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90 RECENT ADVANCES ON GLUTEN TOXICITY involved in the pathogenesis of coeliac disease is higher than previously thought further reduces the technical feasibility of targeted inactivation of gliadins (and glutenins) genes. The most recent results of the Sollid's group are on the same line of Koning. Even in adults, DQ2-restricted mucosal T-cells recognize an additional a-gliadin epitope and several new g-gliadin peptides, confirming also that deamidation is not an absolute prerequisite for T-cell activation. Interestingly the new and the previously identified peptides are not randomly scattered accross gliadin molecules but cluster in regions of 5 the proteins with a high content of proline residues . In apparent contrast with these recent studies indicating a wide array of a,/g-gliadin and glutenin peptides playing a complementary role in coeliac disease activation, a 6 recent study identified a 33-mer peptide having several characteristics suggesting it is the primary initiator of the inflammatory response in this condition. First of all, the 33- mer peptide appeared to be stable toward digestion by gastric, pancreatic and brushborder proteases. Secondly, it reacted with tTG with substantially greater selectivity than known natural substrates of the enzime. Finally, it turned out to be a potent inducer of gut-derived coeliac T-cell lines and its homologs were absent in cereal that are not toxic for coeliac patients. Besides these important features, the aminoacid sequence of the peptide included the residues 57-89 of a-gliadin, largely overlapping with the 57-68 1 2 and the 62-75 Arentz-Hansen and the Anderson 57-73 peptides. In addition it should be noted that the 33-mer peptide is particularly rich in proline residues (n=13) and that its exposure to a bacterial prolyl-endopeptidase catalyzes the breakdown of the peptide diminishing its toxic effect. Should the 33-mer peptide be the dominant epitope in coeliac disease, this would offer a possible strategy for oral peptidase supplement therapy for the treatment of this condition. The apparent discrepancy between multiple and a single toxic peptide in the 7 pathogenesis of coeliac disease has been addressed in a recent editorial . It has been hypothesized a multi-step sequence in which, in an early phase, T-cell response is directed to a wide array of native gluten (glutenin plus gliadin) epitopes as a consequence of an epitope spreading due to the ubiquitous presence of the same highly repetitive sequence. In a more advanced phase the immune response becomes polarized to an immunodominant peptide (the 33-mer ?) as a consequence of an epitope focusing catalized by tTG increasingly released from the tissue lesions. It should be underlined that this view does not preclude a selective immunotherapy. Several lines of evidence suggest that the primary problem is understanding the hierarchy of epitope spreading in coeliac disease, since in other animal and disease models it has been shown that immunodominant T-cell epitopes behave as potent 8 tolerogens when ingested by alternative routes and that this process may induce tolerance to the whole antigenic molecule in a mechanism of intramolecular epitope 9 suppression . Alternative strategies may be represented by DNA vaccines based on the 10 construction of plasmids containing multiple epitopes and by the use of antigen presenting cells engineered to present both the dominant gluten peptide and the FAS 11 ligand molecule to target and kill FAS positive antigen-specific coeliac T-cells . Toxic peptides must reach the sub-epithelial environment to exert their pathogenic role. At the Paris meeting new data have been presented on the interaction between
RECENT ADVANCES ON GLUTEN TOXICITY 91 gliadin and the intestinal mucosa leading to functional changes of the gut barrier function. Zonulin represents a novel eukaryotic protein that reversibly opens intestinal 12 tight junctions (tj) . It has been recently demonstrated that zonulin expression is 13 increased during the early stage of CD , suggesting that the reported opening of tj at the early stage of the disease could be mediated by zonulin. Recent studies indicate that gliadin activates the zonulin-signaling pathway both in 14 normal and celiac disease-derived intestinal tissues . In normal intestinal epithelial cells in vitro, the cellular response to gliadin was observed only a few minutes after incubation and was characterized by a zonulin-dependent cytoskeleton reorganization with a redistribution of actin filaments mainly in the