Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.
Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA-gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA-gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD.
Matysiak-Budnik
Tamara
T
Institut National de la Santé et de la Recherche Médicale (INSERM), U793, Paris 75730, Cedex 15, France.
Moura
Ivan Cruz
IC
Arcos-Fajardo
Michelle
M
Lebreton
Corinne
C
Ménard
Sandrine
S
Candalh
Céline
C
Ben-Khalifa
Karima
K
Dugave
Christophe
C
Tamouza
Houda
H
van Niel
Guillaume
G
Bouhnik
Yoram
Y
Lamarque
Dominique
D
Chaussade
Stanislas
S
Malamut
Georgia
G
Cellier
Christophe
C
Cerf-Bensussan
Nadine
N
Monteiro
Renato C
RC
Heyman
Martine
M
D015703:Antigens, CD / Q000096:biosynthesis; D001706:Biopsy; D002446:Celiac Disease / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D020895:Enterocytes / Q000378:metabolism; D005903:Gliadin / Q000737:chemistry*; D005922:Glomerulonephritis, IGA / Q000175:diagnosis / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008954:Models, Biological; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry*; D011990:Receptors, Transferrin / Q000096:biosynthesis / Q000737:chemistry*
D015703:Antigens, CD; C068126:CD71 antigen; D007070:Immunoglobulin A; D010455:Peptides; D011990:Receptors, Transferrin; D005903:Gliadin