1. Celiac Disease

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

4. Celiac Disease Yes, It is Here! Larry E Lyon M.D. Sioux Valley Clinic Luverne October, 2005

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

6. 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

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

8. Symptoms Young Children –Impaired growth –Diarrhea –Abdominal distension –Growth delays iron and folate deficiency

9. Symptoms Older children –Abdominal pain –Defects in dental enamel –Depression –Dermatitis

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

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

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

13. 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

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

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

19. 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

20. 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?

21. HLA-DQ2-with gluten epitope A.electron density map of peptide  1 gliadin peptide, poly proline conformation C.HLA-DQ with gliadin peptide

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

23. 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

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

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

27. Binding of inhibitor extensive hydrogen bonding

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

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

30. 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

31. 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

32. 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

33. 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