Tissue Transglutaminase in Celiac Disease: Role and Management
Tissue transglutaminase (tTG) is the primary autoantigen in celiac disease that plays a crucial role in disease pathogenesis by deamidating gluten peptides, making them more immunogenic, and serving as a target for autoantibodies that contribute to intestinal damage and must be managed through strict lifelong gluten-free diet.
Role of Tissue Transglutaminase in Celiac Disease Pathogenesis
Enzymatic Function and Autoimmunity
- tTG is a calcium-dependent ubiquitous enzyme that catalyzes post-translational modification of proteins and is released from cells during inflammation 1
- In the small intestine, tTG deamidates glutamine-rich gluten peptides (converting glutamines to negatively charged glutamic acid residues), which increases their immunogenicity and facilitates binding to HLA-DQ2 or HLA-DQ8 molecules 2
- This deamidation is a key step in celiac disease pathogenesis, as it enables the presentation of gluten peptides to CD4+ T cells, triggering the immune response 1
Dual Role in Celiac Disease
- tTG serves two crucial functions in celiac disease: as a deamidating enzyme enhancing gluten immunogenicity and as a target autoantigen in the immune response 1
- The humoral immune response in celiac disease is directed against both the exogenous antigen gluten and the autoantigen tTG 2
- Autoantibodies against tTG recognize distinct functional domains of the enzyme, with the N-terminal and C-terminal regions harboring the dominant epitopes 3
Contribution to Intestinal Damage
- tTG autoantibodies can induce cytoskeletal changes in intestinal epithelial cells and promote epithelial cell proliferation, potentially contributing to the pathological changes seen in celiac disease 4
- These autoantibodies interact with extracellular membrane-bound transglutaminase, playing a role in the epithelial cell proliferation characteristic of celiac disease 4
Diagnostic Utility of Tissue Transglutaminase
Serological Testing
- The discovery of tTG as the major autoantigen in celiac disease led to the development of highly sensitive and specific assays for IgA transglutaminase antibodies (TG2-IgA) 2
- TG2-IgA testing has become the first-line screening test for celiac disease with high sensitivity (93%) and specificity (98%) 2
- Human recombinant tTG-based ELISA tests have shown superior sensitivity compared to guinea pig tTG-based tests and comparable specificity to IgA antiendomysial antibodies (EMA) 5
Special Testing Considerations
- Since celiac disease is associated with selective IgA deficiency (occurring in 2.6% of celiac patients vs. 0.2% in general population), IgG anti-tTG antibodies may be used as alternative diagnostic markers 2
- In IgA-deficient patients, IgG deamidated gliadin peptides (DGP) are recommended as an option for testing 6
- For children under 2 years of age, combining tTG-IgA with IgG and IgA deamidated gliadin peptides is recommended for improved sensitivity 6
Diagnostic Algorithm
- Serological testing should be performed while patients are on a gluten-containing diet to avoid false negative results 6
- A quantitative serum IgA level should be obtained at the time of celiac disease screening to rule out IgA deficiency 7
- For patients with elevated tTG levels, referral to a gastroenterologist for small-bowel biopsy is recommended, even in the absence of gastrointestinal symptoms 7
- In adults, duodenal biopsy with histological analysis remains necessary for definitive diagnosis, while in some pediatric cases with high antibody titers, diagnosis may be possible without biopsy 2
Management Implications
Gluten-Free Diet
- The primary management of celiac disease involves strict adherence to a gluten-free diet, which eliminates the trigger (gluten) that activates tTG-mediated deamidation and subsequent immune response 2
- Successful dietary management leads to normalization of tTG antibody levels, which can be used to monitor treatment adherence 8
Monitoring Disease Activity
- Serial measurement of tTG antibody levels is useful for monitoring adherence to a gluten-free diet and disease activity 2, 8
- In treated celiac disease patients, persistent elevation of tTG antibodies may indicate ongoing gluten exposure or poor dietary compliance 8
Associated Conditions Management
- Pancreatic insufficiency is common in celiac disease and may require pancreatic enzyme supplementation in addition to a gluten-free diet 7
- For patients with chronic pancreatitis related to celiac disease, management should focus on gluten elimination, with celiac plexus block considered only in cases of debilitating pain unresponsive to other measures 7