Immune Mechanisms in Inflammatory Bowel Disease ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 568 HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN II Edited by Andrew J. Pollard and Adam Finn Volume 569 EARLY NUTRITION AND ITS LATER CONSEQUENCES: NEW OPPORTUNITIES Edited by Berthold Koletzko, Peter Dodds, Hans Akerbloom, and Margaret Ashwell Volume 570 GENOME INSTABILITY IN CANCER DEVELOPMENT Edited by Erich A. Nigg Volume 571 ADVANCES IN MYCOLOGY Edited by J.I. Pitts, A.D. Hocking, and U. Thrane Volume 572 RETINAL DEGENERATIVE DISEASES Edited by Joe Hollyfield, Robert Anderson, and Matthew La Vail Volume 573 EARLY LIFE ORIGINS OF HEALTH AND DISEASE Edited by Marelyn Wintour-Coghlan and Julie Owens Volume 574 LIVER AND PANCREATIC DISEASES MANAGEMENT Edited by Nagy A. Habib and Ruben Canelo Volume 575 DIPEPTIDYL AMINOPEPTIDASES: BASIC SCIENCE AND CLINICAL APPLICATIONS Edited by Uwe Lendeckel, Ute Bank, and Dirk Reinhold Volume 576 N-ACETYLASPARTATE: A UNIQUE NEURONAL MOLECULE IN THE CENTRAL NERVOUS SYSTEM Edited by John R. Moffett, Suzannah B. Tieman, Daniel R. Weinberger, Joseph T. Coyle and Aryan M.A. Namboodiri A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. Immune Mechanisms in Inflammatory Bowel Disease Edited by Richard S. Blumberg Gastroenterology Division and Laboratory of Mucosal Immunology, Brigham and Women's Hospital, Harvard, Massachusetts, USA Markus F. Neurath 1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany Springer Science+Business Media Landes Bioscience / Eurekah.com Springer Science-I-Business Media Eurekah.com / Landes Bioscience Copyright ©2006 Eurekah.com and Springer Science+Business Media All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system; for exclusive use by the Purchaser of the work. Printed in the U.S.A. Springer Science+Business Media, 233 Spring Street, New York, New York 10013, U.S.A. Please address all inquiries to the Publishers: Eurekah.com / Landes Bioscience, 810 South Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 http://www.eurekah.com http://www.landesbioscience.com Immune Mechanisms in Inflammatory Bowel Disease, edited by Richard S. Blumberg and Markus F. Neurath, Landes Bioscience / Eurekah.com / Springer Science+Business Media dual imprint / Springer series: Advances in Experimental Medicine and Biology. ISBN: 0-387-30831-8 While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefiiUy review and evaluate the information provided herein. Library of Congress Cataloging-in-Publication Data Immime mechanisms in inflanmiatory bowel disease / edited by Richard S. Blumberg, Markus F. Neurath. p.; cm. ~ (Advances in experimental medicine and biology ; v. 579) Includes bibliographical references and index. ISBN 0-387-30831-8 1. Inflammatory bowel diseases-hnmunological aspects. 2. Inflammatory bowel diseases-Pathogen- esis. 3. Gastrointestinal mucosa-Immunology. [DNLM: 1. InflanMnatory Bowel Diseases-immunology. 2. Inmiunity, Mucosal. WI420133 2006] I. Blumberg, R. S. (Richard Steven) II. Neurath, M. (Markus) III. Series. RC862.I53I44 2006 616.3'44-dc22 2005037056 PREFACE Inflammatory bowel diseases (IBD: Crohn's disease, ulcerative colitis) are defined as inflammations of the gastrointestinal tract not due to specific pathogens. IBD were first described in clinical reports from the last half of the 19th century. Since then, major discoveries have been made in the field of IBD (particularly in the past decade) that allow a more detailed understanding of its pathogenesis. Specifi cally, recent key advances include the field of genetics and a better understanding of the role of the bacterial flora as well as of the mucosal immune system. This book aims at providing a timely overview of key concepts and recent progress in the field of IBD. First, the structure and function of the mucosal immune system are reviewed. Next, the book features new