Coeliac Disease – Symptoms, Aetiology and More: How an understanding of tissue transglutaminase 2 autoimmunity can enable practitioners to resolve many different disorders in the community By Dr. Peter H Kay, PhD, FCMA
Introduction
Coeliac disease (CD – spelled “Celiac” in the USA), is an autoimmune disorder in which the immune machinery targets the enzyme tissue transglutaminase 2 (tTG).
For many years, it was thought that CD was an uncommon gastrointestinal disorder that mainly affected children who appeared to suffer from malnutrition. Common symptoms included growth retardation and diarrhoea.
In recent years, however, investigations have revealed that it is an autoimmune disease. Because of the discovery of the causative autoimmune processes, specific and sensitive diagnostic tests for CD have been developed. The application of these new tests has shown that at least 1% or more of the population of all ages suffer from this disorder. It is thought that many others suffer from undiagnosed CD.
Coeliac Disease symptom profile
Those who suffer from autoimmune tTG or Coeliac Disease may exhibit a wide range of symptoms including bloating, diarrhoea, nausea, flatulence, constipation, tiredness, anaemia, mouth ulcers, sudden or unexpected weight loss. In the long term, untreated CD may lead to the development of more serious complications such as osteoporosis, reproductive disorders, some cancers, brain disorders and dermatitis herpetiformis, an unpleasant immune mediated skin disease. Clearly, because there is such a wide range of symptoms associated with CD, it is difficult to diagnose this condition on symptom profile alone.
Pathogenesis of Coeliac Disease
Basically, the CD associated autoimmune processes (outlined below) attack enterocytes. Enterocytes are cells which line the luminal or inner wall of the gastrointestinal tract, particularly the small intestine, (1). They play an important role in absorption of vital food derived nutrients. They also provide immunological protection for the gastrointestinal tract because they house a wide range of immunocompetent cells.
Enterocytes may be damaged by different types of immune mediated inflammatory processes induced by gluten and its derivatives.
What is gluten?
Gluten is a structural protein found in the seeds of cereals rye, wheat and barley (2). Gluten and its derivatives in these cereals are quite difficult to digest by proteolytic enzymes in the stomach because they contain stretches that are rich in the amino acids, proline and glutamine.
In the small intestine, some partially digested gluten is broken down into various sub-components including glutenin, gliadin and peptides by tTG. These reactions enable tTG to modify gluten peptides in a way that triggers the immune response seen in CD. Specifically, tTG deamidates certain glutamine residues in gluten peptides, creating a strong immune response, initially involving T cells that leads to the body attacking its own intestinal tissues in genetically susceptible subjects. (Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine or glutamine is removed or converted to another functional group.)
tGT is a multifunctional enzyme expressed in most cells in the body. It is involved in many biological processes; thus, it is not surprising that autoimmunity against tGT can lead to development of many different symptoms.
The luminal surface of enterocytes is covered with finger-like projections called villi. Spaces between villi are called crypts. This cellular configuration increases the surface area of the gastrointestinal lining to maximise absorption of digested food components and vital nutrients. The autoimmune processes involved in CD cause loss of villi reducing the surface area of the intestinal lumen thus limiting the absorption of vital nutrients.
Aetiology of Coeliac Disease
Gluten induced damage to the absorptive enterocyte layer is bought about firstly by initiation of the adaptive immune system and subsequently the innate immune system, particularly the complement system, and an apoptotic process.
With respect to the adaptive immune system, as indicated above, treatment of gluten and its derivatives by tGT releases peptides which have a strong affinity for the human leukocyte antigen (HLA) class 2 molecules HLA DQ2 and/or DQ8. (That is why there is a strong association between HLA DQ2 and DQ8 and increased susceptibility to the development of CD.
Presentation of HLA-DQ2/DQ8/gluten peptide complexes to specific CD4+ helper T cells induces two levels of immune response, enterocyte damage by CD8+ cytotoxic T cells and activation of specific B cells which produce antibodies against them. Because the enzyme tGT is bound to gluten derived fragments including gliadin, some B cells see this complex as an immunogen and consequently produce antibodies against tGT as well as parts of gliadin. In fact, tGT is now recognised as the primary disease specific autoantigen in CD.
Significance of different antibody types
There are a number of different antibody types. Two classes of antibody are significant with respect to the pathogenesis of CD namely IgG (and its sub-classes) and IgA antibodies.
It is important to understand the significance of antibody types and subclasses because they have a major influence on CD pathogenicity and diagnosis.
IgG and sub-classes
There are four different IgG sub-classes, IgG1, 2, 3 and 4. IgG1 and IgG3 subclasses, when bound to their immunological targets activate and fix the complement system very efficiently.
The complement system comprises a series of enzymes which interact sequentially to promote a profound inflammatory response and attract phagocytic cells. It also kills cells to which the terminal complement component C9 is bound by inflicting a lethal molecular hole in them. On the other hand, IgG2 and IgG4 sub-classes activate the complement system very poorly, if at all. Interestingly, it is now becoming clear that CD is associated mostly with anti-gluten/tTG antibodies that are of the IgG1 and 3 sub-classes (3).
IgA antibody
As well as the production of IgG antibodies, the enterocytic layer houses B cells that can synthesise anti -tGT antibodies of the IgA type. IgA antibodies can exist in a dimeric form which enables them to pass through to the outside of the enterocytic layer further hindering the absorption of vital nutrients.
