CELIACDISEASE  FROM  PATHOPHYSIOLOGY  TO  ADVANCED  THERAPIES   Editedby PeterKruzliakandGovindBhagat CELIACDISEASE–FROM PATHOPHYSIOLOGYTO ADVANCEDTHERAPIES  EditedbyPeterKruzliakandGovindBhagat            Celiac Disease – From Pathophysiology to Advanced Therapies Edited by Peter Kruzliak and Govind Bhagat Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Romina Skomersic Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published July, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechopen.com Celiac Disease – From Pathophysiology to Advanced Therapies, Edited by Peter Kruzliak and Govind Bhagat p. cm. ISBN 978-953-51-0684-5    Contents  Preface IX Section 1 New Insights on Pathophysiology of Celiac Disease 1 Chapter 1 Mucosal Expression of Claudins in Celiac Disease 3 Dorottya Nagy-Szakál, Hajnalka Győrffy, Katalin Eszter Müller, Kriszta Molnár, Ádám Vannay, Erna Sziksz, Beáta Szebeni, Mária Papp, András Arató and Gábor Veres Chapter 2 Antioxidant Status of the Celiac Mucosa: Implications for Disease Pathogenesis 17 Vesna Stojiljković, Jelena Kasapović, Snežana Pejić, Ljubica Gavrilović, Nedeljko Radlović, Zorica S. Saičić and Snežana B. Pajović Chapter 3 Heat Shock Proteins in Coeliac Disease 37 Erna Sziksz, Leonóra Himer, Gábor Veres, Beáta Szebeni, András Arató, Tivadar Tulassay and Ádám Vannay Section 2 Clinical Manifestations and Complications of Celiac Disease 69 Chapter 4 Celiac Disease and Diabetes Mellitus Type 1 71 Mieczysław Szalecki, Piotr Albrecht and Stefan Kluzek Chapter 5 Hematologic Manifestations of Celiac Disease 83 Peter Kruzliak Chapter 6 Multiple Sclerosis and Celiac Disease 101 Carlos Hernández-Lahoz and Luis Rodrigo Section 3 Detection of Cereal Toxic Peptides Based on New Laboratory Methods 113 Chapter 7 Sensitive Detection of Cereal Fractions that Are Toxic to Coeliac Disease Patients, Using Monoclonal Antibodies to a Main Immunogenic Gluten Peptide 115 Carolina Sousa, Ana Real, Mª de Lourdes Moreno and Isabel Comino VI Contents Section 4 Advanced Therapies in Celiac Disease 137 Chapter 8 Enzyme Therapy for Coeliac Disease: Is it Ready for Prime Time? 139 Hugh J. Cornell and Teodor Stelmasiak Section 5 Follow-up of Patients with Celiac Disease 165 Chapter 9 Principles and Strategies for Monitoring Individuals with Celiac Disease 167 Mohsin Rashid Chapter 10 On Treatment Outcomes in Coeliac Disease Diagnosed in Adulthood 179 Claes Hallert and Susanne Roos   Preface  CeliacDisease(CD)orGlutenSensitiveEnteropathy(GSE)isalife‐longdisorder.Itis characterized by inflammation in the small intestine of genetically predisposed individualscausedbyinappropriateimmuneresponsetogluten,aproteinenrichedin some of our common grains (wheat, rye and barley). The toxicity of gluten is manifestedbytheautoimmune actionofT‐lymphocytesonmucosalcellsinthesmall intestine,disruptingitsvitalfunctionofabsorbing nutrients from food. Epidemiological studies conducted during the past decade revealed that CD is one of the most common lifelong disorders worldwide. CD can manifest with a previouslyunsuspected range of clinical presentations,includingthe typical malabsorption syndrome and a spectrum of symptoms potentially affecting any organ system. Since CD is oftenatypical or even silent on clinical ground, many casesremainundiagnosed andexposedtotheriskoflongtermcomplications,suchas anemia and other hematological complications, osteoporosis, neurological complicationsorcancer. Inrecentyears,therehavebeennoticeableshiftsintheageofonsetofsymptomsand in the clinical presentation of CD, changes that seem to be associated with a delayed introduction of gluten coupled with its reduced amount in the complications in the diet.Another controversialtopicconcernsthecomplicationsofuntreatedCD.Multiple studiesthathavefocusedonthebiochemistryandtoxicityofgluten‐containinggrains and the immune response to these grains suggest that individuals affected by CD should be treated,irrespective of the presence or absence of symptoms and/or associatedconditions.Nevertheless, thereisgeneralagreementthatthepersistenceof mucosalinjury,withorwithouttypicalsymptoms,canleadtoseverecomplicationsin CDpatientswhodonotstrictlycomplywithagluten‐freediet. Researchintoglutensensitivityhasneverb eenmorepopularnormoreexciting.With regard to gluten sensitivity we  are in a period of great change occasioned by the applicationof new methods toidentify glutensequences as T‐cellantigens, thestudy ofgenetic andmollecularpathophysiology,theuseofimmunohistocytochemicaland mRNAprobingresponsetoglutenandtheresearchoffuturetherapeuticoptions. Thisbookcovers mostof theaforementioned controversialandyet unresolved topics by including the contributions of experts in CD. What the reader will surely find X Preface stimulating about this book is not only its exhaustive coverage of our current knowledge of CD, but also provocative new concepts in disease pathogenesis and treatment. Todothisbookwouldhavebeenimpossiblewithoutthecontributionsoffriendsand colleaguesfromaroundtheworldwhohavedevotedsomuchinterest totheproject.It hasalsobeennecessary forthem to masterthe uniquechapter‐writing skills required ofeverymanuscriptinthisbook.Thisprojetwouldnothavebeenpossiblewithoutthe expertiseandinvaluablecontributionandtechnicalsupportofMs.RominaSkomersic andMs.NataliaReinicandof theInTechpublishingteam. It has been a privilege to put together „Celiac Disease‐From Pathophysiology to Advanced Therapies“ that is offered in the hope that its pages will contain the necessary information for researches, gastroenterologists, physicians, and others who areinterestedinthisfieldofmedicineandscience. Even if  I do not give you any big answers inthis book, I am still proud that you are holding it in your hands. It is because I learned, during my time as an editor and authorofthis book,that even if wedonot reach theendpoint ofour journey,we can stillmakeagreatcontributiontravellingtoit.  