Tissue Transglutaminase Triggers Celiac Disease

The answer to what triggers celiac disease is a combination of factors including genetics, gluten exposure, tissue transglutaminase, internal gut environment, and external environmental factors. We will explain each in greater detail and how these contribute to developing celiac disease.

A quick definition of celiac disease: in reaction to eating gluten, an immune response is triggered that attacks the small intestine and damages the villi that line the small intestine. When the villi get damaged, nutrients cannot be absorbed properly into the body.

What triggers celiac disease: genetics
People with celiac disease have immunologic agents known as human leukocyte antigens (HLAs).

One such antigen, HLA DQ2, plays an important role in gluten intolerance/celiac disease. Each HLA subtype is capable of recognizing and binding to a specific foreign protein. This HLA and foreign-protein-binding-pair form what is known as a “complex.” The creation of this complex signals a specific type of white blood cell (a T Cell) to initiate an immune response.

In people with celiac disease, HLA DQ2 specifically binds to gluten, and the resulting complex, then triggers T cells located in the small intestine, which leads to inflammation.

What triggers celiac disease: external environment
Several environmental factors have been proposed, including exposure to toxic metals and toxic chemicals; infectious agents, including bacteria and viruses. Significant stress and trauma have also been identified in many cases. 

What triggers celiac disease: gluten exposure
Why gluten?

As gluten is not digestible by humans, our enzymes can only break gluten apart into large fragments.

Left on their own, these large gluten fragments wouldn’t cause any problems. They’d be excreted along with the other unusable parts of the food we eat. But in genetically susceptible individuals, in combination with certain environmental factors, the interaction of gluten fragments with tissue transglutaminase (tTG) launches an immunological chain reaction.

tTG is a common enzyme found in many locations throughout the body including the cells residing below the inner lining of the small intestine.

In the small intestine when tTG interacts with gluten protein fragments, this causes a biochemical change—deamidation—that primes gluten fragments to set off a widespread immune response.

tTG and HLA: A perfect storm
HLA DQ2s and DQ8s will not normally interact with gluten fragments. But when the enzyme tTG changes a gluten fragment in the process of deamidation, the modified gluten protein structure causes it to be snatched up by HLA DQ2 and DQ8 antigen-displaying proteins. In a series of responses, your body now reacts to the gluten proteins as if they were a threat.

What triggers celiac disease: internal gut environment
A major research question asks: why do only a small proportion of people who are genetically susceptible to gluten intolerance develop symptoms?

Approximately 40% of individuals have the HLA DQ2 and HLA DQ8 genes, but only 1% of them will develop celiac disease.

Why is that?

The key to understanding this difficult question is that genetics is not the only important factor. How the genetic sequence is expressed is very important, but the internal environment of the individual also represents a critical dynamic.

pyramid depicting spectrum of gluten intolerance

Why one person develops celiac disease and another won’t even if both are genetically susceptible.

Person A and person B may have an identical genetic sequence. Both may have sequences coding for antigen-presenting HLA DQ. But only person A will manufacture DQ2 or DQ8 proteins and possibly develop gluten intolerance, all owing to person A’s internal molecular environment.

Why does this happen? This goes back to tTG.

How do gluten proteins in the small intestine come in contact with tTG, which is contained within certain cells in the lamina propria, which is protected by the epithelial barrier—a sort of “wall” that is supposed to prevent foreign materials from gaining access to the cells and tissues of the host? Environmental triggers.

Bacterial and viral infections cause immune responses and inflammatory reactions that can break down structures in the small intestine; leading to increased permeability (the “wall” becomes more permeable). Similarly, a sufficiently high fever, prolonged use of antibiotics or NSAIDs, poor diet, excessive alcohol intake, stress, and yeast overgrowth can lead to increased permeability. Infection, inflammation, and wound healing may also cause the release of tTG from cells in the lamina propria. All of these things can contribute to increased gut permeability allowing gluten protein fragments to come into contact with the now-available tTG.

Going back to the previous statement that person A’s internal environment is a contributing factor to developing celiac disease or not. Person A’s internal environment depends to a large extent on his or her external environment, as just mentioned. Has the person experienced frequent infections or fevers? Have they used antibiotics or NSAIDs for an extended period of time? Do they have a poor diet? If any of these are true, this could be the contributing factor that leads person A to develop celiac disease or gluten intolerance while person B doesn’t.

Another common question related to gluten exposure relates to the length of exposure. Will the amount of time I’ve been exposed to gluten increase my chance of developing additional autoimmune diseases?

The amount of time a genetically predisposed individual is exposed to gluten has been shown to be directly correlated with the risk of developing additional autoimmune diseases. A large multicenter trial conducted in Italy studied more than 900 patients with celiac disease.

Overall, the prevalence of autoimmune disorders in this group was 14%, compared to a prevalence of 2.8% in 1268 controls. Additionally, the prevalence of autoimmune diseases increased in patients with celiac disease the longer celiac disease remained undiagnosed or, in other words, the longer these patients were exposed to gluten.

