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Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for celiac disease. Questionmark
  1. Anna Bas (anna.bas{at}
  1. Umeå University, Sweden
    1. Göte Forsberg (gote.forsberg{at}
    1. Umeå University, Sweden
      1. Veronika Sjöberg (veronika.sjoberg{at}
      1. Umeå University, Sweden
        1. Sten Hammarström (sten.hammarstrom{at}
        1. Umeå University, Sweden
          1. Olle Hernell (olle.hernell{at}
          1. Umeå University, Sweden
            1. Marie-Louise Hammarström (marie-louise.hammarstrom{at}
            1. Umeå University, Sweden


              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 (CD2+CD7+TCR-) IELs (≈ 8 mRNA copies/18S rRNA U). PreTα was expressed almost exclusively in CD2+CD7+TCR- 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.

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