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The Puzzle of Coeliac Disease: Pieces of the Molecular Pathogenesis ISBN 90-393-4180-X

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The Puzzle of Coeliac Disease: Pieces of the Molecular Pathogenesis ISBN 90-393-4180-X The puzzle of coeliac disease: pieces of the molecular pathogenesis ISBN 90-393-4180-X The work presented in this thesis was performed at the DBG-Department of Medical Genetics of the University Medical Center Utrecht, within the Research School of Developmental Biology. Financial support was provided by the Netherlands Organisation for Medical and Health Research (NWO) grant 902-22-094. Financial support for the publication of this thesis by the DBG-Department of Medical Genetics of the UMC Utrecht, NWO, the University of Utrecht, the Section of Experimental Gastroenterology (SEG) of the Netherlands Society of Gastroenterology (NVGE), AstraZeneca B.V., Ferring Pharmaceuticals B.V., Nutricia Nederland B.V., Dr Ir van de Laar Foundation and the J.E. Jurriaanse Foundation is gratefully acknowledged. The puzzle of coeliac disease: pieces of the molecular pathogenesis De puzzel van coeliakie: stukken van de moleculaire pathogenese (met een samenvatting in het Nederlands) El puzle de la enfermedad celiaca: piezas de su patología molecular (con el sumario en español) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. dr. W.H. Gispen ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op dinsdag 21 maart 2006 des namiddags te 14:30 uur door María Begoña Diosdado Calvo geboren op 30 januari 1976, te Valladolid (Spanje) Promotor: Prof. dr. C. Wijmenga Complex Genetics Section DBG - Department of Medical Genetics University Medical Center Utrecht Utrecht University, the Netherlands A mis padres Gonzalo y Begoña, a mis hermanos Beatriz y Rodrigo y a Eric. Contents Preface 9 Part I General introduction Chapter 1 Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients. Expert Rev Mol Diagn. 2005 Sept;5(5):681-700. 11 Chapter 2 “Coelionomics”: towards understanding the molecular pathology of coeliac disease. Clin Chem Lab Med. 2005;43(7):685-95. 33 Part II Genetic profiling studies in coeliac disease Chapter 3 A microarray screen for novel candidate genes in coeliac disease pathogenesis. Gut. 2004 July;53(7):944-51. 47 Chapter 4 A genomics view on coeliac disease points to enhanced neutrophil recruitment and barrier imparement. Submitted. 57 Part III Candidate genes studies Chapter 5 No genetic association of the human prolyl endopeptidase gene in the Dutch celiac disease population. Am J Physiol Gastrointest Liver Physiol. 2005 Sept;289(3):G495-500. 73 Chapter 6 The down-stream modulator of interferon-gamma, STAT1 is not genetically associated to the Dutch celiac disease population. Submitted. 81 Part IV General discussion 89 Summary 107 Sumario 111 Samenvatting 117 Acknowledgements/ agradecimientos 123 Curriculum vitae 127 List of publications 128 Color Figures 129 Preface Preface Coeliac disease (CD) is a chronic inflammatory disorder with a multifactorial predisposition that affects the small intestine. The known causative factors responsible for this disease are the environmental factor gluten, the genes that encode for the HLA-DQ2/DQ8 molecules on chromosome 6, and the MYO9B gene on chromosome 19. Together these genes can explain approximately 55% of the familiar aggregation. Gluten is a dietary protein able to trigger specific structural changes in the mucosa of the small intestine with a distinct sequence of development. Based on the description of these histological modifications, it has been established that the disease progresses through three stages: the first stage, called Marsh I, in which gluten triggers the activation of an inflammatory response in the mucosa, and that is thought to lead first to crypt hyperplasia (Marsh II stage) and eventually to villous atrophy (Marsh III stage). In trying to understand the molecular mechanisms that drive these histological changes, much attention has been focused on the role of inflammation in the disease process. Our initial research was based on previous genetic knowledge, in particular the role of HLA-DQ2/DQ8. These studies have contributed to our understanding of how gluten is recognized by HLA-DQ2/DQ8 molecules and how it activates specific αβ CD4+ T-cells located in the lamina propria. Later on the influence of tissue transglutaminase on the recognition of gluten peptides, and the involvement of the innate immune response through IL-15 at the epithelial layer of coeliac mucosa was studied. These studies led to different molecular pathways being proposed to explain how villous