Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007570 (celiac disease)
 13,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The low serum transglutaminase found in various intestinal disorders (celiac disease and IBD) suggested to us to study the serum and mucosal transglutaminase behaviour in an experimental model of small intestine resection in rats to reduce cellular mass and induce enterocyte hyperproliferation in the proximal part left in continuity. Transglutaminase activity in the intestinal mucosa was significantly higher in resected rats than in control and sham operated animals from days 4 (121 +/- 10 v basal 94 +/- 3 mU/g protein, p < 0.01) to 10 (165 +/- 37 mU/g protein, p < 0.05) after surgery; no significant difference was observed at days 12 and 15 (110 +/- 15 and 105 +/- 23 respectively). Both serum alkaline phosphatase activity (partly produced in enterocytes) and serum transglutaminase were significantly lower in resected rats at each time-point beginning at day 6 (208 +/- 34 v 557 +/- 125 UI and 1.55 +/- 0.11 v 3.78 +/- 0.70 mU/ml, p < 0.001 respectively). These data suggest an involvement of transglutaminase in enterocyte proliferation and confirm the association between reduced intestinal mass and low levels of the enzyme in serum.
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PMID:Transglutaminase changes in intestinal mucosa after experimental small bowel resection in the rat. 136 17

Transglutaminase (TG) activity is increased in the mucosa of patients with coeliac disease. Among 18 patients with untreated coeliac disease we have found a significant decrease (p less than 0.001) in serum levels of TG activity (0.72 (0.23) mU/ml). There was no significant differences between 16 treated coeliacs (1.24 (0.28) mU/ml) and 30 normal controls (1.63 (0.42) mU/ml). To evaluate the connection between serum and mucosal TG activity we used the experimental model of methotrexate induced acute hypoplastic enteropathy in the rat. Transglutaminase activity was unchanged in serum and mucosa 24 and 48 hours after MTX administration, but increased in mucosa (2.606 (0.95) v basal 0.207 (0.026) mU/mg protein, p less than 0.001) and significantly decreased in serum at 72 hours (2.08 (0.38) v basal 5.56 (1.50) mU/ml, p less than 0.001) during intestinal cell proliferation. Activity of the enzyme in the mucosa and serum returned to baseline levels within 120 hours. This experimental animal model helps to explain the data of TG activity in human intestinal mucosa and serum reported in this study. Results are mean (SD).
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PMID:Human serum transglutaminase and coeliac disease: correlation between serum and mucosal activity in an experimental model of rat small bowel enteropathy. 256 34

The distribution of intestinal transglutaminase was investigated by immunofluorescence microscopy using rabbit anti-guinea pig transglutaminase immunoglobulin. Transglutaminase-related antigen was demonstrated principally in the cytoplasm of villous core interstitial cells with some activity in the brush border region of the villous epithelial cells. Implications for the pathogenesis of coeliac disease are discussed.
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PMID:Immunofluorescent localization of transglutaminase in rat small intestine. 289 85

The action of tissue Transglutaminase (TGase) on specific protein-bound glutamine residues plays a critical role in numerous biological processes. Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated enteropathy, celiac disease (CD). The intestinal inflammation in CD is precipitated by exposure to wheat gliadin in the diet and is associated with increased mucosal activity of TGase. This enzyme has also been identified as the main target for CD-associated anti-endomysium autoantibodies, and is known to accept gliadin as one of its few substrates. We have examined the possibility that TGase could be involved in modulating the reactivity of gliadin specific T cells. This could establish a link between previous reports of the role of TGase in CD and the prevailing view of CD as a T-cell mediated disorder. We found a specific effect of TGase on T-cell recognition of gliadin. This effect was limited to gliadin-specific T cells isolated from intestinal CD lesions. We demonstrate that TGase mediates its effect through an ordered and specific deamidation of gliadins. This deamidation creates an epitope that binds efficiently to DQ2 and is recognized by gut-derived T cells. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of autoimmune disease.
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PMID:Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. 962 70

