title: Celiac disease: how complicated can it get?
abstract: 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.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, RC Leiden, The Netherlands. j.m.l.tjon@lumc.nl
authors.forename: Jennifer May-Ling
authors.initials: JM
authors.lastname: Tjon
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D000328:Adult; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002446:Celiac Disease / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D019204:GTP-Binding Proteins; D018628:Gene Dosage; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000209:etiology; D018448:Models, Immunological; D015995:Prevalence; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000502:physiology
chemical_list: D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; C000717608:TGM2 protein, human; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins