Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues

Arentz‐Hansen, Helene; McAdam, Stephen N.; Molberg, Øyvind; Fleckenstein, Burkhard; Lundin, Knut E.A.; Jørgensen, Thomas J. D.; Jung, Günther; Roepstorff, Peter; Sollid, Ludvig M.

doi:10.1053/gast.2002.35381

Cited by 321 publications

(262 citation statements)

References 19 publications

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“…Interestingly, a sequence region (M36999 residues 61-140) was identified in which all peptides showed competitions Ͼ56% (M7-M13). The same set of 20-mer peptides was screened for recognition after TG2 treatment by six gluten-specific, polyclonal intestinal T cell lines generated from six different celiac disease patients, and the results are reported in detail elsewhere (21). Although these T cell lines recognized different numbers of peptides (from one to six) and varied in their response to the recognized peptides, the six T cell lines together recognized eight of the 23 ␥-gliadin peptides: M2, M7, M8, M10, M12, M13, M23, and M24 (Fig.…”

Section: Separation and Quantification Of Tg2-catalyzed Reactionmentioning

confidence: 99%

Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease

Fleckenstein

Molberg

Qiao

et al. 2002

Journal of Biological Chemistry

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206

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Tissue transglutaminase (TG2) can modify proteins by transamidation or deamidation of specific glutamine residues. TG2 has a major role in the pathogenesis of celiac disease as it is both the target of disease-specific autoantibodies and generates deamidated gliadin peptides that are recognized by CD4؉ , DQ2-restricted T cells from the celiac lesions. Capillary electrophoresis with fluorescence-labeled gliadin peptides was used to separate and quantify deamidated and transamidated products. In a competition assay, the affinity of TG2 to a set of overlapping ␥-gliadin peptides was measured and compared with their recognition by celiac lesion T cells. Peptides differed considerably in their competition efficiency. Those peptides recognized by intestinal T cell lines showed marked competition indicating them as excellent substrates for TG2. The enzyme fine specificity of TG2 was characterized by synthetic peptide libraries and mass spectrometry. Residues in positions ؊1, ؉1, ؉2, and ؉3 relative to the targeted glutamine residue influenced the enzyme activity, and proline in position ؉2 had a particularly positive effect. The characterized sequence specificity of TG2 explained the variation between peptides as TG2 substrates indicating that the enzyme is involved in the selection of gluten T cell epitopes. The enzyme is mainly localized extracellularly in the small intestine where primary amines as substrates for the competing transamidation reaction are present. The deamidation could possibly take place in this compartment as an excess of primary amines did not completely inhibit deamidation of gluten peptides at pH 7.3. However, lowering of the pH decreased the reaction rate of the TG2-catalyzed transamidation, whereas the rate of the deamidation reaction was considerably increased. This suggests that the deamidation of gluten peptides by TG2 more likely takes place in slightly acidic environments.The food-sensitive enteropathy celiac disease (CD) 1 is a chronic inflammatory disorder with a multifactorial etiology (1, 2). The disease is precipitated by dietary wheat gluten and related proteins in barley and rye. The ingestion of such proteins induces mucosal lymphocyte infiltration and villus atrophy. Subjects with active disease have autoantibodies specific for the enzyme tissue transglutaminase (3). CD shows a strong genetic association with the genes encoding for HLA-DQ2 and -DQ8 (1). Gluten-reactive CD4 ϩ T cells isolated from the small intestine of CD patients are almost exclusively restricted by either of these HLA molecules (4, 5), and activation of such T cells is probably a critical event in the disease development (1). Interestingly, the gluten-reactive T cells of the celiac lesion predominantly recognize gluten peptides in which certain glutamines are converted to glutamic acid by deamidation (6). Evidence indicates that tissue transglutaminase (TG2) can mediate this deamidation in vivo (7-9). TG2 is best known for its ability to catalyze an acyl transfer reaction in which the carboxamide group of a p...

