Inappropriate T-cell responses to ingested gluten in genetically predisposed individuals results in the intestinal injury that characterizes celiac disease [30-31]. The discovery that tissue tTG is a target of the immune response in celiac disease has enhanced the understanding of the patho-genesis of the disease and led to the development of new diagnostic tests [32]. Prolamins (gliadin in wheat, secalin in rye and hordein in barley, collectively referred to as gluten) have been identified as the component of those grains capable of inducing damage in celiacs [3334]. Over 50 peptides have been shown to stimulate T cells in celiac subjects, although a given patient may react to only a few of these peptides. Most recent studies suggest that avenin in oats does not induce immunoreactivity [35], although there are reports to suggest that some T cells may react to oat-derived peptides [36]. There is also some evidence that in celiac subjects regulation of the intestinal tight junctions is altered such that levels of zonulin are increased [37] and permitting enhanced uptake of gluten via the tight junctions [38, 39].

Genetic factors are suggested by the 70% concordance rate in identical twins and a prevalence of 10-15% in first-degree relatives. HLA studies indicate that most celiacs possess the extended haplotype, DR3-DQ2, or, less often, DR5/7-DQ2. The DQ2 a/(3 heterodimer is encoded by the alleles DQA1*0501 and DQB1*0201. Some celiac patients have DR4-DQ8 encoded by the DQA1*0301 and DQB1*0302 alleles. Since approximately one third of the US population has these haplotypes, this suggests that additional susceptibility gene(s) not yet identified are required for the development of celiac disease. Antigen-presenting cells bearing these HLA haplotypes present gliadin peptides to intestinal mucosal T cells [40], which mediate the immune response resulting in intestinal damage through cytokines such as IL-15 and interferon gamma (IFN-7). The deamidating activity of tTG modifies gliadin to become the dominant alpha-gliadin T-cell epitope [41, 42].

Celiac disease is characterized by a two- to six-fold increase in the number of intestinal plasma cells and increased levels of antibodies to mesenchymal proteins including tTG. The number of intraepithelial lymphocytes (IEL) is increased in celiac disease including the CD45RO+ subset that can act as antigen-primed memory cells and CD8- IEL bearing the 7/8 T cell receptor (TCR). Increased IL-15 enhances receptor-ligand interaction between IEL and entero-cytes leading to enterocyte killing [43]. Experimental studies show that mitogen-activated T cells in fetal small bowel explants develop an injury similar in appearance to that of celiac disease, including crypt hypertrophy that is mediated by IFN-7 [44].

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