Endocytotic segregation of gliadin peptide 31-49 in enterocytes.
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.
Zimmer
Klaus-Peter
KP
Zentrum für Kinderheilkundeund Jugendmedizin, Universitätsklinikum Giessen, Germany.
Fischer
Ina
I
Mothes
Thomas
T
Weissen-Plenz
Gabriele
G
Schmitz
Martina
M
Wieser
Herbert
H
Büning
Jürgen
J
Lerch
Markus M
MM
Ciclitira
Paul C
PC
Weber
Peter
P
Naim
Hassan Y
HY
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004386:Duodenum / Q000276:immunology; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000276:immunology; D020895:Enterocytes / Q000276:immunology* / Q000502:physiology; D000939:Epitopes / Q000276:immunology; D005903:Gliadin / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D006684:HLA-DR Antigens; D010446:Peptide Fragments; D005903:Gliadin