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Celiac Disease as a Model of Gastrointestinal Inflammation

Sollid, Ludvig M.

Section Editor(s): Fiocchi, Claudio

Journal of Pediatric Gastroenterology and Nutrition: April 2005 - Volume 40 - Issue - p S41-S42
First International Symposium on Pediatric Inflammatory Bowel Disease: Session IV. The Changing Environment in IBD Manifestation and Pathogenesis

Case Western Reserve University, Cleveland, Ohio, USA

University of Oslo, Oslo, Norway

Address correspondence and reprint requests to Dr. Ludvig M. Sollid (e-mail: l.m.solid@medisin.uio.no).

Celiac disease is a food hypersensitivity disorder of a chronic inflammatory nature. The disease has an autoimmune component represented by disease-specific autoantibodies to tissue transglutaminase (TG2). The lesion in the small intestine is characterized by villous atrophy, crypt hyperplasia and infiltration of inflammatory cells, both in the epithelium and in the lamina propria. The condition is frequent in Western societies affecting about 1 in 100 to 300 individuals, although not all affected have subjective symptoms. Recent advances have improved our understanding of the molecular basis for this disorder.

The celiac enteropathy develops as a result of interplay between genetic and environmental factors. Gluten (consisting of the subcomponents gliadin and glutenin) is clearly a critical environmental component and both Human Leukocyte Antigens (HLA) and non-HLA genes are predisposing genetic factors. HLA is the single most important genetic factor. We have now a quite detailed understanding on how certain HLA genes predispose to disease development. The DQA1*05 and DQB1*02 genes, which encode the DQ2 molecule are chiefly responsible for the HLA effect in the majority of patients. In the few remaining patients, DQ8 encoded by the DQA1*03 and DQB1*0302 genes constitute the HLA susceptibility factor. CD4+ T lymphocytes, which recognize gluten peptides presented by DQ2 or DQ8, can be isolated from small intestinal biopsies of celiac patients but not from controls. Several distinct gluten T cell epitopes exist. A 33-mer fragment of a gliadin, which is resistant to gastrointestinal proteolysis is particularly immunogenic as it contains six partly overlapping DQ2 restricted epitopes. Most of the epitopes are recognized in a post-translationally modified (deamidated) form where some glutamine residues have been converted to glutamic acid. This deamidation is mediated by tissue transglutaminase (TG2), which in the gut is mainly expressed beneath the epithelium. Typically, gluten peptides bind to the DQ2 and DQ8 molecules so that glutamic acid residues created by deamidation are accommodated in pockets of the binding site that have a preference for negatively charged side chains. The recently resolved x-ray crystal structure of DQ2 complexed with a deamidated gluten epitope provides further interesting details as to why DQ2 predisposes to the development of Celiac disease. The T cell epitopes of gluten are clustered to regions of gluten proteins being rich in proline residues. Proline affects gluten immunogenicity by inferring resistance to gut proteolysis, by its importance for TG2 specificity, and by dictating binding of the peptides to the HLA molecules. Upon their activation, gluten reactive T cells produce cytokines of which interferon-γ is dominating. T cell activation will set off an array of inflammatory reactions, and the exact mechanisms responsible for the tissue damage are as yet only partly characterized.

In addition to deamidation, TG2 can also cross-link glutamine residues of peptides to lysine residues in other proteins, including itself. It is possible that complexes between gluten and TG2 permit gluten reactive T cells to provide help to TG2 specific B cells enabling them switch their antibody production from IgM to IgA or IgG by a mechanism of intramolecular help. This mechanism could easily explain the occurrence of gluten dependent IgA and IgG autoantibodies to TG2 in Celiac disease and would negate the need for TG2 specific T cells. Such cells are unlikely to exist due to thymic expression of TG2 and negative selection of TG2 specific T cells.

Overall, the results point to control of the immune response to gluten by intestinal T cells restricted by the DQ2 or DQ8 molecules. This is likely to be a critical checkpoint for the development of Celiac disease and could explain the dominant genetic role of HLA in the disorder. The knowledge of the other predisposing genes is as yet limited. There is evidence for involvement of genes located on chromosomes 2q33 (the CTLA4, CD28, ICOS gene cluster), 5q31-33 and 19p13. It is reasonable to assume that polymorphic genes involved in susceptibility to Celiac disease encode products that influence the immune response to gluten. Possibly, some of the susceptibility genes (e.g., 5q31-33) may be shared between Celiac disease and other inflammatory diseases (e.g., asthma, inflammatory bowel disease).

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Key Questions

1) Why a strong HLA association in Celiac disease but not in IBD?

2) Are there clearly definable antigenic triggers in IBD like in Celiac disease?

3) Can the automimmune components of IBD be driven by T cells responsive to foreign antigen(s)?

4) Is T cell recognition of post-translationally modified antigens also relevant to IBD?

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KEY REFERENCES

1. Sollid LM. Molecular basis of celiac disease. Ann Rev Immunol 2000;18:53-81.
2. Papadopoulos GK, Wijmenga C, Koning F. Interplay between genetics and the environment in the development of celiac disease: perspectives for a healthy life. J Clin Invest 2001;108:1261-6.
3. Sollid LM. Coeliac disease: Dissecting a complex inflammatory disorder. Nat Rev Immunol 2002;2:647-55.
4. McManus R, Kelleher D. Celiac disease-the villain unmasked? N Engl J Med 2003;348:2573-4.
5. Green PHR, Jabri B. Coeliac disease. Lancet 2003;268:383-91.
© 2005 Lippincott Williams & Wilkins, Inc.