Birkh auser Advances in Infectious Diseases

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1 Birkh auser Advances in Infectious Diseases Series Editors Axel Schmidt, University Witten/Herdecke, Faculty of Medicine, Alfred-Herrhausen-Str. 50, Witten, Germany Olaf Weber, Rheinische Friedrich-Wilhelms-University, Institute of Molecular Medicine, and Experimental Immunology, Sigmund-Freud-Str. 25, Bonn, Germany Stefan H. E. Kaufmann, Max Planck Institute for Infection Biology, Charitéplatz l, Campus Charité Mitte, D Berlin, Germany Advisory Board Manfred H. Wolff, University Witten/Herdecke, Faculty of Biosciences, Stockumer Str. 10, Witten, Germany For further volumes:

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3 Joan Stein-Streilein Editor Infection, Immune Homeostasis and Immune Privilege

4 Editor Joan Stein-Streilein Department of Ophthalmology Schepens Eye Research Institute Boston, MA USA ISBN ISBN (ebook) DOI / Springer Basel Heidelberg New York Dordrecht London Library of Congress Control Number: # Springer Basel 2012 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer Basel is part of Springer Science+Business Media (

5 Preface This book is aimed at reviewing the immune homeostatic mechanisms that regulate inflammation in the context of the innate and the adaptive immune response, the microbiome, and the environment at the level of the organ/tissue and in relation to the select infections that invade those organs. A powerful protector of mammalian organs and tissues is an omniscient and plastic immune response. The immune response begins with innate responses that are able to respond immediately to infectious agents or foreign substances. These are induced by cells of myeloid lineage as well as select lymphocytes. The adaptive immune response results from sophisticated processes that sense antigens in the periphery and transport them to the secondary lymphoid organs where cells are poised in G 0 ready to differentiate into a variety of immune effector cells that deal with the antigenic threat both locally and peripherally. Similarly, adaptive immune responses are affected by cells of the myeloid and lymphoid lineage. Adaptive immune responses are associated with cytokines and antibodies that induce the accompanying inflammation. Both the innate and the adaptive immune responses induce inflammation that has the potential of leading to tissue damage. In order to prevent unregulated inflammation that causes tissue destruction and disease, selfimposed regulatory mechanisms are triggered almost simultaneously with the induction of the response to ensure its safe termination and restore immune homeostasis in the organ/tissue. The initiation of the immune response is dependent on secondary lymphoid tissue for the primary response to occur, but the immune regulation of the innate and the adaptive immune response occurs at the level of the tissue. Therefore, the regulatory response is fashioned to preserve the function of that tissue by limiting inflammation. This book seeks to connect the knowledge of immune regulation in one tissue with another. In the eye the tissue is highly protected from inflammation and is left to defeat infectious invaders with mechanisms that lack inflammation. The eye, brain, reproductive tract, and (more recently) the liver are tissues that are commonly accepted to express immune privilege. The lung and gut, however, share many of the mechanisms of immune privilege as the reader will discover when reading these chapters. The lung and gut both have high levels of TGFb and v

