Identification of tissue transglutaminase as the autoantigen of celiac disease.
ABSTRACT Celiac disease is characterized by small intestinal damage with loss of absorptive villi and hyperplasia of the crypts, typically leading to malabsorption. In addition to nutrient deficiencies, prolonged celiac disease is associated with an increased risk for malignancy, especially intestinal T-cell lymphoma. Celiac disease is precipitated by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Gliadin initiates mucosal damage which involves an immunological process in individuals with a genetic predisposition. However, the mechanism responsible for the small intestinal damage characteristic of celiac disease is still under debate. Small intestinal biopsy with the demonstration of a flat mucosa which is reversed on a gluten-free diet is considered the main approach for diagnosis of classical celiac disease. In addition, IgA antibodies against gliadin and endomysium, a structure of the smooth muscle connective tissue, are valuable tools for the detection of patients with celiac disease and for therapy control. Incidence rates of childhood celiac disease range from 1:300 in Western Ireland to 1:4700 in other European countries, and subclinical cases detected by serological screening revealed prevalences of 3.3 and 4 per 1000 in Italy and the USA, respectively. IgA antibodies to endomysium are particularly specific indicators of celiac disease, suggesting that this structure contains one or more target autoantigens that play a role in the pathogenesis of the disease. However, the identification of the endomysial autoantigen(s) has remained elusive. We identified tissue transglutaminase as the unknown endomysial autoantigen. Interestingly, gliadin is a preferred substrate for this enzyme, giving rise to novel antigenic epitopes.
Full-textDOI: · Available from: Detlef Schuppan, Oct 08, 2014
SourceAvailable from: Knut E A Lundin[Show abstract] [Hide abstract]
ABSTRACT: Coeliac disease is a common and important gastrointestinal disease. It affects at least 1%, most Western European populations and in Nordic countries it is even more frequent. It is strongly associated with certain Human Leukocyte Antigen-DQ genes and triggered by ingestion of wheat gluten and related cereals from rye and barley. The diagnosis relies on a combination of clinical signs, serology and small intestinal biopsy. Work during the last couple of decades has shown that gluten-specific, Human Leukocyte Antigen-DQ-restricted T-cells in the intestinal mucosa are of paramount importance in the disease process. The gluten peptides are chemically modified by the endogenous enzyme transglutaminase 2, the same enzyme that serves as target in today's sensitive serological tests for coeliac disease. The increasing knowledge on the disease process allows for development of improved diagnosis, patient care and new treatment modalities.Scandinavian Journal of Gastroenterology 04/2015; DOI:10.3109/00365521.2015.1030766 · 2.33 Impact Factor
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ABSTRACT: While the central role of an adaptive, T cell-mediated immune response to certain gluten peptides in celiac disease is well established, the innate immune response to wheat proteins remains less well defined. We identified wheat amylase trypsin inhibitors (ATIs), but not gluten, as major stimulators of innate immune cells (dendritic cells > macrophages > monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2 toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17 proteins with molecular weights of around 15 kDa and a variable primary but conserved secondary structure characterized by 5 intrachain disulfide bonds and alpha helices. They mostly form di- and tetramers that appear to equally activate TLR4. Relevant biological activity is confined to ATIs in gluten-containing cereals, while gluten-free cereals display no or minimal activities. ATIs represent up to 4% of total wheat protein and are highly resistant to intestinal proteases. In line with their dose-dependent function as co-stimulatory molecules in adaptive immunity of celiac disease, they appear to play a role in promoting other immune-mediated diseases within and outside the GI tract. Thus, ATIs may be prime candidates of severe forms of non-celiac gluten (wheat) sensitivity. © 2015 S. Karger AG, Basel.Digestive Diseases 04/2015; 33(2):260-3. DOI:10.1159/000371476 · 1.83 Impact Factor
01/2011; 01(03). DOI:10.4172/2155-952X.1000102e