The role of epithelial cells differentiation in the pathogenesis of celiac disease

Celiac disease (CeD) is an autoimmune disorder that occurs in genetically predisposed individuals. Around 40% of the general population carry the genetic variations that are regarded as being responsible for celiac disease development, such as HLA-DQ2 and HLA-DQ8. CeD affects around 1% of the general population, however it is estimated, that for every diagnosed case, 5-10 patients remains undiagnosed. Its onset is triggered by the ingestion of gluten or related proteins found in wheat, barley and rye.

The disease primarily affects the small intestine and is characterized by villous atrophy, destruction of enterocytes, crypts hyperplasia, complex remodeling of tissue, and increased numbers of intraepithelial lymphocytes in lamina propria. However, the clinical manifestations are broad, with both intestinal and extra-intestinal symptoms including diarrhea, anemia, osteoporosis, depression, infertility, skin manifestations and neurologic disease. In pediatric celiac disease, extra-intestinal manifestation includes poor growth, short stature and delayed puberty. The broad diversity of manifestations is explained by the nutrient deficiencies that result from malabsorption by damaged villi. Moreover, CeD is associated with increased risk of Grave`s disease, type 1 diabetes and Hashimoto`s thyroiditis. Typical diagnostic findings during histologic investigation, include small intestine crypt hyperplasia and villi atrophy due to intraepithelial T cells killing enterocytes.

Taking into account the highly regenerative potential of the small intestine witch enterocytes shed and replaced after 3-5 days and that CeD pathogenesis cannot be fully explained only by genetic background and presence of gluten, we hypothesize, that regulation of crypt stem cells differentiation into villi enterocytes might play a role. The main aim of the project is identification and characterization of mechanisms regulating intestinal stem cells differentiation in small intestine of patients with celiac disease.