Gastroenterology

Gastroenterology

Volume 132, Issue 7, June 2007, Pages 2371-2382
Gastroenterology

Basic–alimentary tract
Reduced Chemokine Receptor 9 on Intraepithelial Lymphocytes in Celiac Disease Suggests Persistent Epithelial Activation

https://doi.org/10.1053/j.gastro.2007.04.023Get rights and content

Background & Aims: Celiac disease is caused by an inappropriate immune response to dietary gluten, with increased epithelial lymphocyte infiltration in the duodenum/jejunum as a hallmark. The chemokine receptor 9 (CCR9) is a small intestinal homing receptor normally found on most mucosal T cells in this organ. Because CCR9 expression appears to be activation dependent, we examined CCR9 on duodenal T cells from untreated and treated (gluten-free diet) patients with celiac disease and healthy controls. Methods: Duodenal biopsy specimens and blood samples were obtained for histologic analysis and flow-cytometric CCR9 analysis of isolated lymphocytes. CCR9 expression after activation was studied in peripheral blood T cells from healthy volunteers. Results: The median number of CCR9+ cells among CD3+ T cells in epithelium and lamina propria, respectively, was 56% and 48% in controls, 11% and 40% in treated patients, and 1% and 8% in untreated patients. Significant differences occurred between controls and treated or untreated patients in the epithelium but only between controls and untreated patients in the lamina propria (P = .008, all comparisons). No such differences were seen in peripheral blood, but stimulation with phorbol myristate acetate and ionomycin and, to a lesser extent, stimulation via NKG2D reduced the CCR9 expression on blood T cells. Conclusions: CCR9 expression is reduced on epithelial and lamina propria T cells in untreated celiac disease. Down-regulation of CCR9 persists in intraepithelial T cells from well-treated patients. This suggests ongoing immune activation preferentially within the epithelium.

Section snippets

Patients and Sampling

During diagnostic or follow-up gastroduodenoscopy, multiple duodenal biopsy specimens (n = 4–6) and concomitant blood samples were obtained from consecutively recruited patients with treated (n = 7; age range, 22–70 years) and untreated (n = 7; age range, 29–62 years) celiac disease as well as from non–celiac disease controls with a histologically normal mucosa (n = 6; age range, 28–69 years) (Table 1). Untreated patients had clinical symptoms and/or signs suggestive of celiac disease and

CCR9 Is Persistently Down-regulated on Intraepithelial T Cells in Celiac Disease

The dot plots in Figure 1 based on flow-cytometric analysis of isolated duodenal lymphocytes show the frequency of CCR9+ cells among CD3+ (Figure 1AF) and CD8+ (Figure 1GL) cells dispersed from the intestinal epithelium (Figure 1AC and Figure 1GI) or lamina propria (Figure 1DF and Figure 1JL) of a healthy control subject (no. 6; Figure 1A, D, G, and J) vs a treated (no. 7; Figure 1B, E, H, and K) or untreated (no. 19; Figure 1C, F, I, and L) patient with celiac disease. The number of CCR9+

Discussion

Circumstantial evidence suggests that some mucosal immune activation remains in celiac disease after clinically successful treatment with a GFD.13, 14 Because CCR9 is considered to be a small intestinal homing receptor apparently reflecting the cellular activation state, we analyzed epithelial and lamina propria T cells from treated and untreated patients with celiac disease for the expression of this chemokine receptor. In untreated patients, the frequency of duodenal CCR9+ T cells was

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    Supported by the Norwegian Foundation for Health and Rehabilitation through the Norwegian Celiac Society, the University of Oslo, the Research Council of Norway, and the Norwegian Cancer Society.

    The authors have no conflict of interest to disclose.

    1

    M.R.K.’s present affiliation is Dynal Bead Based Separation, Cell Separation and Expansion, Invitrogen Corp, Oslo, Norway.

    2

    M.R.K. and I.N.F. contributed equally to this work.

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