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Section: Separation and Quantification Of Tg2-catalyzed Reactionmentioning

confidence: 99%

Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease

Fleckenstein

Molberg

Qiao

et al. 2002

Journal of Biological Chemistry

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206

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“…Celiac disease (CD) is an autoimmune enteropathy characterized by villous atrophy, crypt hyperplasia and heavy inflammatory infiltrate of both epithelium and lamina propria, caused by a T-cell response to an array of epitopes of dietary gliadin 1,2 in genetically susceptible individuals 3 carrying the HLA-DQ2 or -DQ8 phenotype. It is supposed that tissue transglutaminase, the CD autoantigen, 4 increasingly released as a consequence of increasing tissue injury, 5 catalyses gliadin deamidation and focuses T-cell response towards immunodominant gliadin fragments.…”

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confidence: 99%

Matrix metalloproteinase pattern in celiac duodenal mucosa

Ciccocioppo

Sabatino

Bauer

et al. 2005

Laboratory Investigation

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Matrix metalloproteinases (MMPs) are a family of endopeptidases playing a key role in tissue remodelling in both physiological and pathological conditions. Since little information is available about their role in celiac disease (CD), our aims were to quantify their expression/activity and to investigate their relation to proinflammatory cytokines in this condition. Duodenal biopsies from untreated, treated celiac patients and controls were used to quantify the expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, their inhibitor TIMP-1, IFN-c and TNF-a by using real-time reverse transcription-polymerase chain reaction and the gelatin/casein/elastin activities by gel zymography, and to isolate lamina propria mononuclear cells (LPMCs). These cells and myofibroblasts isolated from jejunal specimens were incubated in the absence or presence of IFN-c and TNF-a. MMP-1 and MMP-12 mRNA levels were significantly increased in active CD compared to treated (Po0.01 and Po0.0005, respectively) and normal mucosa (Po0.01 and Po0.0005, respectively), and this was paralleled by an upregulation of caseinolytic and elastolytic activities. Furthermore, MMP-12 levels significantly (Po0.05) correlated with those of IFN-c and the degree of villous flattening. MMP-2 turned out to be significantly (Po0.05) reduced in untreated and treated celiacs compared to controls. In active CD, transcripts of TIMP-1 were higher than in treated and controls (Po0.005 and Po0.05, respectively), such as those of IFN-c (Po0.05), whereas TNF-a levels were suppressed (P ¼ 0.0001). In physiological condition, myofibroblasts represent the main source of MMP-2, whereas LPMCs produce almost all MMPs only after cytokine stimulation. Conversely, cells isolated from active patients constitutively express MMPs without any increase after cytokine stimulation, while those from treated patients are in a resting condition. In conclusion, our results show the presence of a peculiar MMP pattern in active CD strongly dominated by MMP-12, correlating either with IFN-c or the degree of mucosal damage.

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“…A model was postulated on the basis of the finding that tTG is the main target of immune response in CD (16) and that gliadin is able to act as a tTG substrate (17,18). This model suggests that tTG catalyzes in situ the deamidation of specific glutamine residues present in immunodominant gluten peptides, which are recognized by CD4ϩ DQ2-restricted mucosal T cells (19,20). However, the mucosal environment should be without amine donors to allow the occurrence of such reactions in vivo.…”

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confidence: 99%

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

Orrú

Caputo

D’Amato

et al. 2003

Journal of Biological Chemistry

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Transglutaminase (TG)-catalyzed cross-linking of both intracellular and extracellular proteins is an important biochemical event. However, increased concentrations of cross-linked proteins have been observed in many disorders. Moreover, TG-catalyzed modification of proteins might generate new self-antigens responsible for the autoimmune response, as in celiac disease. The identification of available substrates may offer an understanding of how the TG-catalyzed post-translational modification has an impact on physiology and disease. We used a proteomic approach to identify TG-modified protein targets in human intestinal epithelial cells to determine the extent to which transglutaminase specifically contributes to celiac disease. Two probes were used for endogenous TG activity: 5-(biotinamido)pentylamine, which represents the acyl-acceptor, and a biotinylated glutamine-containing peptide, which represents the acyl-donor. This approach identified >25 proteins, which range from 30,000 to 300,000 Daltons and can serve as acyl-acceptor and/or acyl-donor for transglutaminase. Some of them were known transglutaminase substrates, whereas others had not been previously identified. These targets include proteins involved in cytoskeletal network organization, folding of proteins, transport processes, and miscellaneous metabolic functions.

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Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues

Cited by 321 publications

References 19 publications

Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease

Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease

Matrix metalloproteinase pattern in celiac duodenal mucosa

Proteomics Identification of Acyl-acceptor and Acyl-donor Substrates for Transglutaminase in a Human Intestinal Epithelial Cell Line

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