Unexpected Role of Surface Transglutaminase Type II in Celiac Disease (original) (raw)
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Gastroenterology, 2007
See Leffler DA, et al on page 445 in the April 2007 issue of CGH Background & Aims: Tissue transglutaminase (tTG) autoantibodies are markers of celiac disease, and the enzyme is required for several crucial biological processes. The aim of this study was to determine whether these autoantibodies are involved in the pathogenesis of the mucosal lesion typical of celiac disease. Methods: Using rhodamine-conjugated phalloidin staining, we evaluated whether tTG antibodies, both commercially available and cloned from patients with celiac disease, cause cytoskeletal changes in Caco-2, MCF7, and NIH 3T3 cells. We monitored cell levels of bromodeoxyuridine incorporation to determine whether tTG autoantibodies are able to induce NIH 3T3 fibroblasts and epithelial mucosal cells into S phase. Results: Treatment with tTG antibodies caused a dose-dependent increase of membrane ruffling in Caco-2, MCF7, and NIH 3T3 cells. It also dose-dependently induced G 0-synchronized NIH 3T3 fibroblasts into S phase but did not affect the rate of apoptosis. Similarly, tTG antibodies induced S-phase entry of epithelial cells in cultured intestinal biopsy specimens from patients with celiac disease. They did not affect biopsy specimens from patients without celiac disease. Conclusions: Our results suggest that tTG autoantibodies per se, by interacting with the extracellular membrane-bound transglutaminase, may play an important role in epithelial cell proliferation in celiac disease.
Immunome Research, 2015
Tissue transglutaminase is a multifunctional enzyme, exerting intra and extracellular, enzymatic and nonenzymatic, Ca 2+ dependent and independent functions. Its specific autoantibody, the anti transglutaminase2 autoantibody is multifunctional, affecting many of the enzyme activities. Most of them are due to loss of function, the minority being gain of function of the enzyme. No beneficial protective effects, but only pathogenic ones, were assigned to those celiac disease associated anti TG2 autoantibodies. Taken together, celiac antibodies could collectively promote small bowel intestinal or extraintestinal damage. Yet, most of the transglutaminase2 autoantibody activities where explored in vitro and ex-vivo, very few in animal model but none in vivo, in human. The celiac disease serum contains numerous antibodies, IgA-transglutaminase2 is only one of them and up till now, its differential role in celiac disease induction and maintenance is far from being unraveled. Unraveling them might open some new therapeutic strategies for celiac disease.
Journal of Clinical Immunology, 2012
Purpose Celiac disease is an autoimmune-mediated enteropathy characterized by adaptive and innate immune responses to dietary gluten in wheat, rye and barley in genetically susceptible individuals. Gluten-derived gliadin peptides are deamidated by transglutaminase 2 (TG2), leading to an immune response in the small-intestinal mucosa. TG2 inhibitors have therefore been suggested as putative drugs for celiac disease. In this proof-of-concept study we investigated whether two TG2 inhibitors, cell-impermeable R281 and cell-permeable R283, can prevent the toxic effects of gliadin in vitro and ex vivo. Methods Intestinal epithelial Caco-2 cells were treated with peptic-tryptic-digested gliadin (PT-gliadin) with or without TG2 inhibitors and thereafter direct toxic effects (transepithelial resistance, cytoskeletal rearrangement, junction protein expression and phoshorylation of extracellular-signal-regulated kinase 1/2) were determined. In an organ culture of celiacpatient-derived small-intestinal biopsies we measured secretion of TG2-autoantibodies into the culture medium and the densities of CD25-and interleukin (IL) 15-positive cells, forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) and Ki-67positive proliferating crypt cells. Results Both TG2 inhibitors evinced protective effects against gliadin-induced detrimental effects in Caco-2 cells but the cellimpermeable R281 seemed slightly more potent. In addition, TG2 inhibitor R281 modified the gluten-induced increase in CD25and IL15-positive cells, Tregs and crypt cell proliferation, but had no effect on antibody secretion in celiac-patient-derived biopsies. Conclusions Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo.
BMC Immunology, 2008
In celiac disease gluten, the disease-inducing toxic component in wheat, induces the secretion of autoantibodies which are targeted against transglutaminase 2 (TG2). These autoantibodies are produced in the smallintestinal mucosa, where they can be found deposited extracellularly below the epithelial basement membrane and around mucosal blood vessels. In addition, during gluten consumption these autoantibodies can also be detected in patients' serum but disappear from the circulation on a gluten-free diet. Interestingly, after adoption of a gluten-free diet the serum autoantibodies disappear from the circulation more rapidly than the small-intestinal mucosal autoantibody deposits. The toxicity of gluten and the secretion of the disease-specific autoantibodies have been widely studied in organ culture of small-intestinal biopsy samples, but results hitherto have been contradictory. Since the mucosal autoantibodies disappear slowly after a gluten-free diet, our aim was to establish whether autoantibody secretion to organ culture supernatants in treated celiac disease patient biopsies is related to the duration of the diet and further to the preexistence of mucosal TG2-specific IgA deposits in the cultured biopsy samples.
Clinical Immunology, 2006
The aim of the present study was to evaluate the epitope specific humoral human tissue transglutaminase (tTG) immunoreactivity against 3 different human recombinant tTG constructs [(full-length tTG (a.a. 1-687), tTG (a.a. 227-687); tTG (a.a. 473-687)] before and after the introduction of a gluten-free diet (GFD). To this end, sera from 64 celiac disease (CD) subjects on a gluten-containing diet (44 f, 20 m) and after 0.6 F 0.3 years and 2.1 F 1.3 years of GFD were studied using a quantitative radioimmunoprecipitation assay. All 64 CD patients at diagnosis were full-length anti-tTG (a.a. 1-687)Ab positive. These Abs significantly decreased in frequency and titer after 6 months and 2 years of GFD. However, at low titers, 64.1% (41/64) of CD patients were still fl-tTG (a.a. 1-687)Ab positive after 2 years of GFD. At disease diagnosis, 70.3% (45/64) of the CD patients had Abs directed against fragments (227-687) and/or (473-687) of the tTG protein. This percentage, after 2 years of GFD, significantly decreased to 18.7%, whereas almost 50% of GFD patients had no tTG (227-687) and tTG (473-687) fragment reactivity, but only persistent, low-titer full-length tTG (1-687)Abs. We suggest that the selective loss of immunoreactivity against tTG (227-687) and tTG (473-687) fragments in CD patients with a 1521-6616/$ -see front matter D a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m w w w . e l s e v i e r . c o m / l o c a t e / y c l i m GFD, could be due to quantitative decrease of autoreactivity driven by tTG-gliadin interaction underlying celiac disease pathogenesis. D