In addition, P31-43 transcytosis seems to be enhanced in the presence of anti-gliadin antibodies bound to the transferrin receptor . the other hand, the enzyme can affect the GLUT4 activator 1 biological activity of this peptide. In addition, an intense auto-immune response towards TG2 is a hallmark of CD. Auto-antibodies exert a range of biological effects on several cells, effects that in part overlap with those induced by peptide 31-43. In this review, we delineate a scenario in which TG2, anti-TG2 antibodies and peptide 31-43 closely relate to each other, thus synergistically participating in CD starting and progression. strong class=”kwd-title” Keywords: type 2 transglutaminase, celiac disease, anti-TG2 antibodies, gliadin peptide31-43 1. Introduction The enzyme type 2 transglutaminase (TG2) plays a key role in the pathogenesis of celiac disease (CD), primarily for its enzymatic activity that transforms common food proteins, i.e., gluten proteins contained in cereals, in unhealthy molecules for genetic predisposed individuals . However, a class of gluten peptides, in particular peptide 31-43 of the -gliadin (P31-43), does not require TG2-induced modifications to be toxic for the organism . P31-43 exerts damaging effects directly on cells with which it comes in contact . Interestingly, it is able to modulate TG2 activity and expression; in turn, TG2 may regulate some effects induced by P31-43. Auto-antibodies against TG2, abundantly produced at an early stage of CD development, have themselves a biological activity when interacting with TG2 on the cell surface and in the extra-cellular matrix (ECM) . In some cases, they are able to modulate effects produced by P31-43 stimulation . In this review, we have examined known or potential relationships between TG2, P31-43 and antibodies to TG2, trying to highlight the thin thread connecting them in the molecular mechanism of CD pathogenesis. 2. Generality on Celiac GLUT4 activator 1 Disease Celiac disease (CD) is a complex inflammatory and auto-immune disorder triggered by the ingestion of gluten, a proteic GLUT4 activator 1 component of several cereals, such as wheat, barley and rice . Gluten proteins, at the level of the intestinal mucosa, cause an immune response that leads to an extensive mucosal remodeling and organ damage . CD patients can present a certain grade of mucosal atrophy and crypt hyperplasia, including an increase of the intra-epithelial lymphocytes infiltrate . Besides classical intestinal manifestations of the disease (diarrhea, malabsorption, anemia, weight loss, growth delay, etc.), there is a wide range of possible extra-intestinal symptoms including bone, liver, skin and neurological manifestations [4,5]. An important hallmark of CD is the presence of an auto-immune response towards one main auto-antigen represented by the enzyme TG2 . The research in sera of antibodies to TG2, in particular of IgA class, represents the first screening level for clinical diagnosis of active CD [7,8]. Antibodies to other members of transglutaminase (TG) family can be sometimes detected; for example, antibodies to epidermal (type 3) TG are a typical marker of dermatitis herpetiformis, the dermal manifestation of CD [9,10], whereas antibodies to neuronal (type 6) TG form neuronal deposits in patients affected by gluten ataxia . Even if gluten is the main environmental trigger for CD, other concomitant factors can contribute to the disease, Rabbit Polyclonal to EPHA3 for example, viral infections or microbiota alterations [12,13,14]. However, the environmental contribution is not sufficient to trigger CD, and a genetic background is also necessary. It consists of the presence of particular haplotypes of the human leukocytes antigen (HLA) system of class II, codifying molecules that bind antigens on antigen presenting cells (APC) . CD patients almost invariably possess HLA-DQ2 variants (in more that 90% of subjects) or HLA-DQ8 variants . However, accordingly to the latest CD prevalence studies, these haplotypes are present in about 40%C50% of the population , whereas the incidence of CD is estimated to be about 1% in the general population . Currently, genetic tests targeted to find HLA-DQ2/8 haplotypes have only a negative predictive value in the diagnostic practice. A lot of additional non-HLA genes are under investigation to establish their contribution to the CD genetic susceptibility and data overall come from studies of genome-wide association . 3. Gluten Proteins and the Adaptive/Innate Immune Response Gluten is a heterogeneous mixture of seed-storage proteins present in cereals such as wheat, barley, rye and oats . From a biochemical point of view, gluten is composed by prolamines, i.e., proteins very rich in repetitive sequences containing glutamine and proline residues. Prolamines from wheat divide into two groups named gliadins (subdivided in /, and types), the alcohol-soluble fraction, and glutenins (subdivided in low molecular and high molecular weight subunits), the alcohol-insoluble fraction. Both gliadins and glutenins are toxic for CD patients, however gliadin sequences are better characterized in the context of CD onset [20,21]. The molecular basis of gluten toxicity is related to its typical aminoacidic composition. In gliadins, the high proline content (15%-20%) renders gliadin polypeptides only partially hydrolyzed by digestive peptidases, thus they may reach a high concentration at the level of gut.
- TCR internalization and blockade, induction of anergy, and perturbation from the T helper (Th) 1/Th2 stability possess all been invoked (Hayward and Shriber, 1992; Alegre et al
- For confocal analyses, images were acquired using a C1Si confocal laser-scanning microscope (Nikon) and analyzed using EZ-C1 software (v3
- For example, the incidence of immunogenicity with adalimumab (a fully human IgG) can be as high as 87% (Bender et al
- In addition, P31-43 transcytosis seems to be enhanced in the presence of anti-gliadin antibodies bound to the transferrin receptor 
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