Tissue transglutaminase, or tTG, is an enzyme that accelerates chemical reactions within the body. It is found in various tissues and performs a wide range of functions to maintain cellular and tissue integrity. However, tTG is most widely known for its involvement in celiac disease, where the body’s reaction to it is a primary signal for diagnosis.
The Normal Role of Tissue Transglutaminase
In a healthy body, tissue transglutaminase acts as a biological stabilizer, with one of its primary roles being wound healing. When tissue is damaged, tTG helps create a stable scaffold for repair by cross-linking proteins in the extracellular matrix. It forms strong bonds between proteins like fibronectin, which stabilizes the area and supports the migration of new cells to the injury site.
Beyond wound repair, tTG contributes to programmed cell death, known as apoptosis. When a cell becomes old or damaged, it is removed without causing inflammation in the surrounding tissue. During apoptosis, tTG is activated within the dying cell and polymerizes its internal skeletal structure. This process contains the cell’s contents, preventing them from leaking out and triggering an immune response as the cell is cleared away.
The enzyme also facilitates cell adhesion, helping cells attach to each other and to the extracellular matrix. This function is important for maintaining the structure and integrity of tissues and organs throughout the body.
The Connection to Celiac Disease
The function of tissue transglutaminase changes in individuals with celiac disease when gluten is consumed. Celiac disease is an autoimmune disorder in genetically susceptible people carrying the HLA-DQ2 or HLA-DQ8 gene variants. In these individuals, the immune system perceives gliadin, a protein in gluten, as a threat when it enters the small intestine and encounters tTG.
The tTG enzyme interacts directly with the gliadin protein, targeting specific glutamine residues and modifying them through a chemical reaction called deamidation. This reaction converts the neutral glutamine into a negatively charged glutamic acid. The newly deamidated gliadin peptide then binds with a much higher affinity to the HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells in the gut.
This high-affinity binding allows immune cells to present the gliadin peptide more effectively to T-cells. The result is the activation of an inflammatory response directed against the gliadin. This inflammation leads to the characteristic damage to the lining of the small intestine, including the flattening of the villi responsible for nutrient absorption.
The tTG enzyme does not escape this immune reaction. As tTG binds to gliadin to deamidate it, the two form a complex. The immune system begins to recognize the tTG enzyme itself as part of the threat, not just the gliadin. Consequently, the body generates autoantibodies that specifically target tissue transglutaminase, making the body’s own enzyme a target of the autoimmune attack.
Diagnostic Testing for Celiac Disease
The production of autoantibodies against tissue transglutaminase provides a marker for diagnosing celiac disease. High levels of these anti-tTG antibodies circulate in the blood of individuals with the untreated condition. A blood test to detect them has become the primary, minimally invasive screening method.
The most common screening test is the tissue transglutaminase IgA antibody (tTG-IgA) test, which measures the level of Immunoglobulin A (IgA) antibodies directed against tTG. IgA is the main antibody in mucous membranes, including the digestive tract where the gluten reaction occurs, making its presence in the blood a relevant indicator. The tTG-IgA test is recognized for its sensitivity and specificity in people consuming a gluten-containing diet.
A related test, the tTG-IgG, is used for individuals with selective IgA deficiency, a condition where they do not produce enough IgA antibodies. Since a tTG-IgA test would be falsely negative in these patients, doctors order a tTG-IgG test, which measures a different class of antibodies. This IgA deficiency is more common in people with celiac disease, affecting about 2-3% of this population.
Interpreting Test Results and Next Steps
The results of a tTG antibody test are reported as a numerical value. While laboratories have slightly different reference ranges, a result above a certain threshold is considered positive. A weak positive or borderline result may require further evaluation, while a negative result in a person consuming gluten makes celiac disease less likely.
A positive tTG antibody blood test is an indicator of celiac disease but is not a definitive diagnosis. The standard procedure following a positive result is a referral to a gastroenterologist for an endoscopic biopsy of the small intestine. During this procedure, a specialist obtains small tissue samples from the intestinal lining to be examined for damage, which confirms the diagnosis.
Once a diagnosis is confirmed by biopsy, the primary treatment is a strict, lifelong gluten-free diet. This removes the trigger for the autoimmune reaction, allowing the small intestine to heal. The tTG antibody test is also used to monitor dietary adherence, as antibody levels are expected to decrease and return to a normal range with strict gluten avoidance.