atrophy occurs, i.e. increased oxidative stress, increased apoptotic activity, or lost balance of the metalloproteinases activity. However, the approaches used had revealed technical limitations and were not always focused on the primary processes that take place in the intestinal mucosa of the individuals at risk of coeliac disease when they were exposed to gluten. Hence, the molecular mechanisms responsible for the pathogenesis of coeliac disease were only partially elucidated. Driven by new technological developments, we employed microarray technology on biopsies of coeliac patients in different stages of the disease and on controls to assess the expression of thousands of genes simultaneously. This strategy allowed us to ascertain new pieces of the puzzle, revealing the molecular mechanisms and pathways underlying the initial inflammation processes and the further progression towards mucosal transformation in coeliac disease. This has enabled us to identify putative causative genes. Outline of this thesis The first part of this thesis describes the current knowledge on the pathogenesis of CD. Chapter 1 focuses on the immunological response that takes place in the intestinal mucosa of the individuals susceptible to CD when they sense gluten. This review chapter summarizes the genes and types of studies that have been examined on the adaptive and innate immune response and also considers the pathways involved in the induction of oral tolerance. It then assesses how the immune response might evoke the histological damage seen in CD or whether this is a non-specific defence mechanism. A second review in chapter 2 concentrates on the pathways proposed for mediating villous atrophy in CD. This paper describes the molecular mechanisms thought to be involved in the restructuring of the villous crypt units, and discusses their solidity in the context of current insights from functional, genetic and 9 Preface Preface genomic studies. The second part of this thesis concentrates on the identification of the molecular pathways underlying the pathogenesis of CD. In the first set of experiments, we compared Marsh III stage (MIII) coeliac biopsies to normal control biopsies to identify the genes involved in the tissue remodelling processes. Secondly, we investigated the first molecular events that occur after gluten withdrawal by comparing the expression profiles of MIII CD patients ingesting and later refraining from gluten (chapter 3). In chapter 4, we describe gene expression studies on biopsies from coeliac patients in different stages towards normalization after refraining from gluten intake, and from control individuals. This experiment revealed which immunological processes are modulated by gluten in the intestine of CD patients, and enabled us to monitor the transcriptional activity of the genes involved during the histological normalization of the coeliac mucosa. The processes that emerged from the differentially expressed genes were further corroborated by immunohistochemistry experiments. The last part of this thesis aimed to identify putative primary genes in CD by integrating genetic and microarray data. The genetic studies conducted on two of the putative primary genes identified are described in chapters 5 and 6. This thesis describes some novel pathways and genes involved in the pathogenesis of CD and the genetic studies carried out on two candidate genes that were found during this Ph.D. project. In chapter 7 the results are discussed and looked at in the context of some preliminary data from functional studies on the pathways that drive villous atrophy. Our view on the puzzle of coeliac disease pathogenesis is presented. 10 Part I GENERAL INTRODUCTION Chapter 1 Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients Expert Rev Mol Diagn. 2005 Sept;5(5):681-700 Chapter 1 Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of CD Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients Begoña Diosdado and Cisca Wijmenga† Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several CONTENTS genome screens have been successful in identifying susceptibility loci in celiac disease, What is celiac disease? the only genetic contributors identified so far are the human leukocyte antigen General molecular (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of immunologic mechanisms celiac disease is the activation of a T-helper 1 immune response, when the of the pathogenesis of celiac disease antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4+ T-cells. Recently, new insights into the activation of an innate Gut immune system & the induction of
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