Abstract

Celiac disease is induced by gliadin in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8. The mechanisms underlying the expansion of interferon g-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells (EC) lining the small intestine of celiac patients have remained elusive. Intraepithelial lymphocytes (IELs) can undergo malignant transformation during the course of rare but severe complications of celiac disease: enteropathy associated T-cell lymphomas and refractory sprue. These complications support the idea that celiac disease IELs are permanently submitted to stimuli that promote their expansion and ultimately may favour their transformation. Altogether, these observations underline the importance of understanding the mechanism(s) that drives the expansion of IELs and their role in the pathogenesis of the epithelial lesions. A model enhanced presentation of gliadin peptides by DQ2 or DQ8 molecules to CD4 + cells in the lamina propria which results in secretion of interferon gamma and other cytokines that may be deleterious to gut epithelial cells, however gluten-specific IE-CTL could not be identified. To characterize T cells and protein expression in CD patients in relationship to severe complications, we used for the first time 2D-Dige approaches with well-characterized CD-associated gut biopsies. Fourteen adult patients diagnosed as CD were studied. All patients were characterized for the presence of anti-transglutaminase antibodies, VDJ-TcR and VDJ-BcR genescan pattern, HLA DQ and KIRs/ligand genotypes, villous atrophy, and to clinical response to gluten-free diet (13 out of 14 cases). One of these patients presented a restricted T cell population both in the peripheral blood as well as in the gut biopsy. Another patient presented a concomitant DLCL lymphoma. 2 further patients, with biopsies for intestinal disorders but with HLA-DQ2 and DQ8 negative, were used as controls. Patient with the T cell restriction pattern showed a prevalent Tg clone in peripheral blood and two identical over-expanded Tg clones in the peripheral blood a nd gut biopsy. Moreover in the gut biopsy it was also present a restricted Tb clone. Sequences from these 4 clones were reported in the EMBL database. HLA DQ2+D8 is found only in the case of CD-DLCL associated, 5 cases were DQ2 homozigote, 6 cases were DQ2 heterozygote (including the case with the restricted TCR pattern), 2 cases have neither DQ2 nor DQ8 heterodimer. A complete set of KIR with activating function (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 KIR3DS1) was present only in two samples, one of them with the T cell restricted pattern. Data from comparative protein expression obtained by 2D-Dige analysis, are in course. Although the number of control individuals and patients analysed were still low, the frequency of KIR with activating function was found to be higher in patients, particularly in sprue CD with T cell restriction, than in controls. This indicates that genotypic profiles of NK-T-CD patients may be characterized by an increased presence of activating KIRs.

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