For example, in patients in whom celiac disease was diagnosed before the age of two, only 5% of these individuals had an associated autoimmune disorder. In marked contrast, in patients who were older than age 20 before they received a diagnosis of celiac disease, 34% had an associated autoimmune disease.

Of the study patients with celiac disease, 36 (4%) also had type 1 diabetes, 32 (3.5%) had dermatitis herpetiformis, 12 (1.3%) had mixed connective tissue disease, 12 (1.3%) had autoimmune thyroiditis, 10 (1.1%) had autoimmune hepatitis, and 4 (0.4%) had cerebellar ataxia. Overall, the prevalence of autoimmune disease in young adult and adolescent patients with celiac disease is much higher than in the general population.

While cutting gluten from the diet is a main step in healing from celiac disease, it may not be the only contributing factor. When putting together the complete picture of what triggers celiac disease, a combination of factors should be considered.

How to Diagnose Gluten Intolerance and Celiac Disease in Children, Teenagers, and Adults

Testing for gluten intolerance can be divided into three categories: non-invasive, minimally invasive, and invasive.

The non-invasive approach involves going on a gluten-free diet for at least 3 months. This strategy is known as the elimination diet or the gluten challenge. After going gluten-free for 3 months you introduce gluten back into your diet and see how you react. If your symptoms come back, it is worth it to stick to the diet.

The minimally invasive approach involves blood testing to detect the presence of characteristic autoantibodies, while the invasive approach involves a biopsy of the small intestine (explained below).

What are the symptoms of gluten intolerance?

  • Abdominal bloating
  • Abdominal pain
  • Anemia
  • Behavior problems (especially for children and teens)
  • Constipation
  • Diarrhea
  • Malnutrition
  • Markedly short stature (especially for children and teens)
  • Markedly underweight (especially for children and teens)
  • Nausea
  • Vomiting

How to test for gluten intolerance: non-invasive

Gluten-free diet

The gold standard for diagnosis is the body’s response to a three-month gluten-free diet. If the anti-tissue transglutaminase (tTG) autoantibody is present and/or the person tests positive for the HLA DQ2 or HLA DQ8 genetic marker, the next step is to begin a strict gluten-free diet. If your symptoms have begun to improve by the end of the three-month gluten-free trial, then gluten intolerance and/or celiac disease is an accurate diagnosis. It’s important to remember that other diseases—including autoimmune diseases—may also be present. Regardless, a strict gluten-free diet is the first step on the road to recovery.

How to test for gluten intolerance: minimally invasive blood tests

Test One: Anti-tissue transglutaminase

The most accurate of these serum immunoglobulin tests measures levels of anti-tissue transglutaminase antibody (tTG). An increase in anti-tTG antibody concentration is found in almost all cases of celiac disease.

Test Two: Anti-gliadin antibodies
A second immunological test measures anti-gliadin antibodies (gliadin is a large protein fragment derived from the partial digestion of gluten). Anti-gliadin antibodies are less predictive of celiac disease as they are identified in other diseases as well, but anti-gliadin antibodies indicate the presence of gluten intolerance.

Test Three: Genetic markers HLA DQ2/HLA DQ8
Testing for genetic markers may also be performed. More than than 97% of patients with celiac disease have HLA DQ2 and/or HLA DQ8 antigen-displaying proteins. A positive test—indicating the presence of DQ2 and DQ8 genes—is a very strong predictor that a person has gluten intolerance and celiac disease.

How to test for gluten intolerance: invasive biopsy
Additionally, your doctor may recommend a biopsy of the small intestine. Small tissue samples are obtained using an endoscope, a thin flexible tube. Biopsy material is evaluated for the presence of characteristic changes associated with the chronic inflammation of celiac disease. However, a small intestinal biopsy is not particularly sensitive, as many people with gluten intolerance and celiac disease do not have inflammatory changes. In other words, you may have celiac disease and yet have a normal-appearing small intestine.

If you are diagnosed with gluten intolerance or celiac disease, it is a good idea to get tested for other autoimmune diseases. Gluten intolerance (not necessarily celiac disease) can trigger a chain of immunological and metabolic events eventually causing certain chronic inflammatory and autoimmune diseases. The overall prevalence of autoimmune disease in individuals suffering from gluten intolerance/celiac disease is quite high and our estimation is in the vicinity of 20-30%.

It is much easier to treat gluten-driven autoimmune diseases at their early stages compared to the advanced ones when the diet as a solo therapeutic approach is not sufficient enough. Therefore, it is strongly advised to screen all patients with gluten intolerance/celiac disease for coexistent autoimmune/chronic inflammatory diseases. The extent of the screening depends on the results of an individual’s medical history, physical examination as well as experience of the treating physician.

If you are experiencing the signs and symptoms of gluten intolerance there are several ways to get diagnosed. It is best to consult with your doctor to find the right test for you.