information on the genetic basis of IBD with special emphasis on the role of NOD2/CARD15 mutations in Crohn's disease. In subsequent chapters, environmental factors and bacterial antigens are discussed as triggering mechanisms of IBD pathogenesis followed by new findings on the immunologic and molecular basis of the chronic inflammatory process in IBD. In addition, the pathophysiologic role of individual cell populations in the inflamed gut in IBD is discussed including cells of the mucosal immune system, parenchymal cells and neuroimmune cells. Finally, the implications of the new findings for the design of novel diagnostic and therapeutic approaches for IBD are described. A combined understanding of immunology, microbiology and genetics emerges as a prerequisite for a modem understanding of the pathophysiology of IBD. Hereby, IBD seem to develop as an immunologic dysfunction driven by bacterial antigens from the lumen in genetically susceptible individuals. A key area for future research will be to understand interactions between bacterial antigens and the mucosal immune system in health and disease and to determine the genetic and molecular basis of changes in the innate immune system in IBD patients. We hope that this book serves as a stimulus for modem understanding of IBD pathogenesis. Markus F. Neurath Richards. Blumberg PARTICIPANTS Stephan C. Bischoff Judy H. Cho Division of Clinical Nutrition/Prevention University of Chicago and Immunology Chicago, Illinois University of Hohenheim USA Stuttgart Germany Yingzi Cong Division of Gastroenterology Richard S. Blumberg and Hepatology Gastroenterology Division and University of Alabama at Birmingham Laboratory of Mucosal Immunology Birmingham, Alabama Brigham and Women's Hospital USA Harvard, Massachusetts USA Silvio Danese Division of Gastroenterology Per Brandtzaeg University Hospitals of Cleveland Laboratory for Immunohistochemistry Case Western Reserve University and Immunopathology (LIIPAT) School of Medicine Institute of Pathology Cleveland, Ohio University of Oslo USA Oslo Norway Rainer Duchmann Medizinische Klinik I Jonathan Braun Charite-Universitatsmedizin BerUn UCLA Hospital Center Campus Benjamin Franklin for Health Sciences Berlin Los Angeles, California Germany USA Charles O. Elson Hege S. Carlsen Division of Gastroenterology Laboratory for Immunohistochemistry and Hepatology and Immunopathology (LIIPAT) University of Alabama at Birmingham Institute of Pathology Birmingham, Alabama University of Oslo USA Oslo Norway Participants Claudio Fiocxhi Andr^ ZA. Leite Division of Gastroenterology Division of Gastroenterology University Hospitals of Cleveland University Hospitals of Cleveland Case Western Reserve University Case Western Reserve University School of Medicine School of Medicine Cleveland, Ohio Cleveland, Ohio USA USA Ivan J. Fuss Francisco Leon Mucosal Immunity Section Laboratory of Molecular Immunology Laboratory of Host Defense NIAID NIAID National Institutes of Health National Institutes of Health Bethesda, Maryland Bethesda, Maryland USA USA Thomas Gebhardt Thomas T. MacDonald Department of Gastroenterology, University of Southampton School Hepatology and Endocrinology of Medicine Southhampton Medical School of Hannover UK Hannover Germany Giovanni Monteleone Department of Gastroenterology Trond S. Halstensen University Tor Vergata Institute of Oral Biology Rome University of Oslo Italy Rikshospitalet, Oslo Norway Cathryn Nagler-Anderson Department of Pediatrics (Immunology) Martin H. Holtmann Massachusetts General Hospital 1st Department of Medicine Harvard Medical School Johannes-Gutenberg-University Charlestown, Massachusetts Mainz USA Germany Markus F. Neurath Kenji Ina 1st Department of Medicine Division of Gastroenterology Johannes-Gutenberg-University University Hospitals of Cleveland Mainz Case Western Reserve University Germany School of Medicine