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Licensed Unlicensed Requires Authentication Published by De Gruyter August 22, 2005

“Coelionomics”: towards understanding the molecular pathology of coeliac disease

Begoña Diosdado, Erica van Oort and Cisca Wijmenga

Abstract

Coeliac disease (CD) is an inflammatory disorder of the small intestine characterised by a permanent intolerance to gluten-derived peptides. When gluten-derived peptides reach the lamina propria in CD patients, they provoke specific changes in the mucosa of their small intestine. Although the susceptibility to CD is strongly determined by environmental gluten, it is clearly a common genetic disorder. Important genetic factors for CD are the HLA-DQ genes located in the MHC region on chromosome 6 [ HLA-DQ2 (95%) or HLA-DQ8 (∼5%) heterodimers]. So far, the only treatment for CD consists of a life-long gluten-free diet. A key question in CD is why the gluten-derived peptides are resistant to further breakdown by endogenous proteases and how, in turn, they can activate a harmful immune response in the lamina propria of genetically predisposed individuals. Four mechanisms, namely apoptosis, oxidative stress, matrix metalloproteinases and dysregulation of proliferation and differentiation, are thought to play a role in the pathophysiology of CD. Whether the genes involved in these four mechanisms play a causative role in the development of the villous atrophy or are, in fact, a consequence of the disease process is unknown. In this review we summarise these mechanisms and discuss their validity in the context of current insights derived from genetic, genomic and molecular studies. We also discuss future directions for research and the therapeutic implications for patients.


Corresponding author: Prof. Cisca Wijmenga, Complex Genetics Section, Department of Biomedical Genetics, Stratenum 2.117, University Medical Centre Utrecht, P.O. Box 85060 AT, 3508 AB Utrecht, The Netherlands Phone: +31-30 253 8427, Fax: +31-30 253 8479,

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Received: 2005-1-13
Accepted: 2005-5-19
Published Online: 2005-8-22
Published in Print: 2005-7-1

©2005 by Walter de Gruyter Berlin New York