Transglutaminase 2 (TTG2) is an enzyme found widely throughout the human body. This protein modifier plays a part in numerous cellular processes, operating within and outside cells. TTG2’s primary function involves altering proteins by forming strong bonds between specific amino acid residues. Its activities vary depending on the tissue and cellular environment where it is found.
Normal Functions of TTG2
TTG2 normally functions as a transamidase, creating stable isopeptide bonds that cross-link proteins. This action typically involves joining a glutamine residue from one protein to a lysine residue on another, or within the same protein. Such cross-linking can significantly alter protein stability, solubility, and overall function. These modifications are important for processes like tissue repair, where TTG2 helps stabilize the extracellular matrix, the supportive network surrounding cells.
The enzyme also maintains the structural integrity of various tissues, contributing to the assembly and organization of proteins. For example, it helps form strong, insoluble protein networks important for skin and hair structure. Beyond structural roles, TTG2 influences cell growth and survival by modulating cell adhesion and signaling pathways. It also contributes to programmed cell death, known as apoptosis, by cross-linking proteins inside dying cells, facilitating their removal.
TTG2 and Celiac Disease
In individuals with celiac disease, TTG2 takes on a different, harmful role following gluten consumption. When gluten enters the small intestine, it is partially broken down into smaller peptides, including gliadin. TTG2 then acts on these gliadin peptides, deamidating glutamine residues by converting them into glutamic acid. This modification changes the electrical charge of the peptides, making them more reactive.
These deamidated gliadin peptides have a stronger affinity for specific immune molecules called HLA-DQ2 or HLA-DQ8, present on antigen-presenting cells in genetically susceptible individuals. This enhanced binding leads to a heightened T-cell immune response, where immune cells mistakenly identify these modified peptides as foreign invaders. During this process, the body’s immune system also recognizes TTG2 itself as a target, generating autoantibodies against it.
This autoimmune reaction results in chronic inflammation within the small intestine. The continuous immune assault damages the villi, small, finger-like projections in the small intestine responsible for nutrient absorption. This damage, known as villous atrophy, impairs nutrient absorption, leading to various health complications. The presence of these autoantibodies against TTG2 is a hallmark of active celiac disease.
Using TTG2 Antibodies for Diagnosis
The presence of anti-TTG2 antibodies in celiac disease has become a reliable diagnostic marker. Anti-TTG2 antibodies, specifically of the IgA class (anti-tTG IgA), are commonly measured in blood tests. These antibodies are highly sensitive and specific for celiac disease. For accurate testing, individuals must be consuming gluten regularly for several weeks prior to the blood draw.
A positive anti-tTG IgA test often prompts further investigation, typically including a small intestinal biopsy to confirm the diagnosis by observing villous atrophy. For individuals with an IgA deficiency, an anti-tTG IgG antibody test is used instead. Measuring these antibody levels also helps monitor disease progression and adherence to a gluten-free diet. As the small intestine heals on a gluten-free diet, anti-TTG2 antibody levels typically decrease over time.
Other Roles of TTG2
Beyond its established role in celiac disease, TTG2 is being investigated for its involvement in several other health conditions. Researchers have explored its connection to various types of cancer, where TTG2 may influence cell survival, drug resistance, and the spread of cancerous cells. Its activity can promote tumor growth and metastasis in some contexts, such as certain ovarian or breast cancers. These roles are still under active research and are not yet fully understood or clinically applied.
TTG2 also has potential implications in neurodegenerative diseases, including Huntington’s disease and Alzheimer’s disease. In these conditions, the enzyme’s protein cross-linking capabilities may contribute to the formation of abnormal protein aggregates, characteristic features of neurodegeneration. Furthermore, TTG2 has been implicated in fibrotic conditions, such as liver cirrhosis and pulmonary fibrosis, where it contributes to excessive tissue scarring and extracellular matrix remodeling. While promising for research, TTG2’s direct clinical application in these areas is not as established as its diagnostic role in celiac disease.