2-immunoreactive substances which mixed with bacteria. The bulbourethral gland of Cowper displayed the GP2 immunoreactivity among the male reproductive organs. The vaginal epithelium contained many GP2-immunoreactive goblet-like cells, the occurrence of which dramatically changed according to the estrous cycle. These findings show that GP2 is a popular secretory product released from mucous glands and secretory cells and may support defense mechanisms against pathogenic bacteria in the tubular organs open to the external milieu.
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Distinct Anti-IFI16 and Anti-GP2 Antibodies in Inflammatory Bowel Disease and Their Variation with Infliximab Therapy. Inflamm Bowel Dis 2016; 22:2977-2987. [PMID: 27636380 DOI: 10.1097/mib.0000000000000926] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the expression and function of pattern recognition receptors, including the IFI16 protein. Because this protein is a target for autoantibodies and its aberrant expression was reported in colonic mucosa from active patients with ulcerative colitis, we studied its expression and specific seroresponse in patients with IBD before and after infliximab (IFX) therapy. METHODS Anti-IFI16 antibodies (IgG and IgA subtypes) were measured in the sera of 74 patients with IBD: 48 patients with Crohn's disease (CD) and 26 patients with ulcerative colitis, prospectively harvested before and after IFX therapy. Anti-GP2 antibodies (both IgG and IgA subtypes) were also tested for comparison. The patient antibody statuses were qualitatively and quantitatively associated with disease phenotype and response to IFX therapy. RESULTS Significantly higher titers of anti-IFI16 IgG were found in both CD and ulcerative colitis patients compared with healthy controls. Anti-IFI16 IgA titers were also present in patients with CD. Anti-GP2 IgG subtype titers were significantly increased in patients with CD, as were IgA subtype titers. Significant changes in anti-IFI16 IgG subtype titers were observed after IFX in patients with CD who correlated with clinical remission or response. CONCLUSIONS Our results highlight the importance of IFI16 in IBD pathogenesis showing that its de novo overexpression in the gut epithelial cells leads to a breakdown in immune tolerance and the subsequent development of specific autoantibodies. Anti-IFI16 IgG antibodies hold the potential to serve as a biomarker of response to IFX therapy.
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Serologic Anti-GP2 Antibodies Are Associated with Genetic Polymorphisms, Fibrostenosis, and Need for Surgical Resection in Crohn's Disease. Inflamm Bowel Dis 2016; 22:2648-2657. [PMID: 27753692 PMCID: PMC5082182 DOI: 10.1097/mib.0000000000000936] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The presentation of Crohn's disease (CD) is heterogeneous and often leads to serious complications and need for surgery. We tested serum anti-zymogen granule glycoprotein 2 (GP2) antibodies, including its novel isoform alpha, for association with genetic variants, diagnosis, disease stratification, and prediction of CD courses in a combined cross-sectional and cohort study. METHODS Serum samples of 303 CD, 108 ulcerative colitis, 72 other inflammatory gastrointestinal diseases, and 206 controls without predominant gastrointestinal diseases controls (HC) were tested for the presence of Anti-GP2 and Anti-Saccharomyces cervisiae (ASCA) by enzyme-linked immunosorbent assay. Genetic analysis was performed using the Illumina Immunochip. RESULTS GP2 IgA and IgG had the highest discriminatory capability for CD versus ulcerative colitis and CD versus inflammatory gastrointestinal diseases. We identified an association of GP2 IgA and IgG each with 5 distinct single-nucleotide polymorphisms. Levels of anti-GP2 IgG were moderately associated with ileal disease location. Interestingly, both, anti-GP2 IgA and IgG were exclusively associated with the occurrence of stenosis and need for surgery, independently of disease location, but not with fistulizing CD, early disease onset or disease activity. ASCA IgG and IgA were qualitatively and quantitatively linked to CD, CD complications, and need for surgery. Increased levels of ASCA IgG and IgA and positivity for ASCA IgG, but neither levels nor positivity for GP2 IgG or IgA were predictive of the earlier occurrence of complications or surgery. CONCLUSIONS Anti-GP2 antibodies may aid as a tool for diagnosis and differentiation of CD and could indicate a more complicated CD course.
