Abstract
Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Vα24-Jα18 (invariant TCRα chain of human iNKT cells), IFNγ and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Vα24-Jα18 mRNA levels than non-CD controls (I and C-controls). The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with Vα24-Jα18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.
Highlights
Celiac disease (CD) is an inflammatory disorder of the small intestine induced by wheat gluten and other prolamins from rye, barley and some varieties of oats [1] in genetically susceptible individuals
Because CD samples were characterized by increased duodenal Messenger RNA (mRNA) expression of Vα24-Jα18 (Figure 2A,B) and decreased expression of FoxP3 (Figure 4A,B), we studied whether the joint analysis of these two molecules could help us to identify a CD-like molecular profile
We studied whether the increased Vα24‐Jα18 mRNA expression could be used as a marker of the increased number of intraepithelial invariant NKT (iNKT) cells found by flow cytometry (Figure 6A)
Summary
Celiac disease (CD) is an inflammatory disorder of the small intestine induced by wheat gluten and other prolamins from rye, barley and some varieties of oats [1] in genetically susceptible individuals. It is characterized by an interferon (IFN)-γ mediated type I cytokine profile [2]. Gut intraepithelial lymphocytes (IEL) comprise a heterogeneous population of cells outside the normal circulation. In addition to conventional T lymphocytes (CD3` TCRαβ, either CD4` or CD8`) with an outstanding CD3` CD8` prevalence, Natural Killer (NK) cells and unconventional IEL populations such as CD8αα, TCRγδcells, CD3`CD4 ́CD8 ́ cells and NKT lymphocytes are widely represented [5,6]
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