How Are Food Protein-Derived Antigens Involved In Type-1 Diabetes? [Jun Wei]
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How Are Food Protein-Derived Antigens Involved In Type-1 Diabetes? [Jun Wei]
- 1. Creating the University of the Highlands and Islands Department of Diabetes and Cardiovascular Science How are the food protein-How are the food protein- derived antigens involvedderived antigens involved in type-1 diabetes?in type-1 diabetes? Jun Wei, MD, PhD
- 2. Type-1 Diabetes (T1D) • Autoimmune disorder Immune-mediated beta-cell destruction • Age of onset Childhood • Prevalence 0.4% affected in the European population
- 3. Autoantibodies in T1D • ICA12 • IAA • GAD • ICA512/IA2 • IA-2ß/phogrin • Others: ICA69, GM2-1, GLIMA38
- 4. The Causes for T1D • Genetic risk Relatives: 6% vs 0.4% Twins: up to 50% GWAS: >10 genes identified • Environmental trigger Gluten proteins Cow’s milk caseins Infections
- 6. Expression of MHC Molecules • Class I –all nucleated cells • Class II –APCs only MØ, DC and B cells
- 7. Class I HLA Molecules β2MG Peptide HLA class I molecule Cytoplasm Cell Surface α
- 8. Class II HLA Molecules Peptide Cytoplasm Cell Surface α β
- 9. Gluten Proteins • Sources Wheat, barley & rye • Wheat gluten Gliadin and glutenin • Gliadins 4 subfamilies: α, ß, γ and ω
- 10. Features of Dietary Gliadins • Rich in proline and glutamine Xaa-Pro-Gln sites • Resistant to digestive enzymes Trypsin, pepsin and chymotrypsin • Antigens CD4+ T-cell restricted
- 11. Cow Milk Caseins • Milk proteins Casein & whey proteins Isoforms: α-s1, α-s2, ß & κ • Polymorphisms 13 forms of ß-casein Frequency varies in cows
- 12. Bioactive Peptides inβ-Casein • Rich in proline Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-Asn- Ser-Leu • β-casomorphins Tyr-Pro-Phe-Gly-Pro-Ile-Pro (BCM7) related to many conditions
- 13. Permeability of the Gut in T1D Gluten peptides Increased permeability Deamidated by TGM2APC CD4+T cell Villous epithelia
- 14. Gluten Hypothesis for T1D Permeability altered Influx of gluten Modified by TGM2 Binding to DQ8 molecules T cell response toward Ab T1D
- 15. Binding Motif of Gluten Epitopes • TGM2 Deamidation of gluten epitopes • DQ2 restriction PQPqLPYPQ -> PQPeLPYPQ • DQ8 restriction qQPQQPFPq -> eQPQQPFPe
- 16. Insulin-Derived Autoantigen • DQ8 signature P1 P9 xxxxxxxExxxxxxxExxxxxxx • Insulin B Insulin B 9-23: SHLVEALYLVCGERG
- 17. Research Strategies • Correlations between auto-Abs and Abs to gluten and caseins • Identification of toxic fragments • Identification of low toxic strain of wheat
- 18. Acknowledgements • Scottish Funding Council • Highlands & Islands Enterprise • European Regional Development Fund • Schizophrenia Association of Great Britain • NHS Highland R&D Office
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