Celiac disease (CD) is an immune-mediated condition with a known environmental trigger. Its pathogenesis explains why an ordinary dietary protein becomes the target of an intestinal immune attack in some people and not in others: the attack needs both a particular set of genes and the dietary antigen, and neither alone is enough.
How the mechanism was worked out
Celiac disease is one of the conditions first described in the first century AD. In the 18th century a Dutch physician described it as “aphthous disease”, because most of these patients presented with labial aphthous ulcers, and another Dutch physician of that century observed that “if there is only one cure for the celiac disease, it would be change of diet”. In the 20th century it was established that celiac disease is linked to the consumption of cereals. In the late 1980s it was shown that a particular haplotype of HLA-DQ2 predisposes a person to celiac disease, and in the 1990s that individuals with HLA-DQ2 preferentially present gluten-derived gliadin peptide, or deaminated gliadin peptide (DGP), to the intestinal T cells as antigen. The enzyme tissue transglutaminase (tTG) type 2 was then identified as the enzyme that chemically changes the gluten and makes DGP. The modern picture is therefore that tTG type 2-derived DGPs are the epitope presented to intestinal T cells in HLA-DQ2 individuals.
An immune reaction to gluten
Celiac disease is a complex disorder with environmental and genetic risk factors. It is immune-mediated: the genetically susceptible person mounts an immune reaction to the water-insoluble protein moiety, or gliadin, of certain cereals. CD is therefore a model of an autoimmune condition with an environmental trigger. Susceptibility is inherited, but the disease appears only when the dietary antigen is present, which is why the two must be considered together.
The antigen: gluten and prolamins
Gluten is the general term for the parts of the proteins of wheat that are insoluble in water and dissolve in ethanol. The word for the ethanol-soluble proteins of wheat is prolamin, and the prolamins of wheat are referred to as gliadin. The prolamins of wheat are similar to those of rye and barley, so there is cross-reactivity between the prolamins of these three cereals, and all three must be avoided in treatment. Grains whose prolamin is not similar to the prolamin of wheat, such as rice and corn, do not activate an immune response. Oats are a partial exception: they contain a gluten very similar to that of wheat, but the low quantity present does not by itself produce a celiac disease reaction.
The next step is chemical rather than genetic. Tissue transglutaminase released from the enterocytes deamidates gliadin and forms DGPs, and it is these modified peptides that induce the T-cell immune response.
Environmental cofactors
Several environmental exposures beyond gluten are associated with the development of CD:
- rotavirus infection
- reovirus infection
- H. pylori infection, which has an inverse relation with CD, so that lower infection with H. pylori is associated with more CD in the population
These are associations rather than proven causes. They suggest that infection can influence how the intestinal immune system handles dietary antigens, but none of them is necessary for the disease to occur.
Genetic susceptibility
Genetic factors play an important role in the pathogenesis of celiac disease: the concordance of celiac disease in first-degree relatives is about 8-18%. The most important genetic predisposition is the haplotype of HLA-DQ2, and there is a dose-effect relation between HLA-DQ2 and the severity and risk of the condition, so that homozygous subjects are at the greatest risk of developing CD. Most of the remaining patients carry HLA-DQ8, and the two molecules together account for almost every case.
Two facts about HLA-DQ2 put this association in perspective:
- Not all subjects with HLA-DQ2 have CD. More than 35% of European people carry the haplotype, but only 1% of Europeans have CD.
- More than 90% of the population with CD carries the HLA-DQ2 haplotype.
The genes are therefore necessary but not sufficient: they explain who is susceptible, while the trigger and other exposures decide who actually develops the disease. What the immune attack does to the mucosa is the subject of Pathology of Celiac Disease.