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Dissection of the complex molecular and cellular events occurring in the biopsies of small intestine isolated from celiac patients

Dissection of the complex molecular and cellular events occurring in the biopsies of small intestine isolated from celiac patients as a response to gliadin challenge yielded several new findings. Data obtained through collaborative effort demonstrated that the gliadin molecule induces several immunological type responses. The complex signalling mechanism is now better understood.

The data we have obtained show that the DQ8-restricted gliadin epitope, identified for its activity on T cell clones is also active in the organ culture system of the treated coeliac mucosa. In fact, for the first time gliadin peptides have been shown to display different biological activity in different subsets of coeliac patients. It is still unclear if the response of coeliac patients is directed against a few or multiple peptides, but our observations raise the issue of their immunogenicity depending on the genetic make up of the patient. No differences were noted between the native or the deamidated form of the peptides, when all the in vitro responses were analysed. Though recent studies provided the molecular basis controlling the recognition and generation of immunodominant gliadin cell epitopes by mucosal CD4+ T cells there is evidence, supported by studies of several groups, that an other region of alpha gliadin has the ability to induce disease specific modifications. This region of gliadin is not a T cell epitope.

There is also evidence suggesting that an early induction of an inflammatory response precedes the antigen specific T celI response and the definition of this early response represents an important quest to define the full picture of the pathogenesis of coeliac disease. Our data provide a new angle to interpret the pathogenic cascade of CD. Gliadin specific T cell activation is the fundamental step in CD, but it remains to be explained why only a small proportion of HLA DQ2 individuals produce a pathogenic and disease specific T cell activation. The biochemical rules controlling HLA binding of gliadin peptides are obviously identical in all HLA DQ2, coeliac and non coeliac, individuals but a series of other genetic loci have been implicated. It has been reported that IFN-B therapy might be a factor in the initiation of CD and potentially concomitant viral infections, by inducing IFN- release, might contribute to disease initiation and evolution. These studies further indicate the essential involvement of innate response, as the type II interferon are mainly produced by cells of the innate immune system.

However, a recent study on identical twins has demonstrated a very high, compared to other autoimmune diseases, concordance rate. These data argue against the idea that danger signal is always provided by a second environmental factor, besides gliadin. It follows that gliadin should have the ability to induce a complete activation of the immune system (adaptive and innate). The induction of IL-15 release by gliadin supports this notion as IL-15 is a typical cytokine of the innate immune system. In CD IL-15 could represent an ideal therapeutic target as it directly induces some epithelial disease specific changes and sustaining a persistent activation of the adaptive immune system. In this context it is very well known that IL-15 provides powerful anti-apoptotic signal for recently activated T cells, allows their migration and set a Thl like response as observed in CD. The inhibition of activation of the innate immune system in CD may therefore represent a useful therapeutic strategy to control disease evolution.

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University Federico II
Via S. Pansini 5
80131 Naples
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