1. Coeliac Disease Jaide Brown Breea Buckley Krissy Rowe

2. What is Coeliac Disease (CD)? An immune-mediated disease triggered by gluten- containing grains Presents in 2 forms –Typical CD –Atypical CD

3. What is Gluten? A protein found in the endosperm of seeds –Wheat’s gliadin and glutenin –Barley’s hordeins –Rye’s secalins Responsible for the elastic texture of bread http://www.jci.org/articles/view/30253/figure/2

4. What are the Forms and Associated Symptoms of CD? Typical CD –Chronic Diarrhea/Constipation –Abdominal pain, gas and distension –Anemia –Weight loss/malnutrition http://www.nature.com/nrgastro/journal/v6/n1/full/ncpgasthep1298.htm

5. Atypical CD –Bone/Joint Pain –Delayed Puberty or Infertility –Fatigue –Tingling/Numbness in Extremities These cases are very rare What are the Forms and Associated Symptoms of CD?

6. CD may be asymptomatic If untreated can lead to; –Vitamin and iron deficiencies, osteoporosis, pancreatic insufficiencies, intestinal lymphomas or other GI Cancers What are the Forms and Associated Symptoms of CD?

7. Epidemiology Affects ~1% of US population –Potentially affects a higher percentage –Many individuals go undiagnosed RISK FACTORS –Genetic Intestinal permeability, MHC –TGase enzyme –Enteric Infection –Co-morbidity with other autoimmune disease

8. CD OVERVIEW http://www.jci.org/articles/view/30253/figure/2

9. What is the Immunological Mechanism of CD? Role of Gluten Peptides: Gluten peptides are not easily digest by gastric, pancreatic or brush border enzymes –High concentration of proline and glutamine amino acids Accumulation of large gluten peptide fragments –Some may be involved in the immune response

10. Associated Risk Factors/Triggers Consumption of Gluten Intestinal Permeability (Genetics) Accumulation is not enough to develop CD Healthy vs. afflicted individuals show no difference in ability to digest these large peptides

11. What is MHC’s Role in Developing CD? MHC-II alleles –HLA-DQ locus HLA-DQ2 = 90-95% of CD cases HLA-DQ8 = 5-10% of CD cases What is it about these alleles that increases the risk for CD? –APCs with HLA-DQ2 and HLA-DQ8 MHC-II can bind “gluten” peptides

12. MHC-II Genetics HLA-DQ and HLA-DQ8 haplotypes can bind gluten These binding grooves favor negatively charged residues Not naturally found within lumen Associated Risk Factors/Triggers

13. What is the Role of TGase in Development of CD? What is TGase? Transglutaminase enzyme Involved in tissue repair by crosslinking peptides Its Role? Under certain conditions (low pH) TGase will deaminate glutamine to form negatively charged glutamic acid DEAMINATION L-GlutamineGlutamic Acid

14. Release of TGase into the mucosal layer when gluten peptides are present Associated Risk Factors/Triggers

15. Activation of CD4+ T cells HLA-DQ2 and HLA-DQ8 restricted T cells interact with APCs and become activated Activated CD4+ T cells secrete cytokines – IFN-γ (Interferon-gamma) Associated with a TH1 immune response Intracellular pathogen/autoimmunity –Associated with initiation of mucosal damage –Neutralization shown to prevent gluten-induced damage

16. Why so rare? 40% of population has HLA-DQ2 and HLA-DQ8 antigens Enteric Infection Role: –DQ2 and DQ8 MHC is poorly expressed in normal mucosa –TGase enzyme is poorly expressed in normal mucosa –Enteric viral infection up-regulates production of HLA antigens and cytokine production Cytokines cause inflammation/tissue damage Release of TGase enzyme leads to deamination

17. The Big Picture:

18. Who Should Be Tested? 1st and 2nd degree relatives of CD patients Relatives of patients and patients with Type-I diabetes Individuals with Sjögren/Down/Turner Syndrome People with immune, thyroid, and liver disorders

19. How to Diagnose? Serology –IgA Endoscopy/Biopsy –Small Intestine HLA –Absence of HLA-DQ2 or HLA-DQ8

20. Treatment Gluten-free diet Current research focuses on: –Genetically detoxified grains –Celiac vaccines (oral or intranasal) –Inhibitors of TGase –Inhibitors of effects of zoulin on intestinal permeability

21. References Ahn R, Ding YC, Fasano A, Green PHR, Murray J, Neuhausen S, Garner C. 2012. Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Independent Susceptibility Loci. PLoS One 7(5): e36926. Carlo C, Fasano A. 2001. Current Approaches to Diagnosis and Treatment of Celiac Disease: An Evolving Spectrum. Gastroenterology 120: 636-651. Evans KE, Sanders DS. 2012. Celiac Disease. Gastroenterology clinics of North America. 41(3): 639-650. Kagnoff MF. 2007. Celiac Disease: Pathogenesis of a Model Immunogenetic Disease. The Journal of Clinical Investigation. 117(1): 41-49. Pietzak MM. 2005. Follow-up of Patients with Celiac Disease: Achieving Compliance with Treatment. Gastroenterology 128: S135-S141. Walker MM, Murray JA. 2011. An update in the diagnosis of coeliac disease. Histopathology. 59: 166-179.

22. Questions For You! 1.Celiac disease is caused by... A.A specific allele that is present in all cases of Celiac Disease. B.Increased intestinal permeability. C.A viral infection that leads to inflammation. D.A variety of factors contribute to the onset of Celiac Disease including specific genotypes of MHC, genes involved in permeability of mucosa, and other genetic factors.

23. 2. A woman is suspected of having coeliac disease; she undergoes an HLA test and an endoscopy. Which scenario most points to a diagnosis of coeliac disease? A) Negative HLA test, positive for villous atrophy B) Positive HLA test, negative for villous atrophy C) Positive HLA test, positive for villous atrophy D) Negative HLA test, negative for villous atrophy E) Both A and D Questions For You!

24. 3.What is “gluten” A.A brush-border enzyme responsible for digesting cereal grains within the small intestine B.B)A generic term referring to proteins found in the endosperm of wheat, barley, and rye grains C.C)An enzyme responsible for deaminating glutamine to produce glutamic acid D.D)None of the above Questions For You!

25. 4. An enteric infection leads to an increased risk of developing CD by… A.Upregulating MHC expression and cytokine production which results in inflammation and intestinal damage B.Overwhelming the immune system so it cannot combat both the viral infection and accumulation of gluten peptides C.Forming complexes of pathogenic toxins and gluten peptide fragments which cause intestinal inflammation and damage D.All of the above Questions For You!

26. 5. Name 2 risk factors/triggers and give a brief explanation of how they contribute to the development of CD Questions For You!