Celiac disease (CD) is a chronic autoimmune condition triggered by the ingestion of gluten, a protein found in wheat, barley, and rye. In individuals with a specific genetic predisposition, the immune system mistakenly targets the body’s own tissues following gluten exposure. The key target of this misguided immune response is an enzyme called tissue transglutaminase (TTG), making it the primary self-antigen in the disease. Understanding the function of TTG, how it becomes involved in the immune response, and its role in diagnostic testing is central to managing celiac disease.
The Role of Tissue Transglutaminase in the Body
Tissue transglutaminase (TGM2) is a naturally occurring protein widely distributed throughout the body. Its normal function is to catalyze cross-linking, a reaction that creates strong, stable bonds between proteins. This calcium-dependent enzymatic activity is important for constructing and maintaining the structural integrity of the extracellular matrix.
TTG plays a significant part in wound healing and tissue repair by stabilizing damaged tissue and promoting cell adhesion. It also has roles in various cellular processes, including cell survival, programmed cell death (apoptosis), and cell differentiation.
The Autoimmune Mechanism of Celiac Disease
The pathology of celiac disease begins when gluten, rich in the protein fraction gliadin, is only partially digested in the small intestine. These protease-resistant gliadin peptides pass through the intestinal lining and enter the underlying connective tissue, the lamina propria. Here, the peptides encounter the TTG enzyme, which is activated by inflammation in the gut wall.
TTG modifies specific glutamine amino acids within the gliadin peptides through deamidation. This process converts neutral glutamine residues into negatively charged glutamic acid residues. This chemical change transforms the gliadin peptide into a highly immunogenic molecule.
The newly modified, deamidated gliadin peptides have a much stronger affinity for specific immune receptors, the HLA-DQ2 and HLA-DQ8 molecules, present on antigen-presenting cells in genetically susceptible individuals. These receptors bind the deamidated peptides and present them to T-cells. T-cell activation initiates a powerful inflammatory cascade that attacks the intestinal lining, causing the characteristic villous atrophy of celiac disease.
The body also produces autoantibodies that target the TTG enzyme itself. These anti-TTG autoantibodies are a measurable marker of the disease, reflecting the immune system’s attack on the TTG protein. The resulting immune response is directed against both the gluten component and the TTG host protein.
Diagnostic Testing and Interpretation
The discovery of TTG’s role led to the development of the anti-TTG antibody assay, a highly sensitive and specific blood test for celiac disease. The standard diagnostic test measures the immunoglobulin A (IgA) class of anti-TTG antibodies (IgA anti-tTG). Since many individuals with celiac disease also have IgA deficiency, a total IgA level must be measured concurrently.
If a patient is IgA deficient, the IgA anti-tTG test will be falsely negative. Clinicians must then rely on immunoglobulin G (IgG) based alternatives, such as IgG anti-tTG or IgG anti-deamidated gliadin peptide (DGP) antibodies. For the serology test to be accurate, the patient must be consuming a gluten-containing diet, typically for several weeks, before the blood is drawn.
A positive result is reported as a titer, reflecting the concentration of antibodies. A strongly positive result, often defined as ten times the upper limit of normal (ULN), is highly indicative of celiac disease. In children, a very high titer may sometimes allow for diagnosis without an intestinal biopsy, depending on clinical guidelines. Although the anti-TTG blood test is the primary screening tool, a positive serology result often requires confirmation with an endoscopy and small bowel biopsy to observe characteristic damage to the intestinal villi.
Monitoring Disease Activity
Once a diagnosis is confirmed and a patient begins a strict gluten-free diet (GFD), anti-TTG antibody levels serve as a tool for monitoring the disease. Adherence to the GFD should lead to a gradual reduction in the autoantibody titer as the small intestine heals and the inflammatory stimulus is removed. The half-life of the IgA anti-tTG antibody is approximately 30 to 60 days, meaning the concentration should halve within that timeframe on a successful diet.
Normalization of the TTG titer, where levels drop back into the negative range, suggests the patient is following the GFD and that mucosal healing is likely occurring. This process is not immediate; antibodies may take up to a year or more to fully normalize. Periodic monitoring, often every six to twelve months, is performed to ensure continued dietary compliance and assess the long-term response to treatment.
Persistently elevated or slowly declining anti-TTG levels indicate that a patient may still be consuming gluten, perhaps unknowingly through cross-contamination or hidden ingredients. In rare cases, persistently elevated antibodies despite strict adherence may suggest refractory celiac disease, a more complex form of the condition. The anti-TTG level thus acts as an objective, measurable biomarker for treatment effectiveness.