Celiac disease: caught between a rock and a hard place.
ABSTRACT Celiac disease (CD) is an intestinal disorder caused by an intolerance to gluten, proteins in wheat. CD is an HLA-associated disease: virtually all patients express HLA-DQ2 or HLA-DQ8. Recent work has shown that these disease-predisposing HLA-DQ molecules bind enzymatically modified gluten peptides and these HLA-DQ peptide complexes trigger inflammatory T-cell responses in the small intestine that lead to disease. In addition, gluten induces innate immune responses that contribute to the tissue damage that is characteristic for CD. Thus, CD patients are caught between a rock and a hard place: the disease is caused by a combination of adaptive and innate immune responses that both are triggered by gluten. These findings explain the disease-inducing properties of gluten and provide valuable clues for the development of alternative treatment modalities for patients. They also may be of relevance for our understanding of other multifactorial disorders including IBD and HLA-associated autoimmune diseases.
[show abstract] [hide abstract]
ABSTRACT: Heat shock protein (HSP) 72, a known chaperone, has potential epithelial barrier protecting, antiapoptotic, and immune system regulatory effects; therefore, our aim was to study its involvement in the pathology of celiac disease (CD). Duodenal biopsy specimens were collected from children with untreated and treated CD and from controls. mRNA expression, protein level, and localization of HSP72 were determined. Elevated HSP72 mRNA expression and higher protein levels were found in the duodenal mucosa of children with untreated CD as well as in children with treated CD compared with those in controls. In the duodenal mucosa of children with treated CD, HSP72 mRNA expression was decreased and HSP72 protein levels were lower than those in children with untreated CD. We detected intensive HSP72 staining in the villous enterocytes and immune cells of the lamina propria in the duodenal villi of children with untreated CD compared with that in controls. The increased expression and altered localization of HSP72 in CD indicate that HSP72 should have a role in protection against gliadin-induced cytotoxicity. HSP72 may exert antiapoptotic effect and contribute to preservation of intestinal epithelial barrier integrity. Moreover, HSP72 as a ligand of TLR2 and TLR4 may promote innate immune responses and warn the cells of the potential injury.Journal of pediatric gastroenterology and nutrition 11/2010; 51(5):573-8. · 2.18 Impact Factor
Article: A universal approach to eliminate antigenic properties of alpha-gliadin peptides in celiac disease.[show abstract] [hide abstract]
ABSTRACT: Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the α-gliadins. It has been shown that α-gliadins harbor several major epitopes involved in the disease pathogenesis. A major step towards elimination of gluten toxicity for celiac disease patients would thus be the elimination of such epitopes from α-gliadins. We have analyzed over 3,000 expressed α-gliadin sequences from 11 bread wheat cultivars to determine whether they encode for peptides potentially involved in celiac disease. All identified epitope variants were synthesized as peptides and tested for binding to the disease-associated HLA-DQ2 and HLA-DQ8 molecules and for recognition by patient-derived α-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the α-gliadin derived peptides involved in celiac disease that eliminate the antigenic properties of the epitope variants. Finally, we provide proof of principle at the peptide level that through the systematic introduction of such naturally occurring variations α-gliadins genes can be generated that no longer encode antigenic peptides. This forms a crucial step in the development of strategies to modify gluten genes in wheat so that it becomes safe for celiac disease patients. It also provides the information to design and introduce safe gluten genes in other cereals, which would exhibit improved quality while remaining safe for consumption by celiac disease patients.PLoS ONE 01/2010; 5(12):e15637. · 4.09 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: High prevalence of coeliac disease (CD) has been reported among patients with idiopathic dilated cardiomyopathy (DCM). We evaluated the feasibility and diagnostic accuracy of screening for CD by rapid test of anti-transglutaminase antibodies in the cardiology outpatients' clinic. We screened the blood samples of 104 patients with DCM, 44 of their first-degree relatives, 63 diseased controls and 101 healthy controls for the presence of anti-transglutaminase antibodies in a drop of whole blood using a rapid assay. This test was compared to the enzyme-linked immunosorbent assay and the anti-endomysium antibody test. Our rapid test was positive in three (2.9%) DCM patients, in one (2%) relative and in one (1%) healthy control. These subjects were positive at both control assays. Two DCM patients had iron-deficient anaemia. The healthy relative was asymptomatic, while the healthy control experienced extreme asthenia. The relative refused intestinal biopsy, while the others showed histological evidence of CD. During the gluten-free diet, the patient with the worst left ventricular ejection fraction (LVEF) underwent heart transplant, and LVEF values improved in the other two. Anaemia and tiredness resolved in all patients. Early detection of CD in a cardiological setting allows prompt treatment with a gluten-free diet of gluten-dependent complaints with potential benefits for the course of DCM.Archives of medical science : AMS. 10/2010; 6(5):728-32.