Celiac disease (CD)

Celiac disease: Pathogenesis

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

Genetic factors in celiac disease

A high incidence of celiac 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 recognize foreign molecules. Approximately 90% of people with celiac disease carry the HLA-DQ2 trait, and 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. However, these genes are also found in more than 30-40% of the healthy population.

Exogenous factors in celiac disease

The only exogenous factor known to date that plays a role in celiac 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 called 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 celiac 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 celiac disease

Gluten is usually consumed in large quantities (10-20g) 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) deamides 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 facilitates molecular cross-linking, leading to the formation of TG2-gluten complexes. This activates:

T lymphocytes with the release of cytokines and tumor 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 intestinal atrophy.

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