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.

Celiac disease: diagnostic criteria in progress

“…This leads to increased production of cytokines (e.g., interleukin-15, interferon-c and tumor necrosis factor-a), which recruit nonspecific effector cells responsible for initial tissue damage. The identification of tissue transglutaminase (tTG or TG2) as the predominant autoantigen of CD has allowed researchers to gain new insights into the pathogenesis of this disorder; 12 tTG belongs to a family of cytoplasmic calcium-dependent enzymes found in endothelial cells, erythrocytes, hepatocytes, lamina propria and small intestine epithelial cells. Damage to, or hyperpermeability of, the small intestine mucosa, caused by either toxic gluten fractions or other irritants, triggers the abundant extracellular release of cytosolic tTG.…”

Diagnostic efficacy of the ELISA test for the detection of deamidated anti‐gliadin peptide antibodies in the diagnosis and monitoring of celiac disease

“…It is the trigger factor of celiac disease (CD), as it triggers an immune response by the T lymphocytes with subsequent production of cytokines, anti-gliadin antibodies (AGAs) and anti-tissue transglutaminase antibodies (anti-tTG) (1)(2)(3)(4). This cascade of events requires some predisposing situations, namely (in order of importance): intake of gluten with the diet, increased permeability of the intestinal mucosa, a predisposing genetic makeup characterized by the presence of HLA molecules of class II DQ2 or DQ8 (5)(6)(7).…”

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

“…41 This TfR-mediated retrotranscytosis triggers intestinal inflammation as a result of a progressive accumulation of toxic gliadin peptides in subepithelial areas, initiating CD enteropathy. In the lamina propria, gliadin peptides encounter tissue transglutaminase 2 (TG2), the celiac autoantigen, 43 which selectively deamidates gluten protein, converting glutamine into glutamic acid (Figure 2). 44 This post-translational process may link the immune response against wheat with autoimmunity in the gut.…”