Following both an antibody and cell mediated immunological attack on enterocytes and exposure to gluten derivatives, a localised apoptotic process is initiated which also contributes to the death of enterocytes. (Apoptosis is a term used to describe a specific biological process called programmed cell death in which cells spontaneously self-destruct. Cellular destruction is brought about by expression of a protein called p53. This protein instructs cells to kill themselves by destroying their own DNA.)
Diagnosis of Coeliac Disease
To ensure the accuracy of any diagnostic test for CD it is important that the subject has consumed gluten prior to the test because diagnostic antibodies rapidly disappear on a gluten free diet.
Histological examination
The results of histological and immunohistochemical tests on a biopsy specimen are highly diagnostic for CD. The results of these tests reveal the extent of enterocytic damage and immunological involvement and whether the damage is due to T cell cytotoxicity and/or antibody mediated enterocytic destruction.
Serological analysis
Detection of various antibodies in the blood can be helpful in the diagnosis of CD. Detection of anti-tGT antibody of the IgA type is highly specific and sensitive for the diagnosis of CD. Unfortunately, about 5% of CD patients are IgA deficient. In these cases, suitable diagnostic tests should include identification of IgG antibodies against tTG as well as detection of IgG antibodies directed against deamidated gliadin peptide (DGP) and epithelial membrane antigen (EMA). Detection of IgG antibody against DGP and EMA is highly specific for CD (4).
Exclusion tests
A diagnosis of CD can be excluded by genetic typing for the HLA class 2 antigens DQ2 or DQ8 because at least 95 % of CD sufferers are positive for one or both of these two HLA antigens. Lack of the HLA antigens DQ2 or DQ8 essentially excludes a diagnosis of CD. HLA typing for these antigens cannot be used to confirm a diagnosis of CD because around 30% of the population are positive for one or both of these HLA antigens.
Significance of the gut microbiome
It is clear that gluten is the predominant trigger for the onset of CD, however, recent findings have raised the possibility that changes in the composition of the gut microbiome including bacteria, yeasts and viruses may also play a role in increasing the susceptibility to development of CD in those who are genetically susceptible.
Interestingly, studies have shown that increased susceptibility to development of CD in genetically predisposed individuals may also be influenced by factors such as caesarean birth, formula feeding and drug exposure, all of which can alter the composition of the microbiome. They have also established that intestinal infections also contribute to the risk of development of CD. These findings implicate the composition of the gut microbiome in susceptibility to development of CD (5).
With respect to CD, elevated levels of several genera of undesirable bacteria including bacteroides, escherichia, and prevotella have been found in excess the gastrointestinal tract. By contrast, beneficial bacteria such as lactobacilli and bifidobacteria have been found to be less abundant in the gut microbiome of CD patients (5).
Resolution of Coeliac Disease
Fortunately, because the autoimmune trigger for CD is known, strict life-time adherence to a gluten free diet has been shown to diminish tTG autoimmunity leading to resolution of symptoms associated with CD.
Conclusions
- Tissue transglutaminase autoimmunity is associated with a wide range of symptoms including bloating, diarrhoea, nausea, flatulence, constipation, tiredness, anaemia, mouth ulcers, sudden or unexpected weight loss as well as more serious complications such as osteoporosis, reproductive disorders, some cancers, brain disorders and dermatitis herpetiformis, an unpleasant immune mediated skin disease.
- At least 1% of the community suffer from Coeliac Disease. Many more suffer from undiagnosed CD.
- CD can develop at any age.
- CD can be diagnosed serologically by the presence of IgA or IgG antibodies against tGT or DGP and EMA in the case of IgA deficiency.
- Diagnosis of Coeliac Disease can be excluded by the absence of HLA DQ2 and/or DQ8 antigens.
Consequently, here are two options available to practitioners who are confronted with patients suffering from any of the wide range of symptoms associated with autoimmunity to tGT:
On an empirical basis, practitioners may simply suggest that patients adhere to a strict gluten-free diet. In those that do suffer from tGT autoimmunity, symptoms will subside within weeks or months. Those who do benefit must remain on a gluten free diet permanently.
Adherence to a gluten-free diet will not cause any harm to those who do not suffer from CD.
On the other hand, some practitioners may request that patients seek tests to confirm (serological testing) or exclude (HLA DQ typing) a diagnosis of CD before recommending adherence to a gluten-free diet. Exclusion of a diagnosis of CD will nullify the need for a dietary change. Confirmation of a diagnosis of tGT autoimmunity will confirm the need for an appropriate dietary intervention on a permanent basis.
Personally, I prefer the first, empirical treatment option.
Further reading
You might find the following resources helpful:
Celiac Disease Foundation (USA)
The Physicians Committee for Responsible Medicine – USA – Celiac Research etc.
On The CMA Site:
References
1. Snoeck V et al. The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect. 7(7-8): 997-1004. 2005.
2. Shewry P R et al. The structure and properties of gluten: an elastic protein from wheat grain. Phil Trans R Soc Lond. B357: 33–142. 2002.
3. Uhde et al. Subclass profile of IgG antibody response to gluten differentiates non-celiac gluten sensitivity from celiac disease. Gastroenterology. 159(5): 1965-196. 2020.
4. Caja S et al. Antibodies in celiac disease: implications beyond diagnostics. Cell Mol Immunol. 8(2):103-109. 2011.
5. Lupu VV et al. Advances in understanding the human gut microbiota and its implication in pediatric celiac disease-a narrative review. Nutrients. 15(11): 2499-2516.2023.