Celiac anti-tissue transglutaminase antibodies interfere with the uptake of alpha gliadin peptide 31–43 but not of peptide 57–68 by epithelial cells

Caputo, Ivana; Barone, Maria Vittoria; Lepretti, Marilena; Martucciello, Stefania; Nista, I.; Troncone, Riccardo; Auricchio, Salvatore; Sblattero, Daniele; Esposito, Carla

doi:10.1016/j.bbadis.2010.05.010

Cited by 33 publications

(41 citation statements)

References 49 publications

(58 reference statements)

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“…2C, 3). This is in agreement with Caputo et al [35] who observed a reduced endocytosis of fluorescence signals in cells incubated with labeled P31–43 but only a slightly reduced endocytosis with labeled P57–68. Schumann et al [29], however, reported the inhibition of translocation of intact fluorescence labeled P56–88 by using MβCD.…”

Section: Discussionsupporting

confidence: 93%

Epithelial Transport of Immunogenic and Toxic Gliadin Peptides In Vitro

et al. 2014

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ScopeCeliac disease is an autoimmune disorder caused by failure of oral tolerance against gluten in genetically predisposed individuals. The epithelial translocation of gluten-derived gliadin peptides is an important pathogenetic step; the underlying mechanisms, however, are poorly understood. Thus, we investigated the degradation and epithelial translocation of two different gliadin peptides, the toxic P31–43 and the immunogenic P56–68. As the size, and hence, the molecular weight of peptides might have an effect on the transport efficiency we chose two peptides of the same, rather short chain length.Methods and ResultsFluorescence labeled P31–43 and P56–68 were synthesized and studied in a transwell system with human enterocytes. Fluorometric measurements were done to reveal antigen translocation and flow cytometry as well as confocal microscopy were used to investigate cellular uptake of peptides. Structural changes of these peptides were analysed by MALDI-TOF-MS. According to fluorescence intensities, significantly more P31–43 compared to P56–68 was transported through the enterocyte layer after 24 h incubation. In contrast to previous reports, however, mass spectrometric data do not only show a time-dependent cleavage of the immunogenic P56–68, but we observed for the first time the degradation of the toxic peptide P31–43 at the apical side of epithelial cells.ConclusionConsidering the degradation of gliadin peptides by enterocytes, measurement of fluorescence signals do not completely represent translocated intact gliadin peptides. From our experiments it is obvious that even short peptides can be digested prior to the translocation across the epithelial barrier. Thus, the chain length and the sensibility to degradations of gliadin peptides as well as the integrity of the epithelial barrier seem to be critical for the uptake of gliadin peptides and the subsequent inflammatory immune response.

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Section: Discussionsupporting

confidence: 93%

Epithelial Transport of Immunogenic and Toxic Gliadin Peptides In Vitro

et al. 2014

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“…In addition, some studies have highlighted the ability of anti-TG2 antibodies to direct out-in signalling in different cell models through the interaction with the membrane-bound TG2 [27], [28]. We also reported that celiac anti-TG2 antibodies were able to induce ERK phosphorylation and calcium mobilization from intracellular stores in intestinal epithelial cells [29], [30].…”

Section: Introductionmentioning

confidence: 62%

“…Antibody treatments were performed as previously described [29]. Briefly, cells were plated at 1.5×10 4 cell/cm 2 and 24 h later were cultured for 72 h in medium containing 0.1% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Celiac Anti-Type 2 Transglutaminase Antibodies Induce Phosphoproteome Modification in Intestinal Epithelial Caco-2 Cells

et al. 2013

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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.

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“…Anti-tissue transglutaminase antibodies (anti-tTG), appear to be not only a diagnostic marker in celiac patients on gluten-containing diet, but also have been implicated in the pathogenesis of many CD manifestations [26,27,28], including fertility and pregnancy complications. The enzyme transglutaminase can be found in many organs, and may have a role in interactions of cells with the surrounding extracellular matrix [29], in processes of cell adhesion, migration and spreading.…”

Section: Possible Pathogenic Mechanismsmentioning

confidence: 99%

Celiac Disease and the Risk of Infertility

Olivera¹,

Lasa²

2016

IJCD

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Celiac Disease is a chronic inflammatory disease, caused by an abnormal immune response triggered by intestinal exposure to dietary gluten, the protein fraction of wheat, rye and barley, in genetically susceptible individuals. Among atypical presentations of Celiac Disease, reproductive disorders and adverse pregnancy outcomes have been reported. Infertility is defined as the impossibility of conceiving after 12 months of unprotected intercourse. It can be related to both male and female factors, with the latter subdivided into ovarian, tubal, endometrial or unexplained causes. Celiac Disease has been related to infertility, but the evidence is inconclusive. In this review, we discuss the effect of Celiac Disease in both male and female fertility, as well as the possible mechanisms that may be involved.

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Celiac anti-tissue transglutaminase antibodies interfere with the uptake of alpha gliadin peptide 31–43 but not of peptide 57–68 by epithelial cells

Cited by 33 publications

References 49 publications

Epithelial Transport of Immunogenic and Toxic Gliadin Peptides In Vitro

Epithelial Transport of Immunogenic and Toxic Gliadin Peptides In Vitro

Celiac Anti-Type 2 Transglutaminase Antibodies Induce Phosphoproteome Modification in Intestinal Epithelial Caco-2 Cells

Celiac Disease and the Risk of Infertility

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