Tissue transglutaminase: master regulator of celiac disease?

In 1997, Dieterich and colleagues (1) described that tissue transglutaminase (tTG) is the target of the endomysium specific autoantibodies that are characteristic for celiac disease (CD). As the result of that seminal observation, a series of studies (2–6) have revealed that screening for the presence of tTG-specific antibodies is a very specific indicator for disease and an article in the current issue of the JPGN strengthens that view (7). In addition, there is now overwhelming evidence that tTG is not only linked to the humoral response but is also involved in generating gluten peptides that stimulate T cells present in the small intestine of CD patients (8–13). Due to the activity of tTG glutamine residues in glutenderived peptides are converted into glutamic acid. This introduction of negative charges results in peptides that bind with relatively high affinity to the diseaseassociated HLA-DQ2 or HLA-DQ8 molecules and trigger inflammatory T-cell responses (8–15). This provides a satisfactory explanation for the well-known fact that CD is almost exclusively found in HLA-DQ2 or HLADQ8 positive individuals (16). The importance of the modification of gluten by tTG has been underscored by the observation that the enzyme specificity correlates with the toxicity of cereals for CD patients (13). We found that the enzyme specificity could be combined with the requirements for peptide binding to HLA-DQ2 and that this resulted in search patterns that identified T-cell stimulatory peptides in wheat, barley, and rye but not in oats, the latter of which is considered safe for celiac disease patients (17). Truly, therefore, tTG can be considered a master regulator of CD, involved in both the humoral and cellular immune response and tightly linked to cereal toxicity. Together, these observations have raised multiple questions: why do CD patients make tTG-specific antibodies? Do we still require a small intestinal biopsy for diagnosis since tTG-specific antibodies are such a good indicator of disease? Can we design protocols for mass screening for detecting silent disease? Can we use this knowledge to develop an alternative therapy or better disease prevention? As shown by Agardh et al. in this issue of the JPGN (7), an intestinal biopsy remains the gold standard diagnostic procedure for CD, as a number of patients have false positive or negative results of their “celiac” serum antibodies. On the other hand, the determination of IgAtTG antibodies in serum is an accurate instrument for screening of CD, especially when preformed in for CD genetic-predisposed individuals carrying the HLA-DQ haplotypes associated with the disease (18). However, to decide whether mass screening programs for CD are worthwhile we need more information, among others, on the natural history of CD and on the health effects and costs associated with such screening programs. It is likely, for example, that large-scale screening will identify many individuals with “silent” CD but it is unknown what the long-term benefits of this will be. Why do CD patients make tTG specific antibodies? The most likely explanation was put forward by Sollid and collegues (19). tTG can crosslink itself to gluten and these gluten-tTG complexes will be taken up by B-cells that express tTG-specific immunoglobulin on their membrane. As the result of this uptake, the gluten-tTG complex will be degraded intracellularly and gluten peptides will bind to HLA-DQ and be expressed on the cell surface. In CD patients, glutenspecific T cells will recognize this HLA-DQ-gluten peptide complex and this results in T cell “help” for the production of tTGspecific antibodies by the B cells. Since only CD-patients have measurable numbers of glutenspecific T cells, this explains why only CD patients make tTG-specific antibodies and the antibody titers drop after gluten withdrawal. This editorial accompanies an article. Please see Tissue Transglutaminase Immunoglobulin Isotypes in Children With Untreated and Treated Celiac Disease. D. Agardh, S. Borulf, A. Lernmark, S.A. Ivarsson. J Pediatr Gastroenterol Nutr 2002;36:77–82. Journal of Pediatric Gastroenterology and Nutrition 36:9–11 © January 2003 Lippincott Williams & Wilkins, Inc., Philadelphia