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Coeliac disease: dissecting a complex inflammatory disorder

Nature Reviews Immunology volume 2, pages 647–655 (2002)Cite this article

Key Points

  • Coeliac disease is a prevalent disorder (affecting 1 in 200 Caucasian individuals) that is caused by an inappropriate immune response to gluten (which consists of the subcomponents gliadin and glutenin). The disease enters complete remission when gluten is eliminated from the diet.

  • Patients with active coeliac disease have immunoglobulin (Ig)A and IgG antibodies that are specific for the autoantigen tissue transglutaminase (TG2). The production of these antibodies is controlled by dietary exposure to gluten.

  • Coeliac disease is a complex inflammatory disorder. The environment and several genes contribute to disease development. HLA is the single most important genetic factor.

  • The disease is associated with HLA-DQ2 (DQA1*05/DQB1*02) in most patients, and with HLA-DQ8 (DQA1*03/DQB1*0302) in a minority of patients.

  • Gluten-specific CD4+ T cells can be isolated from the small-intestine mucosa of coeliac-disease patients, but not from non-coeliac controls. These T cells recognize gluten peptides in the context of DQ2 or DQ8, but not other HLA molecules that are expressed by patients.

  • Several gluten epitopes (both in gliadins and glutenins) exist that are recognized by mucosal T cells. Some epitopes are recognized frequently and some infrequently by the T cells of the patients.

  • Most of the gluten T-cell epitopes are recognized in a deamidated form — in other words, some specific glutamine residues have been converted to glutamic acid. This deamidation is mediated by the enzyme TG2.

  • In gliadins, the T-cell epitopes cluster in regions that are rich in proline residues. The influence of proline to protect against digestive proteolysis and to direct TG2-mediated deamidation of glutamines contributes to this epitope clustering.

  • Gluten-specific T cells might help TG2-specific B cells by linked recognition of TG2–gluten-peptide complexes. This could explain how exposure to a foreign antigen controls the formation of autoantibodies.

Abstract

The disease mechanisms of complex inflammatory disorders are difficult to define because of extensive interactions between genetic and environmental factors. Coeliac disease is a typical complex inflammatory disorder, but this disease is unusual in that crucial genetic and environmental factors have been identified. This knowledge has allowed functional studies of the predisposing HLA molecules, the identification of antigenic epitopes and detailed studies of disease-relevant T cells in coeliac disease. This dissection of the pathogenic mechanisms of coeliac disease has uncovered principles that are relevant to other chronic inflammatory diseases.

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Figure 1: Normal and coeliac-disease small-intestine mucosae.
Figure 2: HLA association in coeliac disease.
Figure 3: The coeliac small-intestine lesion.
Figure 4: T-cell epitopes cluster in regions of gliadins with high proline content.

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Acknowledgements

This work was supported by grants from the Research Council of Norway and the European Commission. I thank the former and present members of my laboratory and other collaborators for their contributions to the work cited. Thanks are also extended to S. McAdam, K. E. A. Lundin, Ø. Molberg and A. S. Louka for critical review of the manuscript.

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Authors and Affiliations

  1. Institute of Immunology, Rikshospitalet, University of Oslo, Oslo, 0027, Norway

    Ludvig M. Sollid

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DATABASES

Locus Link

CD14

CTLA4

DQA1

DQB1

ICAM1

IFN-α

IFN-γ

IL-4

IL-6

IL-10

IL-12

IL12B

IL-18

TG2

TNF

transforming growth factor-β

OMIM

asthma

coeliac disease

rheumatoid arthritis

type-1 diabetes

FURTHER INFORMATION

National Digestive Diseases Information Clearinghouse, Celiac Disease

Farrp (Food Allergy Research and Resource Program) Allergen Database

Ludvig Sollid's lab

Glossary

SIBLING RELATIVE RISK

The clustering of a disease in families is indicative of genetic effects. The degree of familial clustering is often expressed as the sibling relative risk (λs), which is the disease risk for a sibling of an affected individual compared with the disease risk in the general population.

T HELPER 1/2

(TH1/TH2). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoral immunity and downregulate TH1 responses.

DEAMIDATION

The modification of glutamine to glutamic acid, or asparagine to aspartic acid. Deamidation leads to a mass increase of 1 Da, which can be detected by mass spectrometry.

HAPTEN

A molecule that can bind antibody but cannot by itself elicit an adaptive immune response. Antibodies specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that is able to elicit a T-cell response.

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Sollid, L. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2, 647–655 (2002). https://doi.org/10.1038/nri885

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