intracellular subcortical 14 compartment . Spectrofluorimetry experiments revealed that such cytoskeleton reorganization was associated to an increment of F-actin amount secondary to an increased rate of intracellular actin polymerization. Experiments performed in Ussing chambers showed that the addition of gliadin peptides to the intestinal mucosa in vitro causes in a few minutes a significant increased of intestinal permeability mediated by zonulin. Considering the results of this study and preliminary data generated by using 15 intestinal tissues from both celiac patients in remission and healthy controls , it is conceivable to hypothesize a possible gliadin mechanism of action leading to zonulinmediated increase in actin polymerization and intestinal permeability. These new findings lead to innovative lines of research possibly relevant for the prevention and treatment of the disease. References 1. Arentz-Hansen H, Korner R, Molberg O, Quarsten H, Vader W, Kooy YMC, et al. The intestinal T cell response in adult coeliac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 2000; 191: 603-12. 2. Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AVS. In vivo antigen challenge in coeliac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T cell epitome. Nat Med 2000; 6: 37-42. 3. Vader W, Kooy Y, van Veelen P, de Ru A, Harris D, Benckhuijsen W, et al The gluten response in children with recent onset celiac disease. A highly diverse response towards multiple gliadin and glutenin peptides. Gastroenterology 2002; 122: 1729-37. 4. Kagnoff MF. Coeliac disease pathogenesis: the plot thickens. Gastroenterology 2002; 123: 39-43. 5. Arentz-Hansen H, Mcadam SN, Molberg O, Fleckenstein B, Lundin KEA, Jorgensen TJD, et al. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 2002;123: 803-9. 6. Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science 202; 297: 2275-9. 7. Martucci S, Corazza GR. Spreading and focusing of gluten epitopes in celiac disease. Gastroenterology 2002; 122: 2072-5. 8. Hoyne GF, O'Henir, Wraith DC, Thomas WR, Lamb JR. Inhibition of T cell and antibody response s to house dust mite allergen by inhalation of the dominant T
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Perspectives on Coeliac Disease Vol
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The AIC Meeting was held in the Aul
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Italian Coeliac Society, Via Picott
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Preface Coeliac disease (CD) is a u
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Contents Current understanding of t
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2 THE BASIS OF COELIAC DISEASE hapl
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4 THE BASIS OF COELIAC DISEASE 1 pr
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6 THE BASIS OF COELIAC DISEASE spre
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8 THE BASIS OF COELIAC DISEASE Ackn
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10 THE BASIS OF COELIAC DISEASE glu
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Catassi C, Fasano A, Corazza GR (ed
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T CELL RESPONSES TO GLUTEN PEPTIDES
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18 A DOMINANT EPITOPE IN GLUTEN PEP
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28 ROLE OF A-GLIADIN 31-49 PEPTIDE
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Catassi C, Fasano A, Corazza GR (ed
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COELIAC DISEASE IN THE SAHARAWI 33
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Page 53 and 54: COELIAC DISEASE IN THE SAHARAWI 39
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 76 and 77: 62 MECHANISMS OF ORAL TOLERANCE the
Page 78 and 79: 64 MECHANISMS OF ORAL TOLERANCE pot
Page 80 and 81: 66 MECHANISMS OF ORAL TOLERANCE Epi
Page 82 and 83: 68 MECHANISMS OF ORAL TOLERANCE typ
Page 84 and 85: 70 MECHANISMS OF ORAL TOLERANCE 51
Page 86 and 87: 72 MECHANISMS OF ORAL TOLERANCE 23.
Page 89 and 90: Catassi C, Fasano A, Corazza GR (ed
Page 91 and 92: GENETICALLY DETOXIFIED GRAINS 77 to
Page 93 and 94: • • GENETICALLY DETOXIFIED GRAI
Page 95 and 96: GENETICALLY DETOXIFIED GRAINS 81 3.
Page 97 and 98: Catassi C, Fasano A, Corazza GR (ed
Page 99 and 100: IMMUNOTHERAPY OF COELIAC DISEASE 85
Page 101 and 102: IMMUNOTHERAPY OF COELIAC DISEASE 87
Page 103: Catassi C, Fasano A, Corazza GR (ed
Page 107 and 108: Index A Antiendomysium antibodies (
Page 109: INDEX 95 W Wheat, 7, 23, 27, 31, 53
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