Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for coeliac disease?
BACKGROUND
Coeliac disease is a small intestine enteropathy caused by permanent intolerance to wheat gluten. Gluten intake by patients with coeliac disease provokes a strong reaction by intestinal intraepithelial lymphocytes (IELs), which normalises on a gluten-free diet.


OBJECTIVE
To investigate whether impaired extrathymic T cell maturation and/or secondary T cell receptor (TCR) gene recombination in IELs are features of coeliac disease which 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 alpha-chain (preTalpha) mRNA were determined in IEL-subsets of children with coeliac disease 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 dominant and expressed in both mature (TCR(+)) and immature (CD2(+)CD7(+)TCR(-)) IELs ( approximately 8 mRNA copies/18S rRNA U). PreTalpha was expressed almost exclusively in CD2(+)CD7(+)TCR(-) IELs ( approximately 40 mRNA copies/18S rRNA U). By contrast, RAG1 and preTalpha mRNA levels were low in patients with coeliac disease 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 patients with coeliac disease compared to controls (p<0.001).


CONCLUSIONS
Patients with coeliac disease 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 downregulate the T cell response to gluten.
Bas
A
A
Department of Clinical Microbiology, Immunology, Umeå University, Umeå, Sweden.
Forsberg
G
G
Sjöberg
V
V
Hammarström
S
S
Hernell
O
O
Hammarström
M-L
ML
D000293:Adolescent; D017398:Alternative Splicing; D000704:Analysis of Variance; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D016654:Genes, RAG-1; D006801:Humans; D007223:Infant; D007413:Intestinal Mucosa / Q000276:immunology*; D007421:Intestine, Small; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090377:pre-T cell receptor alpha