Dataset Information

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease.

ABSTRACT: Celiac disease (CD) is a common intestinal inflammatory disease involving both a genetic background and environmental triggers. The ingestion of gluten, a proteic component of several cereals, represents the main hexogen factor implied in CD onset that involves concomitant innate and adaptive immune responses to gluten. Immunogenicity of some gluten sequences are strongly enhanced as the consequence of the deamidation of specific glutamine residues by type 2 transglutaminase (TG2), a ubiquitous enzyme whose expression is up-regulated in the intestine of CD patients. A short gluten sequence resistant to intestinal proteases, the ?-gliadin peptide 31-43, seems to modulate TG2 function in the gut; on the other hand, the enzyme can affect the 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.

SUBMITTER: Martucciello S

PROVIDER: S-EPMC7279455 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease.

Martucciello Stefania S Sposito Silvia S Esposito Carla C Paolella Gaetana G Caputo Ivana I

International journal of molecular sciences 20200523 10

Celiac disease (CD) is a common intestinal inflammatory disease involving both a genetic background and environmental triggers. The ingestion of gluten, a proteic component of several cereals, represents the main hexogen factor implied in CD onset that involves concomitant innate and adaptive immune responses to gluten. Immunogenicity of some gluten sequences are strongly enhanced as the consequence of the deamidation of specific glutamine residues by type 2 transglutaminase (TG2), a ubiquitous ...[more]

PMID: 32456177

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Project description:BackgroundCeliac serology has evolved, with the identification of newer antibodies against deamidated gliadin peptides (DGP) [e.g., anti-DGP, immunoglobulin A (IgA), and immunoglobulin G (IgG) types] with sensitivity and specificity in detecting celiac disease (CeD) that are equivalent to anti-tissue transglutaminase [anti-tissue transglutaminase (TTG) IgA]-based tests, particularly in populations with high pretest probability of CeD (prevalence of CeD > 50% of the population under study). This opens the possibility that anti-DGP assays can be used to identify CeD in the general population where the prevalence of CeD is very low (≈1%).ObjectiveThis study aimed (1) to determine the diagnostic performance of DGP antibodies-based serologic assays in identifying CeD during the screening of the general population and (2) to compare the levels of anti-DGP antibodies among CeD patients with mild and severe degrees of enteropathy.MethodsSerology tests for DGP antibodies (DGP-IgA, DGP-IgG, and conjugate TTG/DGP antibodies) were performed on 104 serum samples of positive TTG-IgA (100 confirmed and four potential celiac patients) and a randomly selected 1,000 negative TTG-IgA serum samples collected during mass screening of children (aged 6-15 years) in 2014-2015.ResultsSera from 32 of the 1,000 TTG-IgA negative serum specimens (3.2%) tested positive for one or more of the three anti-DGP serology tests. A total of 13 of the 32 anti-DGP seropositive patients had persistent positive results on follow-up samples in 2020 (1.3%). Eight of the 13 underwent endoscopy with biopsies, and only two had confirmed CeD (both DGP-IgG positive) (0.2%). The sensitivity and specificity of the serology assays were as follows: DGP-IgA (62.7%, 40%), DGP-IgG (80.4%, 100%), and conjugate TTG/DGP (96%, 10%). Based on receiver operating characteristic curves, the area under the curve for DGP-IgG (0.919; 95% CI -0.00406 to 0.114) was comparable to TTG-IgA (0.974; 95% CI 0.924-0.995) (P = 0.0679). Titers of antibodies to DGPs were significantly higher in children with severe intestinal damage than in those in children with mild lesions (P < 0.001).ConclusionThe TTG-IgA assay remains the most reliable screening serology test for CeD in mass screening studies. The performance of TTG-IgA has improved marginally by adding DGP-IgG to the mass screening protocol. In CeD patients detected by mass screening, the anti-DGP antibody titer was significantly higher among patients with a severe degree of enteropathy as compared to the group with mild enteropathy.

Project description:BackgroundCeliac disease is an inflammatory condition of the small intestine that affects genetically predisposed individuals after dietary wheat gliadin ingestion. Type 2-transglutaminase (TG2) activity seems to be responsible for a strong autoimmune response in celiac disease, TG2 being the main autoantigen. Several studies support the concept that celiac anti-TG2 antibodies may contribute to disease pathogenesis. Our recent findings on the ability of anti-TG2 antibodies to induce a rapid intracellular mobilization of calcium ions, as well as extracellular signal-regulated kinase phosphorylation, suggest that they potentially act as signaling molecules. In line with this concept, we have investigated whether anti-TG2 antibodies can induce phosphoproteome modification in an intestinal epithelial cell line.Methods and principal findingsWe studied phosphoproteome modification in Caco-2 cells treated with recombinant celiac anti-TG2 antibodies. We performed a two-dimensional electrophoresis followed by specific staining of phosphoproteins and mass spectrometry analysis of differentially phosphorylated proteins. Of 14 identified proteins (excluding two uncharacterized proteins), three were hypophosphorylated and nine were hyperphosphorylated. Bioinformatics analyses confirmed the presence of phosphorylation sites in all the identified proteins and highlighted their involvement in several fundamental biological processes, such as cell cycle progression, cell stress response, cytoskeletal organization and apoptosis.ConclusionsIdentification of differentially phosphorylated proteins downstream of TG2-antibody stimulation suggests that in Caco-2 cells these antibodies perturb cell homeostasis by behaving as signaling molecules. We hypothesize that anti-TG2 autoantibodies may destabilize the integrity of the intestinal mucosa in celiac individuals, thus contributing to celiac disease establishment and progression. Since several proteins here identified in this study were already known as TG2 substrates, we can also suppose that transamidating activity and differential phosphorylation of the same targets may represent a novel regulatory mechanism whose relevance in celiac disease pathogenesis is still unexplored.

Dataset Information

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease.

Publications

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease.

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