ebook img

Immunology, Phenotype First: How Mutations Have Established New Principles and Pathways in Immunology PDF

233 Pages·2008·1.32 MB·English
Save to my drive
Quick download
Download
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.

Preview Immunology, Phenotype First: How Mutations Have Established New Principles and Pathways in Immunology

Current Topics in Microbiology and Immunology Volume 321 Series Editors Richard W. Compans Emory University School of Medicine, Department of Microbiology and Immunology, 3001 Rollins Research Center, Atlanta, GA 30322, USA Max D. Cooper Department of Pathology and Laboratory Medicine, Georgia Research Alliance, Emory University, 1462 Clifton Road, Atlanta, GA 30322, USA Tasuku Honjo Department of Medical Chemistry, Kyoto University, Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Hilary Koprowski Thomas Jefferson University, Department of Cancer Biology, Biotechnology Foundation Laboratories, 1020 Locust Street, Suite M85 JAH, Philadelphia, PA 19107-6799, USA Fritz Melchers Biozentrum, Department of Cell Biology, University of Basel, Klingelbergstr. 50–70, 4056 Basel Switzerland Michael B.A. Oldstone Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA Sjur Olsnes Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello 0310 Oslo, Norway Peter K. Vogt The Scripps Research Institute, Dept. of Molecular & Exp. Medicine, Division of Oncovirology, 10550 N. Torrey Pines. BCC-239, La Jolla, CA 92037, USA Bruce Beutler Editor Immunology, Phenotype First: How Mutations Have Established New Principles and Pathways in Immunology Editor Bruce Beutler Scripps Research Institute Department of Immunology 10550 N. Torrey Pines Rd. La Jolla CA 92037 USA [email protected] ISBN 978-3-540-75202-8 e-ISBN 978-3-540-75203-5 DOI 10.1007/978-3-540-75203-5 Current Topics in Microbiology and Immunology ISSN 0070-217x Library of Congress Catalog Number: 2008926501 © 2008 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights reserved, whether the whole or part of the m aterial is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September, 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, 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. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: WMX Design GmbH, Heidelberg, Germany Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Preface This monograph deals with the impact of classical genetics in immunology, provid- ing examples of how large immunological questions were solved, and new fields opened to analysis through the study of phenotypes, either spontaneous or induced. As broad as biology has become, there are those who do not fully understand what the genetic approach is, and how it differs fundamentally from most of the methods available to natural scientists. They may hold the opinion that genetics has run its course since Mendel read his paper on peas in 1865. “Why bother with classical genetics,” they may ask. “Won’t all genes be knocked out soon anyway?” Or they are intimidated by genetics, with its heavy reliance on model organisms that seem so alien. “What has C. elegans to do with me?” the questioning might go. “It doesn’t even have lymphocytes.” Such skeptics may be unaware that the mouse is fast becoming as tractable a model organism as the fly, and that humans may not be too far behind. So I would like to introduce the topic with a few words about the power of genetics, and why it has contributed so much to immunology, and to biol- ogy in general. Genetics, as the word is used here, is not merely the science of heredity, but much more than that. It is the science of exceptions: the science that takes note of heritable variation and seeks to explain it at the most fundamental level. It is the science that splits phenomena into phenotypes; then assigns them to individual genes and even portions of genes. Through genetics, unambiguous conclusions can be drawn about the function of every protein we have. Although all science seeks to explain phenomena, “phenotype” is available only to biologists. Only in biology is an organism’s life-plan written in its genes, and subject to alteration by changing a letter here or a word there. Geneticists do not shrink from applying the scientific method, but it is not their primary tool. They have something special, something that solves problems that are ineluctable through hypothesis and experimentation. Why is genetics so powerful? Several reasons might be cited. First, genetic analysis is unbiased, while hypothesis-driven research is not. In principle, hypotheses are merely tools and there is nothing personal about them, and no reason to attach a bias to them. But people like to be right about things, even when being wrong might better serve the advancement of human understanding. Time and again, scientists try to “prove the hypothesis” (and occasionally