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Endocytotic segregation of gliadin peptide 31–49 in enterocytes
  1. Klaus-Peter Zimmer1,
  2. Ina Fischer2,
  3. Thomas Mothes3,
  4. Gabriele Weissen-Plenz4,
  5. Martina Schmitz5,
  6. Herbert Wieser6,
  7. Jürgen Büning7,
  8. Markus M Lerch8,
  9. Paul C Ciclitira9,
  10. Peter Weber10,
  11. Hassan Y Naim2
  1. 1Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Giessen, Germany
  2. 2Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
  3. 3Institut für Labormedizin, Universitätsklinikum Leipzig, Leipzig, Germany
  4. 4Universitätsklinikum Münster, Münster, Germany
  5. 5Institut für Anatomie, Universitätsklinikum Münster, Münster, Germany
  6. 6Deutsche Forschungsanstalt für Lebensmittelchemie, Garching, Germany
  7. 7Medizinische Klinik I, Lübeck,Germany
  8. 8Abteilung Gastroenterologie, Klinikum der Ernst-Moritz-Arndt Universität, Greifswald, Germany
  9. 9Department of Gastroenterology, St Thomas' Hospital, London, UK
  10. 10Universitäts-Kinderspital, Basel, Switzerland
  1. Correspondence to Professor Hassan Y Naim, Department of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany; hassan.naim{at}tiho-hannover.de

Abstract

Objective Coeliac disease (CD) is a multisystemic autoimmune inflammation of the intestinal tract induced by wheat gluten and related cereals in human leucocyte antigen (HLA)-DQ2/8-positive individuals. The molecular mechanisms relevant to oral tolerance induction towards toxic cereals such as gliadin remain poorly understood. Enterocytes, which express predominantly HLA-DR proteins, are capable of processing, transcytosing and presenting food antigens from the intestinal lumen to T lymphocytes of the lamina propria.

Methods Epitope-specific monoclonal antigliadin antibodies are utilised to unravel the intraepithelial transport processes of gliadin peptides in human duodenal biopsy specimens from patients with CD and reconstitute the transepithelial and endocytic pathways of gliadin in intestinal epithelial HT29 cells.

Results The gliadin peptide AA 31–49 is segregated from the peptides AA 56–68 and AA 229–246 along the endosomal pathway. Thus, AA 31–49 bypasses HLA-DR-positive late endosomes in intestinal cells and in biopsy specimens of patients with untreated CD. Further, it is localised in early endosomes and consequently escapes antigen presentation at the basolateral membrane, unlike peptides AA 56–68 and AA 229–246 that reach HLA-DR-positive late endosomes. Strikingly, forms of gliadin peptide AA 31–49 conjugated to cholera toxin B are sorted into late endosomes of HT29 cells.

Conclusions Endocytic segregation of gliadin peptide AA 31–49 seems to be a constitutive process. It explains why this peptide cannot stimulate gluten-sensitive T cells. Presentation of gliadin peptides by HLA-DR proteins via late endosomes within enterocytes might induce a tolerogenic effect and constitutes a potentially promising therapeutic approach for induction of tolerance towards gliadin.

  • Coeliac disease
  • small intestine
  • gliadin toxicity
  • endocytosis
  • transepithelial transport
  • MHC I and II
  • celiac disease
  • cell biology
  • gluten sensitive enteropathy
  • intestinal cell lines
  • mucosal immunity

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Footnotes

  • Linked articles 183608, 189332.

  • Dr Enrique Mendez has since died.

  • Funding This study has been supported by grants from the German Research Foundation (Zi 294/6-3, 6-4 to KPZ and SFB 621, C8-project to HYN), the German Coeliac Disease Society and the Interdisciplinary Center for Clinical Science (IZKF: C19), as well as the programme Innovative Medical Science (IMF ZI 5 2 04 07) of the University of Münster.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the University of Muenster.

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

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