Celiac disease: How complicated can it get?

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, RC Leiden, The Netherlands.
Immunogenetics (Impact Factor: 2.23). 10/2010; 62(10):641-51. DOI: 10.1007/s00251-010-0465-9
Source: PubMed


In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4(+) T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4(+) T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.

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Available from: Jennifer May-Ling Tjon
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    • "Due to presence of glutamine and proline in the amino acid sequence, a number of gluten peptides directly bind DQ2 or DQ8 in the binding groove while other peptides require prior modification to enhance binding. The HLA DQ2 and DQ8 receptors preferentially bind peptides with negatively charged amino acids and bulky amino acids at certain anchor residues (Tjon and others 2010). Moreover, tissue-bound transglutaminase selectively deamidates glutamine to create glutamic acid, which allows certain gluten peptides to fit in the binding pockets of HLA DQ2 and DQ8 (van de Wal and others 1998; Arentz- Hansen and others 2000; Vader and others 2002a; Kim and others 2004; Stepniak and others 2005). "
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