even v vi Preface write that they have done so) though they have been taught from their earliest days that the goal is to “test the hypothesis.” Genetic inquiry is different. Either the phenotype exists or it does not; either the phenotype is strong enough to map or it is not; either the mutation is found or it is not. Finding a mutation may be disappointing insofar as it may reside in a gene with well-known functions, in which case little progress may have been made. But there is no question of bending the rules. The geneticist is an explorer. His or her prior conceptions about how a biological system works will help in forming a decision as to whether a particular phenomenon is worth investigating, and may also help in deciding how to construct a screen. But preconceptions will not mislead. Second, genetics is calculated to produce surprise. In foreswearing hypotheses, there is a certain humility, an admission that biological complexity outstrips our ability to guess at how a given process works. Instead, we surrender to the possibil- ity of surprise, and even trust in surprise. Of course, it may be argued that hypothe- sis-driven research also produces surprise. One devises experiments to test hypotheses, and the outcome may run contrary to expectation. All the same, the genetic approach does not even ask a question. It merely seeks exceptions to the status quo. And some of those exceptions may be bizarre, or even undreamed of. Third, genetics asks why things go wrong. It is a deconstructive process, rather than one of invention. It must be granted that looking at the effects of damage is not unique to genetics, but all the same, it is fundamental to genetics, and is a powerful approach whenever it is applied in biology. By studying the effects of strokes, tumors, and traumatic injuries, clinical neurologists and pathologists were able to deduce the function of many parts of the human brain. For example, they inferred that a “homunculus” must exist in the posterior frontal cortex (and close by it, a second homunculus in the anterior parietal cortex), wherein each part of the body is spatially reflected, so that a lesion might affect adjacent areas of the body: the face, neck, arm, and trunk, for example, or the trunk and the legs and feet; but never the face and feet without involvement of intermediate structures. Geneticists follow much the same practice as neurologists, focusing intently on the effects of sponta- neous mutations or those induced at random by mutagens, brought to their attention because something has gone wrong. They are able to decipher the function of each part of the genome, which contains its own “homunculus” just as the brain does, but one that is enormously more fractured and complex. The proteins that are required for limb development (or innate immune sensing, or any complex func- tion) each have their physical representation in the genome, and though the corre- sponding genes may be widely scattered, they can all be found through mutagenesis and careful phenotypic screening. Fourth, genetic conclusions are comparatively solid. The reliability of genetic conclusions is derived from the reliability of the technology upon which genetic research is based (the unbiased mapping of phenotypes to critical regions, and ultimately, DNA sequencing). This is not to say that geneticists are never wrong, or that there was never a case in which a phenotype was incor- rectly attributed to a particular mutation. But such mistakes are rare. When genetic data conflict with biochemical data, or data developed from immunological Preface vii assays, or data from cell transfection studies, or any combination thereof, the genetic data are usually correct. The stories told in this book are some of the most important in immunology. Each begins with a phenotype and comes to a profound conclusion about cause. In some cases autoimmunity was at issue; in others cancer; in others a failure to detect or respond to infection. But in all instances, the biological function of a given pro- tein or protein family was discovered. Finding the mechanism through which that protein functions presents the next challenge, and in all cases, the challenge has yet to be met in full. Ultimately, the geneticist must usually make hypotheses after all. Usually he or she is not alone: the field has been opened to many other workers once the key genetic advance has been made. Reverse genetic methods are among the most powerful tools to be used in testing these hypotheses. Again, the situation might be compared to that of the neuroscien- tist, who creates brain lesions in experimental animals in order to test the function of distinct parts of the brain, alone or in conjunction with one another. Reverse geneticists, who deliberately target genes for destruction, attempt to test the func- tion of particular parts of the genome. In both cases, nothing may be found, either because of functional redundancy, or because the investigator simply does not know what to look for. But at times, concrete and specific understanding is gained. The interpretation of phenotypes is facilitated when there is a strong conceptual framework within which to operate. This is certainly the case in immunology, a relatively sophisticated science that has taught us quite a lot, though enormously less than it has left to teach. We know of innate immunity and adaptive immunity; we know of humoral immunity and cellular immunity. We know of antibody and complement. And we know of T cells, B cells, T-regulatory cells, antigen-presenting cells, natural killer cells, macrophages, and granulocytes. Each has a distinct role to play in protecting us from infection, or conversely, in causing inflammatory dis- ease. Mutations can make things go very wrong where every cell and protein just mentioned is concerned. Yet we still lack a fully coherent understanding of exactly why we reject cells from unrelated individuals yet tolerate the placental allograft. We do not know why some among us develop autoimmunity while the majority does not. We do not understand why all microbes are recognized (for some, recog- nition receptors have yet to be found), and why some defy the immune response so effectively even when they are detected. This is the perfect playground for a geneti- cist: a desirable mixture of ignorance and understanding. And it is likely to remain this way for a very long time. Yes, all genes will soon be knocked out. But many knockout mutations will be embryonic lethal, or will have other effects that mask the essential immunological function of the proteins concerned. Others will present no obvious phenotype, not because the gene in question has no function, but because we simply do not know what to look for. There is no escape from starting with phenotype. Biologists will always return to the phenotype-first approach. We live at the dawn of a golden age of genetics, in which a phenovariant may be seen in the morning and the causal mutation known by noon. Stories formally similar to the ones presented here may soon be increasingly common, and we must all hope viii Preface that they will be. But it should not be forgotten that these particular discoveries— whether in mice or in humans, most of them pursued before the respective genomes were sequenced and some of them at a time when sequencing was performed mostly manually—were heroic in their own time and have laid the foundation for some of the most important concepts in immunology. La Jolla, USA Bruce Beutler Contents Part I Immunodeficiency The Forward Genetic Dissection of Afferent Innate Immunity.................. 3 B. Beutler, E.M.Y. Moresco Genetic Analysis of Resistance to Infections in Mice: A/J meets C57BL/6J ....................................................................................... 27 J.-F. Marquis, P. Gros Host Defenses Against Human Papillomaviruses: Lessons from Epidermodysplasia Verruciformis ......................................... 59 G. Orth Innate Resistance to Flavivirus Infections and the Functions of 2´-5´ Oligoadenylate Synthetases .............................................................. 85 T. Mashimo, D. Simon-Chazottes, J.-L. Guénet Cmv1and Natural Killer Cell Responses to Murine Cytomegalovirus Infection ............................................................................. 101 A.A. Scalzo, W.M. Yokoyama Genetic Dissection of Host Resistance to Mycobacterium tuberculosis: The sst1 Locus and the Ipr1 Gene ........................................... 123 I. Kramnik Part II Self-Reactivity Scurfy, the Foxp3 Locus, and the Molecular Basis of Peripheral Tolerance .................................................................................. 151 M.W. Appleby, F. Ramsdell Fevers, Genes, and Innate Immunity ............................................................ 169 J.G. Ryan, D.L. Kastner ix x Contents Itchy Mice: The Identifi cation of a New Pathway for the Development of Autoimmunity .......................................................... 185 L.E. Matesic, N.G. Copeland, N.A. Jenkins TIM Gene Family and Their Role in Atopic Diseases ................................. 201 D.T. Umetsu, S.E. Umetsu, G.J. Freemen, R.H. DeKruyff Index ................................................................................................................. 217

Description:
This monograph deals with the impact of classical genetics in immunology, prov- ing examples of how large immunological questions were solved, and new fields opened to analysis through the study of phenotypes, either spontaneous or induced. As broad as biology has become, there are those who do not
See more

The list of books you might like

Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.