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• W2023802816 abstract "INTRODUCTION Celiac disease (CD) is a permanent intolerance to cereal proteins, characterized by chronic intestinal inflammation induced by the ingestion of dietary wheat gliadin and related prolamines from barley and rye. The disease occurs in genetically predisposed individuals: only HLA-DQ2 and/or DQ8 positive subjects are affected (or subjects carrying genes coding for at least one of the two DQ2 heterodimer molecules) (1). Nonetheless, the inheritance is multifactorial; several other polymorphisms are likely to be involved, probably located in genomic areas identified by whole genoma screening studies (2). These different polymorphisms, altogether, are responsible for the genetic susceptibility to CD. Toxic prolamines have, among dietary proteins, a very peculiar structure. The proteins responsible for CD are characterised by a high percentage of proline (approximately 20%) and glutamine (approximately 38%) residues. Oat prolamines, which are likely to be tolerated by CD patients, have only 10% of proline residues. Several features of toxic prolamines are relevant to the pathogenesis of CD. In particular: a) Their low digestibility; b) The presence of epitopes for intestinal T cells (A gliadin 56–68 is a prototype), as well as their modification by tissue transglutaminase (TG2) and the resulting higher affinity to HLA molecules; c) The presence of biologically active sequences not recognised by T cells (A gliadin 31–43 is a prototype); d) Their ability to activate innate immunity; e) Their ability to interfere with cellular growth, potentiating the activity of tyrosine kinase receptors LOW DIGESTIBILITY Enzymes are present in the brush border of enterocytes that are able to hydrolyse peptide bonds containing pro-line (and glutamic acid) (3); in treated celiac patients these enzymes show an activity comparable to that exhibited by controls (4). On the other hand, immunodominant epitopes from gliadin are highly resistant to intraluminal and mucosal digestion (5,6), although they are largely hydrolysed during the transport through the small intestinal mucosa (7), the hydrolysis is reduced only during the passage through the atrophic celiac mucosa (7). It is possible to hypothesize that incomplete degradation favour the immunostimulatory and toxic effects of these sequences. T-CELL EPITOPES Complementary studies by Sollid and Koning have provided a model explaining the interplay between gliadin, DQ2 or DQ8 and TG2 (8). Susceptibility to CD is strongly associated with the presence of CD4+ T cells in the small intestine of patients that recognize gliadin in the context of HLA-DQ2 or HLA-DQ8. These gliadin-specific T-cell responses have been found to be enhanced by the action of TG2 (8). The enzyme converts particular glutamine residues into glutamic acid, which results in higher affinity of these gliadin peptides for HLA-DQ2 or HLA-DQ8. A large number of T-cell stimulating peptides have been characterized in gluten proteins (9). The specificity of TG2 in deamidation of gliadin is largely dependent on the spacing between glutamine and proline (10). By combining rules for deamidation with the peptide-binding motifs of HLA-DQ2, novel epitopes for celiac intestinal T cells have been predicted and found in barley and rye prolamines (11). An example of T cell epitope is A gliadin 56–68; more recently, a 33-mer peptide has been identified that has several characteristics suggesting it is the primary initiator of the inflammatory responses to gliadin in celiacs (6). All this evidence assigns a central role to adaptative immunity in the genesis of CD inflammation with gliadin-specific CD4+ T cells proliferating and differentiating along the Th1 pathway. GLIADIN BIOLOGICALLY ACTIVE SEQUENCES, NOT RECOGNISED BY T CELLS Although this is strong evidence in favour of a mucosal Th1 response to gliadin peptides in CD, it is also likely that other non T-cell mediated phenomena, related to physicochemical properties of other gliadin peptides play a role in the pathogenesis of the celiac lesion. In recent years several experimental systems have shown direct effect of gliadin peptides interacting with cultured cell lines (12) and foetal rat or chick intestine (13) and inducing damage in vitro or in vivo on the celiac mucosa (13,14). These studies highlight the function of a A-gliadin peptide, 31–43, from the N-terminal end of gliadin, usually referred to as the “toxic” peptide. In contrast to peptide 56–68, found to be a dominant epitope recognized by T cells isolated from intestine of CD patients, peptide 31–43 does not show immunogenic activity on T cells, but reproduces the ability of total peptic-tryptic gliadin hydrolysate to induce agglutination of K562S cells, prevents recovery of atrophic duodenal CD mucosa and induces significant histologic changes in mucosa from CD patients in a state of clinical remission. Until very recently there was no molecular basis for understanding the biologic effects of A gliadin peptide 31–43. More recently, two series of observations have renewed the interest for such biologic effects: 1) the role of 31–43 in triggering the innate immunity mechanisms in the treated celiac mucosa; and 2) the effect of 31–43 peptide on the activity of EGF through modifications of the kinetics of its receptor. An Innate Response to 31–43 (and Other Gliadin Peptides) Precedes Activation of Pathogenic T Cells Gliadin has the ability to induce a complete activation of the immune system (adaptive and innate). In fact, in celiac mucosa in remission, on a gluten-free diet only the non-immunodominant peptide 31–43 (and not the peptide 56–68) induce rapid activation of the innate immune system, as revealed by rapid, IL-15, CD83 (a marker of mature dendritic cells), COX-2 (an enzyme rapidly induced during inflammation) and CD 25 expression by CD3- cells (non T cells) of the innate immune system (15). A particular gliadin fragment, therefore, activates the innate immune system timing the in situ T-cell recognition of dominant gliadin epitopes. EPIDERMAL GROWTH FACTOR-LIKE ACTIVITY OF PEPTIDE 31–43 (AND CRUDE GLIADIN DIGEST) In studies on CaCo 2 cells (epithelial cells of intestinal origin), on MCF7 (a human epithelial cell line derived from mammary carcinoma) and on NIH 3 T3 (a mouse fibroblast cell line), these gliadin peptides induce rapid actin rearrangement that is mediated by EGF receptor (EGFR) and Src activation. They also reproduce the effect of EGF on the cell-cycle by interfering with EGFR endocytosis and, therefore, with the EGF pathway. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a protein essential to EGFR inactivation, shows strong similarities to 31–43 and, when overexpressed, prevents gliadin-induced cell cycle stimulation. A model is proposed where gliadin fragments interfering with the endocytosis could amplify the effects of trace amounts of EGF, and possibly other growth factors, by prolonging receptors activation. CONCLUSION Gliadin and related rye and barley prolamines are among dietary proteins unique for their structure and for their ability to interact with the intestinal mucosa of genetically predisposed individuals, activating multiple mechanisms of damage and inflammation in the mucosa. Where the peculiarity of celiac patients reside is still unclear: molecular biology and genetics studies will provide the key to solve the dilemma." @default.
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• W2023802816 title "Dietary Proteins and Mechanisms of Gastrointestinal Diseases: Gliadin as a Model" @default.
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