Contribution of Celiac Disease Autoantibodies to the Disease Process

Katri Lindfors; Katri Kaukinen


Expert Rev Clin Immunol. 2012;8(2):151-154. 

In This Article

Abstract and Introduction


Transglutaminase 2 is a multifunctional protein involved in cellular adhesion. Moreover, transglutaminase 2 has been identified as the autoantigen in celiac disease, and in untreated celiac disease, in addition to being present in the serum, the transglutaminase 2-targeted autoantibodies are bound to their antigen in the basement membrane underlining the small-bowel mucosal epithelium. Furthermore, the disease-specific transglutaminase 2-targeted autoantibodies have been experimentally shown to exert various biological effects on different cell types. Using Caco-2 intestinal epithelial cells, it has now also been demonstrated that serum transglutaminase 2-targeted autoantibodies from untreated celiac patients inhibit the adhesion of these cells. These findings provide an important direction for future research to improve our general understanding of celiac disease pathogenesis and especially the role of the disease-specific autoantibodies during the progression of the disorder.


The mucosal immune response is considered a central event in the pathogenesis of celiac disease, an enteropathy triggered by a single and well-characterized exogenous antigen – gluten – derived from dietary wheat, rye and barley. Ingestion of gluten by celiac patients leads to the development of small intestinal villous atrophy, crypt hyperplasia and inflammation paralleled by the appearance of clinical symptoms such as malabsorbtion and diarrhea. Both innate and adaptive immune responses are thought to contribute to the development of the disease-characteristic small-bowel mucosal lesion. Gastrointestinal enzymes are not able to completely proteolyse gluten-derived gliadin, and thus even fairly long peptides reach the small intestine. Once they have gained access to the lamina propria, a subset of the gliadin peptides are post-translationally modified, namely deamidated, by an enzyme called transglutaminase 2 (TG2), and this event is considered to be the cornerstone in the activation of the adaptive immune system.[1] Experimental evidence also points to autoimmunity as a contributor in celiac disease. Celiac disease autoimmunity is best exemplified by the presence of disease-specific endomysial autoantibodies, which have experimentally been shown to target TG2.[2] The significance of these autoantibodies in the pathogenesis of celiac disease remains a controversial issue, although there are data from cell based experiments demonstrating their ability to induce biological effects in many different cell types.[1]

The celiac disease autoantigen, TG2, is a ubiquitously expressed protein with a number of functions in several cellular processes, such as apoptosis, fibrosis, wound healing and adhesion.[3] Its enzymatic functions include the aforementioned deamidation, as well as transamidation. TG2-mediated transamidation reactions can lead to acylation, amine incorporation or protein cross-linking, the latter being involved in cell adhesion by taking part in extracellular matrix protein cross-linking.[3] However, the protein has also been ascribed a role in adhesion independent of its enzymatic functions. TG2 interacts with fibronectin and functions as its integrin-binding adhesion coreceptor.[4] Moreover, TG2 is directly associated with heparin sulfate chains of syndecan-4, this interaction being of major importance in integrin-independent adhesion.[5]

In the small intestinal mucosa, epithelial cells are attached to the basement membrane situated directly beneath them. The subepithelial basement membrane consists of numerous proteins, including fibronectin and TG2, and interestingly, celiac patients have TG2-targeted IgA-class autoantibodies deposited there.[6] In spite of the overall importance of the basement membrane and especially TG2 in adhesion, investigators have not addressed the effect of celiac disease-specific TG2-targeted autoantibodies on intestinal epithelial cell adhesion. A recent study published by Teesalu and coworkers has now addressed this issue and described how celiac patient TG2-autoantibodies influence intestinal epithelial cell adhesion.[7]