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Celiac Disease

Celiac Disease. CELIAC DISEASE. A Lifetime Without Beer. Kyle Mulligan Northwestern Ontario Medical Program. Celiac Disease Yes, It is Here!. Larry E Lyon M.D. Sioux Valley Clinic Luverne October, 2005. What is it?. Autoimmune disease Also called celiac sprue

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Celiac Disease

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  1. Celiac Disease

  2. CELIAC DISEASE A Lifetime Without Beer Kyle Mulligan Northwestern Ontario Medical Program

  3. CeliacDiseaseYes, It is Here! Larry E Lyon M.D. Sioux Valley Clinic Luverne October, 2005

  4. What is it? • Autoimmune disease • Also called celiac sprue • Reaction to gluten found in certain grains • Not an allergy, T cell mediated

  5. Who gets it? • Highest prevalence in Europe • Women more than men • May be more prevalent in US but not properly diagnosed Prevalence 1/200 30,000 in US, 300,000 projected

  6. Related diseases • Thyroid • Lupus • Diabetes • Liver • Collagen vascular disease • Arthritus • Sjogren’s syndrome

  7. Symptoms • Young Children • Impaired growth • Diarrhea • Abdominal distension • Growth delays iron and folate deficiency

  8. Symptoms • Older children • Abdominal pain • Defects in dental enamel • Depression • Dermatitis

  9. Symptoms • Adults • 20% in adults > 60 • Episodic diarrhea, flatulence • Tiredness • Fe deficiency

  10. Celiac Disease Histology Partial atrophy II Partial atrophy I Normal Partial atrophy III Total atrophy Subtotal atrophy

  11. Diagnosis • Small bowel biopsy • Blood tests • Immunoglobin A • Anti-tissue transglutaminase • IgA anti-endomysium antibodies (AEA)

  12. Treatment • Strict gluten free diet • Avoid wheat, rye, barley • Avoid beer, ale • Wine OK • Avoid oat and lactose until remission • 70% improve within two weeks

  13. What is gluten? • Refers to a group of proteins that are found in wheat products • Gliadins • Glutenins • Makes flour elastic

  14. Are there structures related to celiac disease? • HLA-DQ2 complex with a gliadin epitope 1S9V • 2 endopeptidases 1YR2, 2BKL

  15. Background • Gluten reactive T cells recognize peptides in the context of HLA-DQ2 or DQ8 • Multiple Pro and Gln residues are resistant to proteolysis • Gln is easily deaminated and is more immunogenic

  16. Questions • How does Pro rich sequence of I gliadin affect MHC binding? • What is structural basis for increased immunigenicity of deamidated gluten peptides? • Why is HLA_DQ2 uniquely suited for presentation of gluten derived epitopes?

  17. HLA-DQ2-with gluten epitope • electron density map of peptide • 1 gliadin peptide, poly proline conformation • HLA-DQ with gliadin peptide

  18. Peptide protein interaction Hydrogen bonding in epitope binding site of DQ2 • P6 involved in extensive H bonds, Gln would disrupt • Waters in network

  19. What is practical application? • Superior ability of protein to bind to peptide because of rigid structure of proline rich peptide • Knowing precise structure can be the starting point for designing competitive peptides- possible therapeutic agent

  20. Prolyl Endopeptidases • Open form from springomonas capsulata • Inhibitor bound closed form from myxococcus xanthus • These PEPs cleave prolyl peptides

  21. Closed and open PEPs • Closed form binds Z alanyl prolinal • Both have a catalytic domain with hydrolase fold and a propellor domain

  22. Binding of inhibitor • extensive hydrogen bonding

  23. Modeling • Used crystal structure information to model a an prolyl containing peptide • Identified critical residues • Confirmed using mutation studies

  24. Medical Implications • Gives idea of how to engineer PEP’s for use as a pharmaceutical agent against celiac sprue

  25. National Institutes of Health Consensus Conference • June, 2004 • Conference with national and world experts • Prevalence of 1% of U.S. population • Disease is widely underrecognized

  26. National Organizations • Celiac Sprue Association/USA,Inc Web site: www.csaceliacs.org • Celiac Disease Foundation • www.celiac.org • GIG (Gluten Intolerance Group) • www.gluten.net

  27. Web Sites • www.consensus.nih.gov • www.celiacdiseasecenter.columbia.edu • www.glutenfreedrugs.com/ • digestive.niddk.nih.gov/ddisases/pubs/celiac • www.fmn.on.ca/files/CELIAC.ppt

  28. References • Green, Peter & Jabri,B. Coeliac disease.The Lancet, 2 August 2003Vol. 362, No.9381 Pages 383-391 • Kim, C.Y., Quarsten, H., Bergseng, E., Khosla, C., and Sollid, L.M. (2004). Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A 101, 4175-4179. • Shan, L., Mathews, II, and Khosla, C. (2005). Structural and mechanistic analysis of two prolyl endopeptidases: role of interdomain dynamics in catalysis and specificity. Proc Natl Acad Sci U S A 102, 3599-3604. • Moustakas, A.K., van de Wal, Y., Routsias, J., Kooy, Y.M., van Veelen, P., Drijfhout, J.W., Koning, F., and Papadopoulos, G.K. (2000). Structure of celiac disease-associated HLA-DQ8 and non-associated HLA-DQ9 alleles in complex with two disease-specific epitopes. Int Immunol 12, 1157-1166. • Bergseng, E., Xia, J., Kim, C.Y., Khosla, C., and Sollid, L.M. (2005). Main chain hydrogen bond interactions in the binding of proline-rich gluten peptides to the celiac disease-associated HLA-DQ2 molecule. J Biol Chem 280, 21791-21796. • Gastroenterology Volume 128No. 4 April Supplement 1, 2005 Official Journal of the American Gastroenterological Association • Celiac Disease, National Digestive Diseases Information Clearinghouse; 8/23/2001 • Fasano, Alessio et al; Prevalence of Celiac Disease in At-Risk and Not-At-Risk Groups in the United States. Archives Internal Medicine Vol 163, Feb 10, 2003 • Frissora, C and Green, P: Celiac Sprue. Emergency Medicine July 2002 • Abdulkarim, A.S. & Murray, J.A. Review article: The Diagnosis of Coeliac Disease. Aliment Pharmacol Ther 2003; 17: 987-995 • American Gastroenterological Assoc. Medical Position Statement: Celiac Sprue, April 2001 • Celiac Disease: Yes, It is Here! Larry E Lyon M.D., Sioux Valley Clinic Luverne • Farrell and Kelly. “Celiac Sprue” NEJM. Vol 346 #3 January 17, 2002 • Hin et al. “Celiac Disease in Primary Care.” BMJ Vol 318 January 16, 1999 • Pruessner. “Detecting Celiac Disease in Your Patients.” Am Fam Phys March 1/98 • Gillett et al. “High Prevalence of Celiac Disease in Pts with Type I DM Detected by Antibodies to Endomysium and Tissue Transglutaminase.” Can Jour Gastroenterology May 2001

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