Cleveland, Ohio Edward E.S. Nieuwenhuis USA Laboratory of Pediatrics Department of Pediatric Gastroenterology Brian L. Kelsall Erasmus MC, Rotterdam Laboratory of Molecular Immunology The Netherlands National Institutes of Health Bethesda, Maryland USA Participants Reinhard Pabst Stephan R. Targan Center of Anatomy Cedars Sinai Medical Center Medical School of Hannover Los Angeles, California Hannover USA Germany Jon D. Vogel Hermann J. Rothkotter Division of Gastroenterology Institute of Anatomy University Hospitals of Cleveland University of Magdeburg Case Western Reserve University Magdeburg School of Medicine Germany Cleveland, Ohio USA R. Balfour Sartor Division of Gastroenterology Casey T. Weaver and Hepatology Department of Pathology University of North Carolina University of Alabama at Birmingham School of Medicine Birmingham, Alabama Chapel Hill, North Carolina USA USA Phillip D. Smidi Division of Gastroenterology and Hepatology University of Alabama at Birmingham Veterans Administration Medical Center Birmingham, Alabama USA Lesley E. Smythies Division of Gastroenterology and Hepatology Department of Medicine University of Alabama at Birmingham Birmingham, Alabama USA Warren Strober Mucosal Immunity Section Laboratory of Host Defense NIAID National Institutes of Health Bethesda, Maryland USA CONTENTS 1. STRUCTURE AND FUNCTION OF THE GUT MUCOSAL IMMUNE SYSTEM 1 Reinhard Pabst and Hermann J. Rothkotter Introduction 1 Intraepithelial Lymphocytes (lEL) 1 Lamina Propria Lymphocytes (LPL) 3 Lymphocyte-Filled Villi (LFV) 4 Cryptopatches (CP) 5 Isolated Lymphoid Follicles (ILF) 5 Peyer's Patches (PP) 6 Lymphoid Structures in the Large Intestine 7 Mesenteric Lymph Nodes, Part of the Gut Immune System 7 Gut Lymphatics 8 Liver—^Also a Part of the Gut Immune System? 8 Dynamics in the Gut Immune System 9 Conclusions 9 Note Added in Proof 9 2. FUNCTIONAL ASPECTS OF THE MUCOSAL IMMUNE SYSTEM.... 15 Cathryn Nagler-Anderson Phenotypically and Functionally Unique Lymphocyte Populations in the Gut Associated Lymphoid Tissue 15 Mechanisms Governing Non-Responsiveness to Food Proteins and Commensal Bacteria 18 3. RECENT PROGRESS IN INFLAMMATORY BOWEL DISEASE GENETICS 24 Judy H. Cho Introduction 24 IBD Epidemiology 24 The Human Genome Project and the ChaUenge of Complex Genetic Disorders 25 Linkage Studies in IBD 26 Association Studies in IBD 27 Future Directions 30 xi xii Contents 4. MICROBIAL AND DIETARY FACTORS IN THE PATHOGENESIS OF CHRONIC, IMMUNE-MEDIATED INTESTINAL INFLAMMATION 35 R. Balfour Sartor Introduction 35 Evidence of Bacterial Induction and Maintenance of Intestinal Inflammation 38 Induction of Mucosal Immune Responses by Bacterial and Dietary Antigens and Adjuvants 42 Conclusion 48 5. EXPERIMENTAL MODELS OF MUCOSAL INFLAMMATION 55 Warren Strober and Ivan J. Fuss Introduction 55 General Features of Models of Mucosal Inflammation 56 Representative Models of Mucosal Inflammation 68 Tabular Summary of Models of Mucosal Inflammation 80 Conclusion 80 6. OVERVIEW OF ROLE OF THE IMMUNE SYSTEM IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE 98 Thomas T. MacDonald and Giovanni Monteleone Abstract 98 Introduction 98 Crohn's Disease, but Not Ulcerative Colitis Bears the Stigmata of a Thl Mediated Immune Response 99 The Role of T Cells in Ulcerative Colitis 100 The Role of Antibody in Ulcerative Colitis 100 Nonspecific Effector Mechanisms Down-Stream of the Immune System Cause Tissue Injury in Crohn's Disease and Ulcerative Colitis 102 The Immune System Fails to Negatively Regulate in CD and UC 103 7. THE ROLE OF THE EPITHELIAL BARRIER IN INFLAMMATORY BOWEL DISEASE 108 Edward E.S. Nieuwenhuis and Richard S. Blumberg Introduction 108 Bacteria and the Epithelium 108 Bacteria and IBD 109 The Epithelial Cell as Effector CeU in IBD 110 Luminal Antigens, Fate and Processing 112 lEC and Mucosal Barrier Function/Permeability 113 Conclusion 113