Gliadin as stimulator adaptive and innate immune responses in celiac disease.

Abstract

Celiac disease (CD) has been considered as the typical model of disease in which the adaptive branch (T cells) of the immune system produces the whole pathogenic picture (1). The strict genetic association between HLA DQ2/8 alleles and CD (2), the recent and elegant studies which have unveiled the molecular mechanisms that control posttranslational modification of gliadin immunodominant epitopes have strengthen this view (1). Thought T cells are the key elements in the induction and progression of celiac disease, their activation must be preceded by an engagement/activation of the innate immune system. The role of resident professional antigen presenting cells is indeed essential for antigen recognition and T cell activation in CD. This function is operated by tissue myeloid derived cells (usually Dendritic Cells) which process antigen and deliver the appropriate co-stimulatory signal to T cells. In the case of gliadin in CD, another fundamental posttranslational modification is required as discussed above, which is operated by tTG. Interestingly, this enzyme is highly expressed upon maturation of Dendritic Cells (3), further stressing the potential close interaction between adaptive and innate immune systems in the induction of celiac disease. It is therefore natural to expect that the innate branch of the immune system must be involved, at least in the initial phases of celiac disease. It can be expected that this essential phase of the immune response, leading to gliadin specific T cell activation, might be supported by simultaneous and unrelated infections which could provide the required ‘non specific’ but essential cofactors for the induction of gliadin specific T cell activation. This is more than a theoretical option and epidemiologic data lends a hand to support this scenario (4).Despite all the unequivocal results on gliadin recognition by T cells and their critical activation for disease progression, there is increasing evidence that gluten/gliadin can induce specific mucosal changes which are apparently not driven by the activation of the adaptive immune system (5). This non T cell targeted activation might represent an important co-factor in the pathogenesis of celiac disease and we have proposed that a mucosal activation of the adaptive immune system might occur upon encounter of gliadin in the small intestine of celiac patients (5). The clarification of this unforeseen activation of the non adaptive branch of the immune system might hold clues to comprehend not only key steps in the pathogenesis of celiac disease, but also open unexpected scenarios in the whole area of mucosal functional homeostasis. In the context of the presentation it will be discussed how an activation of the innate immune system might occur and might influence CD progression.