Celiac Disease

Celiac disease( Back to main page)
Celiac disease (CD) is the most common food intolerance in the Western hemisphere: approximately 1:200 of the population is intolerant to gluten proteins found in wheat, rye and barley. Due to severe inflammation small intestinal villi, that are required for nutrient uptake, regress leading to malabsorption. Histologically a strong infiltration of lymphocytes (denoted as intraepithelial lymphocytes; IEL) is seen in the small intestinal epithelium. Serology shows these patients have circulating IgA antibodies to gluten and autoantibodies against tissue transglutaminase (TG2). The precise role of this humoral response in disease development is unclear. However, the anti-TG2 response is not coincidental as gluten proteins can be deamidated by TG2 in the gastrointestinal tract. Due to deamidation, negative charges are introduced into gluten peptides that facilitate their binding to the disease-predisposing HLA-DQ2 or HLA-DQ8 molecules which can trigger inflammatory interferon-  (IFN- ) and interleukin-21-driven CD4+ T-cell responses in the small intestine. The only available treatment for CD is a lifelong gluten free diet. Importantly, when insufficiently treated, the disease may lead to a series of complications, ranging from deficiencies associated with small intestinal malabsorption to malignancy in later life.

In our patient studies we first focused on identifying the features that characterize pediatric CD when compared to adult CD. These results demonstrated that an inteleukin-17A-independent increase in interleukin-21 production by CD4+ Thelper cells is characteristic of pediatric CD when compared to disease in adults. Moreover, in children, the percentages of peripheral blood CD4+Foxp3+ Treg cells were comparable between CD patients and healthy age-matched controls. In adult patients on gluten-free diet and in refractory CD increased percentages of circulating natural CD62L+Foxp3+ Treg, but normal mucosally-imprinted CD62LnegCD38+Foxp3+ Treg frequencies were observed.
To unravel why CD patients fail to mount tolerance to gluten we have first established a humanized mouse model of gluten tolerance and discovered that tolerance to gluten is mediated by IL-10 secreting Foxp3 negative T cells. Next, we have dissected the mechanisms that underlie the differentiation of these tolerogenic IL-10 secreting cells and are currently investigating whether disruption of IL-10 signaling leads to gluten-induced enteropathy in mice.

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