Celiac disease is a chronic inflammatory disorder that is triggered by the consumption of gluten in genetically susceptible individuals. Individuals susceptible to celiac disease express either DQ2 or the DQ8 HLA class II antigen. Diagnosis is by intestinal biopsy demonstrating villous atrophy, which disappears upon removal of gluten from the diet. Because all patients are either DQ2 or DQ8 these molecules are crucial in disease development. Recent studies have demonstrated that these molecules present gliadin peptides to inflammatory intestinal CD4+ T cells. However, only 2% of all DQ2 and DQ8 individuals in the Caucasian population develop celiac disease, indicating that factors in addition the DQ haplotype are involved in the development of disease. To better understand how HLA class II molecules affect the development of celiac disease, we have proposed to generate HLA transgenic mice expressing DQ2 and /or DQ8 in the absence of mouse class II expression. Preliminary evidence demonstrates that the DQ8 molecule confers gluten sensitivity but not enteropathy in the B10.DQ8 mouse. The development of gluten sensitive enteropathy can be induced with the introduction of the autoimmune prone NOD background. The resultant NOD.DQ8 mouse, once sensitized to gluten, develops enteropathy similar to celiac disease. Based on this preliminary data, the following aims are proposed. 1. To test the hypothesis that specific HLA class II molecules contribute to gluten sensitivity. 2. We will test the hypothesis that while class II molecules are important for gluten sensitivity, other genes that predispose to autoimmunity are necessary to develop enteropathy. 3. To determine why the BIO DQ8 mice, though sensitive to gluten, do not develop enteropathy. The use of these novel animal models has great potential for elucidating the genetic and environmental components of the initiation and immunopathogenesis of celiac disease and potentially testing new prevention or treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071003-04
Application #
7545857
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Hamilton, Frank A
Project Start
2006-03-01
Project End
2010-06-30
Budget Start
2009-01-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$281,668
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Tian, Na; Leffler, Daniel A; Kelly, Ciaran P et al. (2015) Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease. Am J Physiol Gastrointest Liver Physiol 309:G910-7
Galipeau, Heather J; Wiepjes, Michelle; Motta, Jean-Paul et al. (2014) Novel role of the serine protease inhibitor elafin in gluten-related disorders. Am J Gastroenterol 109:748-56
Lebwohl, Benjamin; Granath, Fredrik; Ekbom, Anders et al. (2013) Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 159:169-75
Ludvigsson, Jonas F; Reichenberg, Abraham; Hultman, Christina M et al. (2013) A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders. JAMA Psychiatry 70:1224-30
Ludvigsson, Jonas F; Lebwohl, Benjamin; Rubio-Tapia, Alberto et al. (2013) Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy. J Gastroenterol 48:1324-31
Marietta, Eric V; Gomez, Andres M; Yeoman, Carl et al. (2013) Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One 8:e78687
Lebwohl, Benjamin; Green, Peter H R; Murray, Joseph A et al. (2013) Season of birth in a nationwide cohort of coeliac disease patients. Arch Dis Child 98:48-51
Ludvigsson, Jonas F; Lindelöf, Bernt; Rashtak, Shadi et al. (2013) Does urticaria risk increase in patients with celiac disease? A large population-based cohort study. Eur J Dermatol 23:681-7
Ludvigsson, Jonas F; Lebwohl, Benjamin; Rubio-Tapia, Alberto et al. (2013) Does celiac disease influence survival in lymphoproliferative malignancy? Eur J Epidemiol 28:475-83
Lebwohl, B; Granath, F; Ekbom, A et al. (2013) Mucosal healing and mortality in coeliac disease. Aliment Pharmacol Ther 37:332-9

Showing the most recent 10 out of 54 publications