Cytokine Production by Intestinal Intraepithelial Lymphocyte Subsets in Celiac Disease

Abstract

One of the earliest signs of mucosal immune activation in celiac disease (CD) is an increase in the intraepithelial lymphocyte (IEL) count in the small intestinal epithelium. Though most of those IELs express T cell receptor (TcR)-alphabeta chains, CD is characterized by an increase in TcR-gammadelta+ IELs and by the loss of CD3- IELs. There is currently little evidence that these changes in IEL subset distribution are of relevance in the pathogenesis of CD. We aimed to determine the pattern of cytokine production by IEL subsets isolated from duodenal biopsy specimens from control subjects and CD patients at different stages of the disease. We quantified the capacity of IEL subsets to produce IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-10 by intracellular staining by flow cytometry. All IEL subsets studied displayed a type I cytokine profile in both CD and control subjects, with TcR-alphabeta+ IELs being the main IFN-y producers. Untreated CD exhibited a trend toward a superior accumulation of IFN-gamma per cell but a reduced proportion of INF-gamma+ cells in vitro in association with a significantly increased apoptotic rate of IELs. IL-4 was almost undetectable in all cases and IL-10 showed a tendency to increase in treated and "silent" celiac patients. IEL subsets have a similar Th1 profile in controls and CD patients, and the superior in vitro apoptosis of IELs from CD patients may reflect their superior in vivo activation. The induction of IL-10-dependent regulatory Tr1 responses may be of potential clinical significance in this disease and merits further investigation.

Non-Celiac Gluten Sensitivity: Literature Review

“…In addition, it has been demonstrated that gliadin can induce T H 17-polarizing cytokines-for example, IL-1beta and IL-23 production in peripheral blood monocytes-providing a possible causative link between gluten exposure and T H 17 cell expansion in CD. Unlike NCGS patients, CD patients show increased levels of adaptive immune markers in the small intestinal mucosa, triggered by DQ2 DQ8-bounded tTG-deamidated gluten peptides and associated with T H 1 and T H 17 clone activation and T H 1-and T H 17-associated cytokine production, including IFN-gamma, IL-17A, IL-6 (pleiotropic cytokine promoting differentiation and function of T H 17 cells), and IL-21 (also related to T H 1 and T H 17 cell pathology) [63][64][65][66][67][68][69].…”

Mucosal lesions of the gastric mucosa in adult patients with coeliac disease

“…Hallmarks of coeliac enteropathy include an early rise of intestinal intraepithelial lymphocytes (IEL), followed by crypt hyperplasia and villous atrophy, in response to oral gluten intake [1].…”

Children diagnosed with both Type 1 diabetes and Celiac disease - An Immunological challenge

“…Besides IFN-γ also for example IL-2 and TNF-β mRNA expression have been observed in biopsies from active celiac patients [91] . In contrast, Th2-associated IL-4 is found equally expressed in patients as in controls [89,[91][92][93] .…”

“…A trend towards a superior accumulation of IFN-γ in vivo [89] promoting inflammatory effects and a non-proliferative activation of CD4 + lamina propria T cells, especially by activation of Th1-like cells secreting IFN-γ [90] have been shown by gluten. Besides IFN-γ also for example IL-2 and TNF-β mRNA expression have been observed in biopsies from active celiac patients [91] .…”

“…Gluten-free diet has shown to also normalize the expression of Th2 gene markers for example IL-4R, IL-13RA1, IL-5 and STAT6 [94] and the production of IL-10 by intraepithelial lymphocytes [89] . Recombinant human IL-10 has even been shown to induce a long term hypo-responsiveness of gliadin specific mucosal T cells [96] .…”