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Creating the University of the Highlands and Islands
Department of Diabetes
and Cardiovascular
Science
How are the food pr...
Type-1 Diabetes (T1D)
• Autoimmune disorder
Immune-mediated beta-cell
destruction
• Age of onset
Childhood
• Prevalence
0....
Autoantibodies in T1D
• ICA12
• IAA
• GAD
• ICA512/IA2
• IA-2ß/phogrin
• Others:
ICA69, GM2-1, GLIMA38
The Causes for T1D
• Genetic risk
Relatives: 6% vs 0.4%
Twins: up to 50%
GWAS: >10 genes identified
• Environmental trigge...
MHC/HLA Regions
Expression of MHC Molecules
• Class I
–all nucleated cells
• Class II
–APCs only
MØ, DC and B cells
Class I HLA Molecules
β2MG
Peptide
HLA class I molecule
Cytoplasm
Cell Surface
α
Class II HLA Molecules
Peptide
Cytoplasm
Cell Surface
α
β
Gluten Proteins
• Sources
Wheat, barley & rye
• Wheat gluten
Gliadin and glutenin
• Gliadins
4 subfamilies: α, ß, γ and ω
Features of Dietary Gliadins
• Rich in proline and glutamine
Xaa-Pro-Gln sites
• Resistant to digestive enzymes
Trypsin, p...
Cow Milk Caseins
• Milk proteins
Casein & whey proteins
Isoforms: α-s1, α-s2, ß & κ
• Polymorphisms
13 forms of ß-casein
F...
Bioactive Peptides inβ-Casein
• Rich in proline
Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro-Asn-
Ser-Leu
• β-casomorphins
Tyr-Pro-Phe-...
Permeability of the Gut in T1D
Gluten peptides
Increased
permeability
Deamidated
by TGM2APC
CD4+T
cell
Villous epithelia
Gluten Hypothesis for T1D
Permeability altered
Influx of gluten
Modified by TGM2
Binding to DQ8 molecules
T cell response ...
Binding Motif of Gluten Epitopes
• TGM2
Deamidation of gluten epitopes
• DQ2 restriction
PQPqLPYPQ -> PQPeLPYPQ
• DQ8 rest...
Insulin-Derived Autoantigen
• DQ8 signature
P1 P9
xxxxxxxExxxxxxxExxxxxxx
• Insulin B
Insulin B 9-23: SHLVEALYLVCGERG
Research Strategies
• Correlations between auto-Abs and
Abs to gluten and caseins
• Identification of toxic fragments
• Id...
Acknowledgements
• Scottish Funding Council
• Highlands & Islands Enterprise
• European Regional Development
Fund
• Schizo...
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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. 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. 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. 3. Autoantibodies in T1D • ICA12 • IAA • GAD • ICA512/IA2 • IA-2ß/phogrin • Others: ICA69, GM2-1, GLIMA38
  4. 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
  5. 5. MHC/HLA Regions
  6. 6. Expression of MHC Molecules • Class I –all nucleated cells • Class II –APCs only MØ, DC and B cells
  7. 7. Class I HLA Molecules β2MG Peptide HLA class I molecule Cytoplasm Cell Surface α
  8. 8. Class II HLA Molecules Peptide Cytoplasm Cell Surface α β
  9. 9. Gluten Proteins • Sources Wheat, barley & rye • Wheat gluten Gliadin and glutenin • Gliadins 4 subfamilies: α, ß, γ and ω
  10. 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. 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. 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. 13. Permeability of the Gut in T1D Gluten peptides Increased permeability Deamidated by TGM2APC CD4+T cell Villous epithelia
  14. 14. Gluten Hypothesis for T1D Permeability altered Influx of gluten Modified by TGM2 Binding to DQ8 molecules T cell response toward Ab T1D
  15. 15. Binding Motif of Gluten Epitopes • TGM2 Deamidation of gluten epitopes • DQ2 restriction PQPqLPYPQ -> PQPeLPYPQ • DQ8 restriction qQPQQPFPq -> eQPQQPFPe
  16. 16. Insulin-Derived Autoantigen • DQ8 signature P1 P9 xxxxxxxExxxxxxxExxxxxxx • Insulin B Insulin B 9-23: SHLVEALYLVCGERG
  17. 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. 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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