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Original article
Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease
  1. Michael Schumann1,
  2. Dorothee Günzel2,
  3. Nataly Buergel1,
  4. Jan F Richter2,
  5. Hanno Troeger1,
  6. Claudia May1,
  7. Anja Fromm1,2,
  8. Detlef Sorgenfrei2,
  9. Severin Daum1,
  10. Christian Bojarski1,
  11. Martine Heyman3,
  12. Martin Zeitz1,
  13. Michael Fromm2,
  14. Joerg-Dieter Schulzke1,4
  1. 1Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany
  2. 2Institute of Clinical Physiology, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany
  3. 3INSERM, U989, Interactions of the Intestinal Epithelium with the Immune System, Université Paris Descartes, Paris Cedex 15, France
  4. 4Department of General Medicine, Campus Benjamin Franklin, Charité Berlin, Berlin, Germany
  1. Correspondence to Professor Dr Joerg-Dieter Schulzke, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, 12200 Berlin, Germany; joerg.schulzke{at}charite.de

Abstract

Background Epithelial barrier defects are well known in coeliac disease, but the mechanisms are only poorly defined. It is unclear, whether barrier disturbance reflects upregulated epithelial transcytosis or paracellular leakage.

Objective To characterise the molecular structure and function of the epithelial tight junction (TJ) and mechanisms of its dysregulation.

Methods Molecular analysis of proteins involved in TJ assembly and their regulation was performed by western blotting and confocal microscopy correlated to electrophysiology.

Results A complex alteration of the composition of epithelial TJ proteins (with more pore-forming claudins like claudin-2 and a reduction in tightening claudins like claudin-3, -5 and -7) was found for protein expression and subcellular localisation, responsible for an increase in paracellular biotin-NHS uptake. In contrast, epithelial apoptosis was only moderately elevated (accounting for a minor portion of barrier defects) and epithelial gross lesions—for example, at cell extrusion zones, were absent. This TJ alteration was linked to an altered localisation/expression of proteins regulating TJ assembly, the polarity complex protein Par-3 and the serine-/threonine phosphatase PP-1.

Conclusions Changes in cell polarity proteins Par-3 and PP-1 are associated with altered expression and assembly of TJ proteins claudin-2, -3, -5 and -7 and ZO-1, causing paracellular leakage in active coeliac disease.

  • Celiac disease
  • epithelial barrier
  • Par-3
  • tight junction
  • apoptosis
  • gastrointestinal lymphoma
  • gamma delta t cells
  • lamina proprial lymphocytes
  • coeliac disease
  • enteropathy
  • endoscopy
  • new imaging technologies
  • confocal laser endomicroscopy
  • chromoendoscopy
  • endoscopic retrograde pancreatography
  • endoscopic ultrasonography
  • endoscopic polypectomy
  • adenoma
  • endoscopic procedures
  • gut immunology
  • epithelial permeability
  • epithelial transport
  • HIV/AIDS
  • Crohn's disease
  • inflammatory bowel disease
  • mucosal immunology
  • HIV-related gastrointestinal disease
  • Helicobacter pylori
  • acid-related diseases
  • non-ulcer dyspepsia
  • genetic polymorphisms
  • gastric neoplasia
  • inflammation
  • IBD
  • 5-aminosalicylic acid (5-ASA)
  • inflammatory mechanisms
  • radiation enteritis
  • apoptosis

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Footnotes

  • Funding Supported by Deutsche Forschungsgemeinschaft (Schu 2389/1-1 and FOR721/2 TP2).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethic committee Charité Benjamin Franklin (#227-44).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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