Coeliac disease

Coeliac disease: pathogenesis

It is clear that the autoimmune disease coeliac disease is a reaction to the gluten protein. But what triggers this disease? Coeliac disease is caused by a complex pathology resulting from the interaction of genetic and exogenous factors.

Genetic factors in coeliac disease

A high incidence of coeliac disease of 10-15% among first-degree relatives and around 50-75% among monozygotic twins suggests a genetic contribution to the pathogenesis. An important genetic factor is the human leukocyte antigen system (HLA system), a gene complex whose task is to recognise foreign molecules. Approximately 90% of people with coeliac disease carry the HLA-DQ2 trait, while almost all of the rest express the HLA-DQ8 gene. Although the presence of both gene complexes is necessary for the disease to develop, they are not solely responsible for it. After all, these genes are also found in more than 30-40% of the healthy population.

Exogenous factors in coeliac disease

The only exogenous factor known to date that plays a role in coeliac disease is gluten, a collective term for the storage proteins found in wheat, rye and barley. These proteins have a high proportion of proline and glutamine residues and are referred to as prolamins. Wheat prolamines include gliadins (α, γ and ω gliadins) and glutenins. They cannot be completely broken down by stomach and pancreatic enzymes and trigger the adaptive immune response in coeliac disease.

Research is currently investigating whether and to what extent additional environmental factors – such as infections and the amount of gluten consumed, together with changes in the gut microbiome – play a role in the development of the disease.

Pathophysiology of coeliac disease

Gluten is usually consumed in large quantities (10-20g/ day) in the normal diet. Some of the gluten peptides are not properly broken down by the stomach and pancreatic enzymes and are absorbed trans-epithelially via the lamina propria (small intestine mucosa).

Transglutaminase (TG2, also known as tissue transglutaminase) deamidateses gluten peptide residues, resulting in better binding to HLA-DQ2 or HLA-DQ8 on antigen-presenting cells (APCs) and potentiating the inflammatory response.

TG2 also causes molecules to link together, leading to the formation of TG2-gluten complexes. This activates:

T lymphocytes with the release of cytokines and tumour necrosis factor alpha (TNF-alpha).
B cells with the release of antibodies (anti-tTG and anti-gliadin antibodies).
Cytotoxic lymphocytes, which interact with intestinal epithelial cells, contributing to tissue destruction and small intestine atrophy.

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