title: Deficient activity of mammalian prolyl oligopeptidase on the immunoactive peptide digestion in coeliac disease.
abstract: OBJECTIVE
  Gliadin digestion-resistant peptides are harmful in coeliac disease (CD), and initiate an autoimmune reaction that cause a cascade of symptoms. The role of the endogenous prolyl oligopeptidase (POP) is still not clear, and its activity over gliadin immunoactive peptides has not been fully established. Our objective was therefore to determine the endogenous POP protein level, tissue distribution and total activity in normal and CD epithelia, to evaluate tissue peptidase activity over gliadin peptides, and compare this with activities of mammalian POP and rat intestinal extracts.
  
  
  METHODS
  POP was assayed in biopsy preparations enzymatically and by Western blot analysis. Distribution was studied by immunohistochemistry using a specific POP antibody. Peptide cleavage was followed by mass spectroscopy-high-performance liquid chromatography (MS-HPLC).
  
  
  RESULTS
  There was no difference in POP activity between normal and CD samples, but those from active CD subjects had an even higher ability to degrade the 33-mer peptide than those from treated CD and healthy humans. POP locates intracellularly in epithelia, similarly to dipeptidyl peptidase IV (DPPIV), but the latter is clearly found in normal microvilli but less so in diseased microvilli. Mammalian POP is unable to digest 33-mer peptide, which, conversely, is a POP inhibitor. Rat intestine is more effective than human intestine in cleaving the 33-mer peptide. However, the products are still harmful epitopes. A surplus of POP eliminates 12-mer and 19-mer peptide products.
  
  
  CONCLUSIONS
  The results rule out a causative role of POP in the pathogenesis of CD and strongly suggest that other peptidases are needed to eliminate gliadin-derived, immunoactive and toxic peptides larger than 33-mer, which is a POP inhibitor.
authors: Centro de Investigación Príncipe Felipe, Valencia, Spain. garciaho@cipf.es
authors: J Arturo
authors: JA
authors: Garcia-Horsman
authors: Jarkko I
authors: JI
authors: Venäläinen
authors: Olli
authors: O
authors: Lohi
authors: I Seppo
authors: IS
authors: Auriola
authors: Ilma R
authors: IR
authors: Korponay-Szabo
authors: Katri
authors: K
authors: Kaukinen
authors: Markku
authors: M
authors: Mäki
authors: Pekka T
authors: PT
authors: Männistö
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001706:Biopsy; D015153:Blotting, Western; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000235:genetics; D004063:Digestion / Q000502:physiology*; D004195:Disease Models, Animal; D016099:Endoscopy, Gastrointestinal; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005903:Gliadin / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D000085822:Prolyl Oligopeptidases; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics; D013552:Swine
chemical_list: D004247:DNA; D005903:Gliadin; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases