The Journal of Experimental Medicine
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Published online December 31, 2007
doi:10.1084/jem.20071204
The Journal of Experimental Medicine, Vol. 205, No. 1, 143-154
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Matysiak-Budnik et al.
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ARTICLE

 Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease

Tamara Matysiak-Budnik1,2,8, Ivan Cruz Moura3,4, Michelle Arcos-Fajardo3,4, Corinne Lebreton1,2, Sandrine Ménard1,2, Céline Candalh1,2, Karima Ben-Khalifa1,2, Christophe Dugave5, Houda Tamouza3,4, Guillaume van Niel6, Yoram Bouhnik7, Dominique Lamarque8, Stanislas Chaussade8, Georgia Malamut1,2,9, Christophe Cellier9, Nadine Cerf-Bensussan1,2, Renato C. Monteiro3,4, and Martine Heyman1,2

1 Institut National de la Santé et de la Recherche Médicale (INSERM), U793, Paris 75730, Cedex 15, France
2 Faculté de Médecine René Descartes, Institut Fédératif de Recherche 94, Université Paris Descartes, Paris 75270, Cedex 6, France
3 INSERM, U699, Paris 75870, Cedex 18, France
4 Faculté de Médecine Paris 7 Denis Diderot, Université Paris 7, Paris 75870, Cedex 18, France
5 Commissariat à l'Énergie Atomique, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette 91191, France
6 Institut Curie, Section de Recherche, Centre National de la Recherche Scientifique, Unité Mixte de Recherche144, Paris 75248, Cedex 5, France
7 Hôpital Beaujon, Clichy 92118, France
8 Hôpital Cochin–Hôtel Dieu, Paris 75181, Cedex 4, France
9 Hôpital Européen Georges Pompidou, Paris 75908, Cedex 15, France

CORRESPONDENCE Martine Heyman: heyman{at}necker.fr OR Renato Monteiro: monteiro{at}bichat.inserm.fr

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.

Abbreviations used: CD, celiac disease; dIg, dimeric Ig; mIg, monomeric Ig; PEG, polyethylene glycol; pIg, polymeric Ig; RP-HPLC, reversed-phase HPLC; SC, secretory component; SIg, secretory Ig; TAMRA, tetramethyl-6-carboxyrhodamine; Tf, transferrin; Tgase, transglutaminase.

I.C. Moura and M. Arcos-Fajardo contributed equally to this work.


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