Visualization of transepithelial passage of the immunogenic 33-residue peptide from alpha-2 gliadin in gluten-sensitive macaques.
BACKGROUND
Based on clinical, histopathological and serological similarities to human celiac disease (CD), we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from alpha(2)-gliadin in the distal duodenum of gluten-sensitive macaques.


RESULTS
Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with "leaky" duodenum, the peptide penetrated beneath the epithelium into the lamina propria.


CONCLUSIONS
The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.
Mazumdar
Kaushiki
K
Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Alvarez
Xavier
X
Borda
Juan T
JT
Dufour
Jason
J
Martin
Edith
E
Bethune
Michael T
MT
Khosla
Chaitan
C
Sestak
Karol
K
D000818:Animals; D002446:Celiac Disease; D004195:Disease Models, Animal; D004386:Duodenum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism*; D005903:Gliadin / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D005983:Glutens / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D008251:Macaca; D010446:Peptide Fragments / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D010539:Permeability; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D021381:Protein Transport
D010446:Peptide Fragments; C000717608:TGM2 protein, human; C489632:alpha2-gliadin (56-88); D005983:Glutens; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2