High Selectivity of Human Tissue Transglutaminase for Immunoactive Gliadin Peptides:  Implications for Celiac Sprue

Piper, Justin L.; Gray, Gary M.; Khosla, Chaitan

doi:10.1021/bi011715x

Cited by 124 publications

(119 citation statements)

References 30 publications

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“…TG2-mediated cross-linking of gluten-derived peptides to cellsurface BCR molecules could be a route for receptor-mediated uptake of gluten peptides by TG2-specific B cells. After incubating Ab, TG2, and a labeled gluten peptide, the peptide was cross-linked to TG2 itself in agreement with previous reports (14,15,25). Additionally, we could detect cross-links between the peptide and the Ab H chains of IgG1, IgG3, and IgD.…”

Section: Tg2-mediated Cross-linking Of Ab Molecules Is Dependent On Asupporting

confidence: 90%

Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease

Iversen

Pré

Niro

et al. 2015

The Journal of Immunology

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Autoantibodies specific for the enzyme transglutaminase 2 (TG2) are a hallmark of the gluten-sensitive enteropathy celiac disease. Production of the Abs is strictly dependent on exposure to dietary gluten proteins, thus raising the question how a foreign Ag (gluten) can induce an autoimmune response. It has been suggested that TG2-reactive B cells are activated by gluten-reactive T cells following receptor-mediated uptake of TG2–gluten complexes. In this study, we propose a revised model that is based on the ability of the BCR to serve as a substrate to TG2 and become cross-linked to gluten-derived peptides. We show that TG2-specific IgD molecules are preferred in the reaction and that binding of TG2 via a common epitope targeted by cells using the IgH variable gene segment (IGHV)5–51 results in more efficient cross-linking. Based on these findings we hypothesize that IgD-expressing B cells using IGHV5–51 are preferentially activated, and we suggest that this property can explain the previously reported low number of somatic mutations as well as the overrepresentation of IGHV5–51 among TG2-specific plasma cells in the celiac lesion. The model also couples gluten peptide uptake by TG2-reactive B cells directly to peptide deamidation, which is necessary for the activation of gluten-reactive T cells. It thereby provides a link between gluten deamidation, T cell activation, and the production of TG2-specific Abs. These are all key events in the development of celiac disease, and by connecting them the model may explain why the same enzyme that catalyzes gluten deamidation is also an autoantigen, something that is hardly coincidental.

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Section: Tg2-mediated Cross-linking Of Ab Molecules Is Dependent On Asupporting

confidence: 90%

Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease

Iversen

Pré

Niro

et al. 2015

The Journal of Immunology

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“…This peptide is selectively deamidated by tTGase at Gln 4 and Gln 11 (7). The CD spectra of PQPQLPYPQPQLPY and its mono-deamidated analog PQPELPYPQPQLPY displayed both characteristics of a polyproline II helix (Fig.…”

Section: Spectroscopicmentioning

confidence: 97%

“…First, they are relatively stable toward further proteolysis by gastric, pancreatic, and intestinal enzymes (6). Second, they are recognized and deamidated by human tissue transglutaminase (tTGase) 1 with high selectivity (7)(8)(9). Third, tTGase-catalyzed deamidation enhances their affinity for HLA-DQ2, the disease-specific class II major histocompatibility complex heterodimer (5).…”

mentioning

confidence: 99%

Circular Dichroism and Nuclear Magnetic Resonance Spectroscopic Analysis of Immunogenic Gluten Peptides and Their Analogs