The prevalence of clinical celiac disease has been shown to vary both across time and between genetically similar populations. Differences in wheat antigenicity and transglutaminase substrate properties are a possible explanation for these differences. This study assessed the antigenicity and transglutaminase substrate specificities of gliadins from regions of high and low celiac disease prevalence. Gliadin was extracted from three commercial US wheat sources and two Irish sources. SDS-PAGE and western blotting revealed minor, but significant variations in the gliadin extracts. However, ELISA showed no difference in the antigenicity of these gliadins. Transglutaminase pretreatment of gliadin resulted in no significant change in gliadin antigenicity and kinetic studies showed that the Kms of the various gliadins were very similar. Purified IgA and IgG had no effect on transglutaminase activity. In summary, minor variations in wheat gliadins are unlikely to explain the observed differences in disease expression across genetically similar populations.
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PMID:No significant difference in antigenicity or tissue transglutaminase substrate specificity of Irish and US wheat gliadins. 1075 47

Transglutaminase 2 (tissue transglutaminase, TGase 2) was recently identified as an endomysial autoantigen in celiac disease (CD). Identification of how TGase 2 expression is increased may allow a better understanding of this autoimmune disease. Certain inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), and the Th type I cytokine interferon-gamma (INF-gamma) are abundant in CD. We have investigated whether these play a role in the regulation of TGase 2 expression in a model rat small intestinal epithelial cell line (IEC-6). After treatment for 24 h, TNF-alpha did not significantly alter TGase 2 mRNA or activity, but TGF-beta decreased mRNA and activity by 4-5-fold. IFN-gamma increased mRNA and TGase 2 activity by about 2-fold in 24 h and 5-fold by 5 days. Our new data suggest that increased TGase 2 expression in the upper small intestine of CD patients may be due to increased IFN-gamma expression, loss of TGF-beta signaling, or both.
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PMID:IFN-gamma induces transglutaminase 2 expression in rat small intestinal cells. 1216 78

Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca(2+)-dependent protein modifications. It acts as a G protein in transmembrane signalling and as a cell surface adhesion mediator, this distinguishes it from other members of the transglutaminase family. The sequence motifs and domains revealed in the recent TG2 structure, can each be assigned distinct cellular functions, including the regulation of cytoskeleton, cell adhesion and cell death. Ablation of TG2 in mice results in impaired wound healing, autoimmunity and diabetes, reflecting the number and variety of TG2 functions. An important role for the enzyme in the pathogenesis of coeliac disease, fibrosis and neurodegenerative disorders has also been demonstrated, making TG2 an important therapeutic target.
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PMID:Transglutaminase 2: an enigmatic enzyme with diverse functions. 1236 90

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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PMID:Proteomics identification of acyl-acceptor and acyl-donor substrates for transglutaminase in a human intestinal epithelial cell line. Implications for celiac disease. 1279 66

Transglutaminase (TGase)2 is an enzyme that is widely used in many biological systems for generic tissue stabilization or immediate defense for wounds. Many reports showed that TGase 2 is aberrantly activated in tissues and cells and contributes to a variety of diseases, including neurodegenerative diseases and autoimmune diseases. In most cases, TGase 2 appears to be a factor in the formation of inappropriate proteinaceous aggregates that may be cytotoxic. However, in other cases, such as celiac disease, arthritis, lupus, and amyotrophic lateral sclerosis, TGase 2 is involved in the generation of autoantibodies. This suggests the possibility that inappropriate expression and/or presentation of TGase 2 to T cells might contribute to these diseases in genetically predisposed individuals. We and others have found that TGase 2 expression is also increased in the inflammation process. Furthermore, we also demonstrated a reversal of inflammation by Tgase inhibition. This review will examine a possibility of TGase inhibitors as therapeutic agents in a variety of inflammatory diseases.
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PMID:New target against inflammatory diseases: transglutaminase 2. 1550 74

Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for anti-transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined.
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PMID:Narrative review: celiac disease: understanding a complex autoimmune disorder. 1571 Sep 62


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