6 vi Preface importantly use mechanisms to suppress the antigen-presenting ability of the local dendritic cell/macrophage populations. Much of our information on immune privilege comes from the eye. In order to protect the visual pathway, highly sophisticated mechanisms cooperated to limit damaging inflammation from occurring. Hazlett s and Stein-Streilein s chapter on the eye focuses on the innate and the adaptive immune regulatory mechanisms in detail and considers the infections that occur mostly in the anterior portion of the eye, as well as how they are treated. The testes and the placental, both considered to be immune privileged sites, have developed similar and unique mechanisms to those we know that exist in the eye. Mark Hedger has very effectively completed his task of clarifying the meaning, mechanisms, and manifestations of immune privilege in the testes with academic grace. Like the eye, although inflammation in the testis is controlled by multiple overlapping mechanisms of immune suppression, the testes do not display an increased susceptibility to tumors or infections compared to other tissues and are actually rare compared to more distal tissues of the male reproductive tract. Nagamatsu and Schust focused their review on how the immune privilege in the placenta allows the genetically disparate fetus to thrive and grow without immune attack by the allogeneic maternal cells. They explain how gestational hormones and placenta-derived substance actively modulate maternal immunity and promote tolerance to the antigenically disparate fetus. Their well-conceived review considers the costs of immune privilege in the placenta in terms of increased infectious disease in mother and fetus. The liver is a tissue that is unique in its ability to regenerate and is the only tissue that can be successfully transplanted across allogeneic lines without the need for immunosuppression. Not only is it accepted, but if a tissue that is normally rejected is cotransplanted with the liver, it too is protected. Wohlleber s and Knolle s review delightfully educates us on the unique qualities of the immune privilege in the liver. Chang, DeKruyff, and Umetsu have carefully focused their review on immune homeostasis in the lungs in the regulation of asthma. Their presentation adds insight into the readers understanding of the Hygiene Hypothesis and stimulates new thoughts that connect the ideas presented about the gut and microbiome to the lung. Last, but ever so important, the bacteria in the gut are controlled by compartmentalization, monitoring, and selection of the microbial ecosystem. Some bacteria promote tolerance while others promote inflammation. Thus the prevention of harmful inflammatory responses is the result of a joint effort on the part of the host s immune system, the physiology of the host, and the members of the gut microbial community (microbiome) and can be directly influenced by the environment. Wroblewska and Nagler have elegantly simplified the complicated interactions and mechanisms of the homeostasis and privileged protection of the gut from food antigens and bacteria in their chapter. Overall, we might conclude that if left unregulated, the inflammatory response can be the most destructive aspect of the immune response. Inflammation is the offense for both the innate and the adaptive immune response. Unlike the adaptive immune response, cells of the innate immune response are not dependent on

7 Preface vii secondary lymphoid organs for their generation and function. Innate cells are able to respond immediately to danger, in part by their expression of receptors that recognize pathogen-associated molecular pattern (PAMP). Such receptors include Toll-like receptors, adhesion molecules, and scavenger molecules. Activation of PAMP receptors induces the production and release of inflammatory cytokines and complement factors. The adaptive immune response requires that the lymphocytes differentiate into effector cells and only after their differentiation they are capable of secreting inflammatory cytokines and contributing to tissue destruction. However, built into the immune response is the simultaneous production of suppressive molecules, the downregulation of activating receptors, the inhibitors of their signaling pathways, and the molecules that when linked to their ligands will induce apoptosis. Within the last decade, the importance of nonlymphoid cells in immune regulation and the immune homeostasis of tissues has become known. Molecules that were thought to be markers of lymphocytes now are known to be expressed by endothelial, epithelial, and various other stromal cells. These molecules and receptors thus allow the stromal cells to interact and regulate the lymphocytes within their environment. And yes, we continue to learn. Boston, MA Joan Stein-Streilein

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9 Contents The Eye as a Model for Immune Privilege... 1 Linda D. Hazlett and Joan Stein Streilein Immune Privilege of the Testis: Meaning, Mechanisms, and Manifestations Mark Peter Hedger The Role of Intrauterine Immune Privilege in Perinatal Infectious Diseases Takeshi Nagamatsu and Danny J. Schust The Liver as an Immune-Privileged Site Dirk Wohlleber and Percy A. Knolle Immune Homeostasis of the Lung: The Role of Regulatory NKT Cells in Asthma Ya-Jen Chang, Rosemarie H. DeKruyff, and Dale T. Umetsu Immune Homeostasis of the Gut Joanna Wroblewska and Cathryn Nagler Index ix

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11 Contributors Ya-Jen Chang Division of Immunology and Allergy, Children s Hospital, Harvard Medical School, Boston, MA, USA Rosemarie H. DeKruyff Division of Immunology and Allergy, Children s Hospital, Harvard Medical School, Boston, MA, USA Linda D Hazlett Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA Mark Peter Hedger Monash Institute of Medical Research, Monash University, Monash Medical Centre Melbourne, Clayton, VIC, Australia Percy A. Knolle Institutes of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Friedrich-Wilhelm-University Bonn, Bonn, Germany Takeshi Nagamatsu Department of Obstetrics, Gynecology and Women s Health, University of Missouri School of Medicine, Columbia, MO, USA Cathryn Nagler Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL, USA Danny J. Schust Department of Obstetrics, Gynecology and Women s Health, University of Missouri School of Medicine, Columbia, MO, USA Joan Stein-Streilein Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA Dale T Umetsu Division of Immunology and Allergy, Children s Hospital, Harvard Medical School, Boston, MA, USA Dirk Wohlleber Institutes of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Friedrich-Wilhelm-University Bonn, Bonn, Germany Joanna Wroblewska Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL, USA xi

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