PeterKruzliak,M.D.,BSc. 5thDepartmentofInternalMedicine UniversityHospitalandMedicalFacultyofComeniusUniversity Bratislava, Slovakia    [...]... of duodenum compared to the bulbus duodeni 5.2 Claudin-mRNA expression in celiac disease and gluten-sensitive disease As described previously, celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten Gluten sensitive individuals cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in celiac disease However, in contrast to celiac disease, the overall... ↑ Celiac disease: CLDN2 and -3 ↑ Gluten-intolerance: CLDN4 ↑ Adenocarcinoma: CLDN2 ↑ IBD: CLDN2 ↑ and CLDN3, -4, -5 and -8 ↓ Stomach Duodenum, Ileum, Jejunum Colon Table 2 Claudin expression in the gastrointestinal tract in different disorders (Abbreviations: CLDN: Claudin, GIST: gastrointestinal stromal tumour, IBD: inflammatory bowel disease) 8 Celiac Disease – From Pathophysiology to Advanced Therapies. .. compared to controls paralleled by significantly increased mRNA expression of claudin4 In comparison to controls, adaptive immunity markers interleukin-6 and interleukin-21 were significantly increased in celiac disease but not in gluten sensitivity, while expression of the innate immunity marker Toll-like receptor 2 was increased in gluten 12 Celiac Disease – From Pathophysiology to Advanced Therapies. .. intraepithelial lymphocytosis (Marsh 1) or intraepithelial lymphocytosis accompanied by crypt hyperplasia (Marsh 2) (n = 9, six Marsh 1 and three Marsh 2, all on GFD) In the Marsh 3a group (n=20, seven asymptomatic 22 Celiac Disease – From Pathophysiology to Advanced Therapies and 13 with active celiac disease) partial villous atrophy was present, while in the Marsh 3b group (n=9, four asymptomatic and five... modulation of barrier function in disease Histochem Cell Biol 130(1):55-70 Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K., & Tsukita S (1998) Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin J Cell Biol 141(7):1539-50 14 Celiac Disease – From Pathophysiology to Advanced Therapies Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura,... such as celiac disease, inflammatory bowel diseases and irritable bowel syndrome In celiac disease, rodent studies suggest that gut microbiota influences mucosal integrity and plays a role in the early pathogenesis of CD (Cinova et al., 2011) In human celiac disease, intestinal flora may be a key component switching oral tolerance to immune response against gliadin (Ray et al., 2012) In celiac disease, ... approach of treatment in several diseases due to the fact that celiac disease may serve as a model for other autoimmune disorders The advantage in celiac disease is that the causative agent (gluten) is well known compared to other autoimmune disorders such as in inflammatory bowel diseases Development of agents making tight junctions close might be used as anti-inflammatory, anti-metastatic and anti-diarrhea... Firmicutes compared to healthy individuals (Sellitto et al., 2012) The metabolomic analysis reveals increased lactate in CD which may be a predicting factor of CD Mucosal Expression of Claudins in Celiac Disease 11 5 Claudins and celiac disease 5.1 Claudin-protein level in patients with celiac disease To the best of our knowledge, there is only one study to address the question to determine the expression... of patients with celiac disease (Madara et al, 1987; Poritz et al, 2011) Decreased intestinal barrier function leads to a continuous abnormal passage of antigens through the 10 Celiac Disease – From Pathophysiology to Advanced Therapies epithelial layer The main antigen of gluten in wheat, the gliadin can regulate cell activation, especially inhibits cell development and induces apoptosis Gliadin almost... 0.0001) 26 Celiac Disease – From Pathophysiology to Advanced Therapies Fig, 3 Data plot and coefficients of Spearman's rank correlation rs between the parameters of antioxidant status and the severity of mucosal lesion in celiac patients MnSOD – manganese superoxide dismutase, CuZnSOD - copper-zink superoxid dismutase, CAT - catalase, GPx glutathione peroxidase, GR - glutathione reductase, GSH – glutathione, . CELIAC DISEASE  FROM  PATHOPHYSIOLOGY  TO  ADVANCED  THERAPIES   Editedby PeterKruzliakandGovindBhagat CELIAC DISEASE – FROM PATHOPHYSIOLOGY TO ADVANCED THERAPIES  EditedbyPeterKruzliakandGovindBhagat            Celiac. Claudin, GIST: gastrointestinal stromal tumour, IBD: inflammatory bowel disease) Celiac Disease – From Pathophysiology to Advanced Therapies 8 Since the damage of the cell-cell adhesion. required ofeverymanuscriptinthisbook.Thisprojetwouldnothavebeenpossiblewithoutthe expertiseandinvaluablecontributionandtechnicalsupportofMs.RominaSkomersic andMs.NataliaReinicandof theInTechpublishingteam. It has been a privilege to put together Celiac Disease ‐ From Pathophysiology to Advanced Therapies  that is offered in the hope that its pages