rowave antigen retrieval procedure in BQ 123 biological activity sodium citrate buffer. The following markers were used: c-Myc, SIRT1, Ki67, and p53. Celiac disease is a complex inflammatory condition of the proximal small intestine caused by a specific response to peptides derived from ingested gliadin. Immunotoxic gliadin peptides initiate a deleterious adaptive and innate immune response in the intestinal epithelium of CD patients. A-gliadin peptide 31-43/49 is the prototype of peptides that modulate the innate response, whereas peptide 5768, which binds to HLA-DQ2/8 molecules, is one of the dominant epitopes recognized by T cells isolated from the intestine of CD patients. However, the innate and adaptive immune systems may respond synergistically to gliadin peptides. The role of posttranslational modifications of gliadin peptides catalyzed by tissue transglutaminase is thought to play a crucial role in CD. Tissue TG is a Ca2+-dependent enzyme that catalyzes the formation of isopeptide linkages between the c-carboxamide group of protein-bound glutamine residues and the e-amino group of protein-bound lysine residues. Glutamine residues can be deamidated to glutamic acid as a side-reaction in the absence of suitable amines or at low pH. Furthermore, tTG also binds and GTP; hence the enzyme can function as a cell signal transducer in association with the a1b-adrenoreceptor. Tissue TG is predominantly an intracellular protein localized in the cytosol, mitochondria, nucleus, and cell membrane compartments, but it is also secreted extracellularly even though it lacks a signal leader peptide. Recently, Zemskov et al. described secretion of tTG that involves phospholipid-dependent delivery into recycling endosomes. Various functions have been ascribed to tTG in both the intraand extracellular environment: in fact, it plays a role in matrix stabilization, cell adhesion and migration, and in cell death and 1 Ca2+ Mobilization Induced by Gliadin survival. The catalytic activity of tTG is implicated in the pathogenesis of several human diseases, including CD. In celiac patients, tTG deamidates specific gliadin glutamines, thus generating a series of gliadin peptides that bind to HLA-DQ2 and DQ8 molecules with high affinity. The resulting HLA-DQ2 -gliadin peptide interaction triggers the proinflammatory T cell response. Moreover, in accordance with the upregulation of tTG in intestinal inflamed sites, tTG may generate additional antigenic epitopes by cross-linking gliadin peptides to itself or to other cellular proteins. Gliadin-tTG complexes may elicit an immune response to tTG by stimulating normally silent autoreactive B-cells. In fact, active CD is associated with serum antibodies against tTG. The exact location at which deamidation of immunogenic gliadin peptides and formation of gliadintTG complexes take place 
is not clear. Although little is known about the processing of gliadin peptides, there is evidence that they enter enterocytes. However, do tTG-induced gliadin modifications in CD patients occur in enterocytes and/or in other antigen-presenting cells, or in the extracellular matrix It has been demonstrated that extracellular tTG is inactive in the intestinal mucosa in the resting state and it is only transiently activated after some inflammatory stimuli and tissue injury. Moreover, under normal conditions, tTG in the intracellular environment is a latent protein due to a low Ca2+ concentration and inhibition by GTP/GDP. However, under extreme conditions of