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Gill HK, Cohen JD, Ayala-Figueroa J, Forman-Rubinsky R, Poggioli C, Bickard K, Parry JM, Pu P, Hall DH, Sundaram MV. Integrity of Narrow Epithelial Tubes in the C. elegans Excretory System Requires a Transient Luminal Matrix. PLoS Genet 2016; 12:e1006205. [PMID: 27482894 PMCID: PMC4970718 DOI: 10.1371/journal.pgen.1006205] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 06/28/2016] [Indexed: 02/07/2023] Open
Abstract
Most epithelial cells secrete a glycoprotein-rich apical extracellular matrix that can have diverse but still poorly understood roles in development and physiology. Zona Pellucida (ZP) domain glycoproteins are common constituents of these matrices, and their loss in humans is associated with a number of diseases. Understanding of the functions, organization and regulation of apical matrices has been hampered by difficulties in imaging them both in vivo and ex vivo. We identified the PAN-Apple, mucin and ZP domain glycoprotein LET-653 as an early and transient apical matrix component that shapes developing epithelia in C. elegans. LET-653 has modest effects on shaping of the vulva and epidermis, but is essential to prevent lumen fragmentation in the very narrow, unicellular excretory duct tube. We were able to image the transient LET-653 matrix by both live confocal imaging and transmission electron microscopy. Structure/function and fluorescence recovery after photobleaching studies revealed that LET-653 exists in two separate luminal matrix pools, a loose fibrillar matrix in the central core of the lumen, to which it binds dynamically via its PAN domains, and an apical-membrane-associated matrix, to which it binds stably via its ZP domain. The PAN domains are both necessary and sufficient to confer a cyclic pattern of duct lumen localization that precedes each molt, while the ZP domain is required for lumen integrity. Ectopic expression of full-length LET-653, but not the PAN domains alone, could expand lumen diameter in the developing gut tube, where LET-653 is not normally expressed. Together, these data support a model in which the PAN domains regulate the ability of the LET-653 ZP domain to interact with other factors at the apical membrane, and this ZP domain interaction promotes expansion and maintenance of lumen diameter. These data identify a transient apical matrix component present prior to cuticle secretion in C. elegans, demonstrate critical roles for this matrix component in supporting lumen integrity within narrow bore tubes such as those found in the mammalian microvasculature, and reveal functional importance of the evolutionarily conserved ZP domain in this tube protecting activity. Most organs in the body are made up of networks of tubes that transport fluids or gases. These tubes come in many different sizes and shapes, with some narrow capillaries being only one cell in diameter. As tubes develop and take their final shapes, they secrete various glycoproteins into their hollow interior or lumen. The functions of these luminal proteins are not well understood, but there is increasing evidence that they are important for lumen shaping and that their loss can contribute to diseases such as cardiovascular disease and chronic kidney disease. Through studies of the nematode C. elegans, we identified a luminal glycoprotein, LET-653, that is transiently expressed in multiple developing tube types but is particularly critical to maintain integrity of the narrowest, unicellular tubes. We identified protein domains that direct LET-653 to specific apical matrix compartments and mediate its oscillatory pattern of lumen localization. Furthermore, we showed that the LET-653 tube-protecting activity depends on a Zona Pellucida (ZP) domain similar to that found in the mammalian egg-coat and in many other luminal or sensory matrix proteins involved in human disease.
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Affiliation(s)
- Hasreet K. Gill
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jennifer D. Cohen
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jesus Ayala-Figueroa
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Rachel Forman-Rubinsky
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Corey Poggioli
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Kevin Bickard
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jean M. Parry
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Department of Biology, Georgian Court University, Lakewood, New Jersey, United States of America
| | - Pu Pu
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - David H. Hall
- Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Meera V. Sundaram
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Abstract
There is currently no single test available to confidently diagnose cases of inflammatory bowel disease (IBD). Physicians rely on a number of diagnostic tools, including clinical evaluation, serum testing, and imaging, which are used on conjunction with endoscopic evaluation. It is often difficult to determine whether patients with abdominal pain and change in bowel habit have functional bowel symptoms or whether they have a true diagnosis of IBD. Even once a diagnosis of IBD has been made, a significant proportion of patients are labeled with the term "indeterminate colitis" where histological sampling cannot confidently subclassify patients as either Crohn's or ulcerative colitis. Colonoscopy is an inconvenient and uncomfortable test for most patients. In addition, it is not without serious risks of perforation, as well as risks which can be associated with sedation and analgesia given during the procedure. The use of biomarkers to aid in the diagnosis, subclassification, and monitoring of IBD is an ever expanding area. In this review, we have concentrated on noninvasive biomarkers of IBD, because these are more acceptable to patients and easier to perform in everyday clinical practice. We will first touch on those biomarkers currently well established and in wide clinical use, such as C-reactive protein, erythrocyte sedimentation rate. Faecal calprotectin and their use in the diagnosis of IBD. Following on, we will review more novel biomarkers and their use in subclassification and monitoring of IBD, including a variety of antibodies, genetics, and microRNAs, as well as touching on metabolomics.
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Soubières AA, Poullis A. Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease. World J Gastrointest Pharmacol Ther 2016; 7:41-50. [PMID: 26855811 PMCID: PMC4734953 DOI: 10.4292/wjgpt.v7.i1.41] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/06/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
There is currently no gold standard test for the diagnosis of inflammatory bowel disease (IBD). Physicians must rely on a number of diagnostic tools including clinical and endoscopic evaluation as well as histologic, serologic and radiologic assessment. The real difficulty for physicians in both primary and secondary care is differentiating between patients suffering from functional symptoms and those with true underlying IBD. Alongside this, there is always concern regarding the possibility of a missed, or delayed diagnosis of ulcerative colitis (UC) or Crohn’s disease. Even once the diagnosis of IBD has been made, there is often uncertainty in distinguishing between cases of UC or Crohn’s. As a consequence, in cases of incorrect diagnosis, optimal treatment and management may be adversely affected. Endoscopic evaluation can be uncomfortable and inconvenient for patients. It carries significant risks including perforation and in terms of monetary cost, is expensive. The use of biomarkers to help in the diagnosis and differentiation of IBD has been increasing over time. However, there is not yet one biomarker, which is sensitive of specific enough to be used alone in diagnosing IBD. Current serum testing includes C-reactive protein and erythrocyte sedimentation rate, which are cheap, reliable but non-specific and thus not ideal. Stool based testing such as faecal calprotectin is a much more specific tool and is currently in widespread clinical use. Non-invasive sampling is of the greatest clinical value and with the recent advances in metabolomics, genetics and proteomics, there are now more tools available to develop sensitive and specific biomarkers to diagnose and differentiate between IBD. Many of these new advances are only in early stages of development but show great promise for future clinical use.
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