Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for celiac disease?

Background: Celiac disease (CD) is a small intestine enteropathy caused by permanent wheat gluten intolerance. Gluten intake by CD patients provokes a strong reaction by intestinal intraepithelial lymphocytes (IELs), which normalizes on a gluten-free diet. Aim: To investigate whether impaired extrathymic T cell maturation and/or secondary T cell receptor (TCR) gene recombination in IELs are features of CD that could contribute to the failure of establishing tolerance to gluten. Methods: Expression levels of the four splice-forms of recombination activating gene-1 (RAG1) mRNA and preT α-chain (preTα) mRNA were determined in IEL-subsets of children with CD and controls. Frequencies of RAG1 expressing IELs were determined by immunomorphometry. Results: In controls, the RAG1-1A/2 splice-form selectively expressed outside the thymus, was dominating and expressed in both mature(TCR) and immature (CD2CD7TCR) IELs (≈ 8 mRNA copies/18S rRNA U). PreTα was expressed almost exclusively in CD2CD7TCR IELs (≈ 40 mRNA copies/18S rRNA U). By contrast, RAG1 and preTα mRNA levels were low in CD patients compared to controls, both with active disease and with inactive, symptom-free disease on a gluten-free diet (p values < 0.01 for mature and < 0.05 for immature IELs). Similarly the frequencies of RAG1 IELs were significantly lower in CD patients compared to controls (p < 0.001). Conclusions: CD patients appear to have an impaired capacity for extrathymic TCR gene rearrangement. This is an inherent feature, which probably plays a pivotal role in the failure to efficiently down-regulate the T cell response to gluten. Gut Online First, published on February 25, 2008 as 10.1136/gut.2007.125526 Copyright Article author (or their employer) 2008. Produced by BMJ Publishing Group Ltd (& BSG) under licence. group.bmj.com on February 23, 2013 Published by gut.bmj.com Downloaded from