Parrot¹,

Huang²,

Khosla³

2002

Journal of Biological Chemistry

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Celiac Sprue, or gluten-sensitive enteropathy, is an inheritable human disease of the small intestine that is triggered by the dietary intake of gluten. Recently, several Pro-and Gln-rich peptide sequences (most notably PQPQLPY and analogs) have been identified from gluten with potent immunogenic activity toward CD4 ؉ T cells from small intestinal biopsies of Celiac Sprue patients. These peptides have three unusual properties. First, they are relatively stable toward further proteolysis by gastric, pancreatic, and intestinal enzymes. Second, they are recognized and deamidated by human tissue transglutaminase (tTGase) with high selectivity. Third, tTGase-catalyzed deamidation enhances their affinity for HLA-DQ2, the disease-specific class II major histocompatibility complex heterodimer. In an attempt to seek a mechanistic explanation for these properties, we undertook secondary structural studies on PQPQLPY and its analogs. Circular dichroism studies on a series of monomeric and dimeric analogs revealed a strong polyproline II helical propensity in a subset of them. Two-dimensional nuclear magnetic resonance spectroscopic analysis confirmed a polyproline II conformation of PQPQLPY, and was also used to elucidate the secondary structure of the most helical variant, (D-P)QPQLPY. Remarkably, a strong correlation was observed between polyproline II content of naturally occurring gluten peptides and the specificity of human tTGase toward these substrates. Analogs with up to two D-amino acid residues retained both polyproline II helical content and transglutaminase affinity. Since the Michaelis constant (K m ) is the principal determinant of tTGase specificity for naturally occurring gluten peptides and their analogs, our results suggest that the tTGase binding site may have a preference for polyproline II helical substrates. If so, these insights could be exploited for the design of selective small molecule inhibitors of this pharmacologically important enzyme.Celiac Sprue (a.k.a. celiac disease, coeliac disease, or glutensensitive enteropathy) is a widely prevalent immune disorder of the small intestine that is triggered by the dietary intake of gluten from sources such as wheat, rye, and barley (2). Like many autoimmune diseases, this inheritable disease is strongly linked to a particular allele of the class II major histocompatibility complex HLA-DQ2 (3). Within the past few years several studies have succeeded in mapping epitopes in gluten that specifically stimulate CD4 ϩ T cells from Celiac Sprue patients (but not control subjects) in an HLA-DQ2-dependent manner. Most of these epitopes are Pro-and Gln-rich peptides. A particular sequence, PQPQLPY, is found in gluten peptides that potently stimulate T cells from nearly all patients and is therefore considered "immunodominant" (4, 5). Gluten peptides containing the sequence PQPQLPY or analogs have three unusual properties. First, they are relatively stable toward further proteolysis by gastric, pancreatic, and intestinal enzymes (6). Second, they are recognized an...

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“…For fluorescein labeling of the ␣I peptide, carboxyfluorescein (Sigma-Aldrich) was coupled to the free N-terminal amino group of the resin-bound peptide using diisopropylcarbodiimede as coupling reagent. Recombinant human TG2 were expressed as either GST (GST-TG2) or hexa-His (His 6 -TG2) fusion protein in E. coli and purified as described previously (12,13).…”

Section: Reagents and Peptidesmentioning

confidence: 99%

Tissue Transglutaminase-Mediated Formation and Cleavage of Histamine-Gliadin Complexes: Biological Effects and Implications for Celiac Disease

Qiao

Piper

Haraldsen

et al. 2005

The Journal of Immunology

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Celiac disease is an HLA-DQ2-associated disorder characterized by an intestinal T cell response. The disease-relevant T cells secrete IFN-γ upon recognition of gluten peptides that have been deamidated in vivo by the enzyme tissue transglutaminase (transglutaminase 2 (TG2)). The celiac intestinal mucosa contains elevated numbers of mast cells, and increased histamine secretion has been reported in celiac patients. This appears paradoxical because histamine typically biases T cell responses in the direction of Th2 instead of the Th1 pattern seen in the celiac lesions. We report that histamine is an excellent substrate for TG2, and it can be efficiently conjugated to gluten peptides through TG2-mediated transamidation. Histamine-peptide conjugates do not exert agonistic effects on histamine receptors, and scavenging of biologically active histamine by gluten peptide conjugation can have physiological implications and may contribute to the mucosal IFN-γ response in active disease. Interestingly, TG2 is able to hydrolyze the peptide-histamine conjugates when the concentrations of substrates are lowered, thereby releasing deamidated gluten peptides that are stimulatory to T cells.

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High Selectivity of Human Tissue Transglutaminase for Immunoactive Gliadin Peptides: Implications for Celiac Sprue

Cited by 124 publications

References 30 publications

Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease

Igs as Substrates for Transglutaminase 2: Implications for Autoantibody Production in Celiac Disease

Circular Dichroism and Nuclear Magnetic Resonance Spectroscopic Analysis of Immunogenic Gluten Peptides and Their Analogs

Tissue Transglutaminase-Mediated Formation and Cleavage of Histamine-Gliadin Complexes: Biological Effects and Implications for Celiac Disease

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