Immuno
`bidlogye
`
`MARK SHLOMCHIK
`
`CHARLES A JANEWAY PAUL TRAVERS
`MARK WALPORT
`
`1 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Immunobiology Table of contents
`
`
`
`Short contents
`
`Preface to the Fifth Edition
`
`Acknowledgments
`
`Part I. An Introduction to Immunobiology and Innate Immunity
`
`1. Basic Concepts in Immunology
`
`2. Innate Immunity
`
`Part II. The Recognition of Antigen
`
`3. Antigen Recognition by B-cell and T-cell Receptors
`
`4. The Generation of Lymphocyte Antigen Receptors
`
`5. Antigen Presentation to T Lymphocytes
`
`Part III. The Development of Mature Lymphocyte Receptor Repertoires
`
`6. Signaling Through Immune System Receptors
`
`7. The Development and Survival of Lymphocytes
`
`Part IV. The Adaptive Immune Response
`
`8. T Cell-Mediated Immunity
`
`9. The Humoral Immune Response
`
`10. Adaptive Immunity to Infection
`
`Part V. The Immune System in Health and Disease
`
`11. Failures of Host Defense Mechanisms
`
`12. Allergy and Hypersensitivity
`
`13. Autoimmunity and Transplantation
`
`14. Manipulation of the Immune Response
`
`Afterword. Evolution of the Immune System: Past, Present, and Future, by Charles A.
`Janeway, Jr.
`
`Appendix I. Immunologists' Toolbox
`
`Immunization.
`
`2 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`The detection, measurement, and characterization of antibodies and their use as research
`and diagnostic tools.
`
`Isolation of lymphocytes.
`
`Characterization of lymphocyte specificity, frequency, and function.
`
`Detection of immunity in vivo.
`
`Manipulation of the immune system.
`
`Appendix II. CD Antigens.
`
`Appendix III. Cytokines and Their Receptors.
`
`Appendix IV. Chemokines and Their Receptors.
`
`Appendix V. Immunological Constants.
`
`Biographies
`
`Glossary
`
`
`
`Full contents
`
`Preface to the Fifth Edition
`
`Acknowledgments
`
`Part I. An Introduction to Immunobiology and Innate Immunity
`
`1. Basic Concepts in Immunology
`
`The components of the immune system.
`
`Principles of innate and adaptive immunity.
`
`The recognition and effector mechanisms of adaptive immunity.
`
`Summary to Chapter 1.
`
`References
`
`2. Innate Immunity
`
`The front line of host defense.
`
`The complement system and innate immunity.
`
`Receptors of the innate immune system.
`
`Induced innate responses to infection.
`
`Summary to Chapter 2.
`
`3 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`References
`
`Part II. The Recognition of Antigen
`
`3. Antigen Recognition by B-cell and T-cell Receptors
`
`The structure of a typical antibody molecule.
`
`The interaction of the antibody molecule with specific antigen.
`
`Antigen recognition by T cells.
`
`Summary to Chapter 3.
`
`References
`
`4. The Generation of Lymphocyte Antigen Receptors
`
`The generation of diversity in immunoglobulins.
`
`T-cell receptor gene rearrangement.
`
`Structural variation in immunoglobulin constant regions.
`
`Summary to Chapter 4.
`
`References
`
`5. Antigen Presentation to T Lymphocytes
`
`The generation of T-cell receptor ligands.
`
`The major histocompatibility complex and its functions.
`
`Summary to Chapter 5.
`
`References
`
`Part III. The Development of Mature Lymphocyte Receptor Repertoires
`
`6. Signaling Through Immune System Receptors
`
`General principles of transmembrane signaling.
`
`Antigen receptor structure and signaling pathways.
`
`Other signaling pathways that contribute to lymphocyte behavior.
`
`Summary to Chapter 6.
`
`References
`
`7. The Development and Survival of Lymphocytes
`
`Generation of lymphocytes in bone marrow and thymus.
`
`4 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`The rearrangement of antigen-receptor gene segments controls lymphocyte development.
`
`Interaction with self antigens selects some lymphocytes for survival but eliminates
`others.
`
`Survival and maturation of lymphocytes in peripheral lymphoid tissues.
`
`Summary to Chapter 7.
`
`References
`
`Part IV. The Adaptive Immune Response
`
`8. T Cell-Mediated Immunity
`
`The production of armed effector T cells.
`
`General properties of armed effector T cells.
`
`T cell-mediated cytotoxicity.
`
`Macrophage activation by armed CD4 TH1 cells.
`
`Summary to Chapter 8.
`
`References
`
`9. The Humoral Immune Response
`
`B-cell activation by armed helper T cells.
`
`The distribution and functions of immunoglobulin isotypes.
`
`The destruction of antibody-coated pathogens via Fc receptors.
`
`Summary to Chapter 9.
`
`References
`
`10. Adaptive Immunity to Infection
`
`Infectious agents and how they cause disease.
`
`The course of the adaptive response to infection.
`
`The mucosal immune system.
`
`Immunological memory.
`
`Summary to Chapter 10.
`
`References
`
`Part V. The Immune System in Health and Disease
`
`11. Failures of Host Defense Mechanisms
`
`5 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Pathogens have evolved various means of evading or subverting normal host defenses.
`
`Inherited immunodeficiency diseases.
`
`Acquired immune deficiency syndrome.
`
`Summary to Chapter 11.
`
`References
`
`12. Allergy and Hypersensitivity
`
`The production of IgE.
`
`Effector mechanisms in allergic reactions.
`
`Hypersensitivity diseases.
`
`Summary to Chapter 12.
`
`References
`
`13. Autoimmunity and Transplantation
`
`Autoimmune responses are directed against self antigens.
`
`Responses to alloantigens and transplant rejection.
`
`Self-tolerance and its loss.
`
`Summary to Chapter 13.
`
`References
`
`14. Manipulation of the Immune Response
`
`Extrinsic regulation of unwanted immune responses.
`
`Using the immune response to attack tumors.
`
`Manipulating the immune response to fight infection.
`
`Summary to Chapter 14.
`
`References
`
`Afterword. Evolution of the Immune System: Past, Present, and Future, by Charles A.
`Janeway, Jr.
`
`Evolution of the innate immune system.
`
`Evolution of the adaptive immune response.
`
`The importance of immunological memory in fixing adaptive immunity in the genome.
`
`Future directions of research in immunobiology.
`
`6 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Summary of the Afterword.
`
`Appendix I. Immunologists' Toolbox
`
`Immunization.
`
`The detection, measurement, and characterization of antibodies and their use as research
`and diagnostic tools.
`
`Isolation of lymphocytes.
`
`Characterization of lymphocyte specificity, frequency, and function.
`
`Detection of immunity in vivo.
`
`Manipulation of the immune system.
`
`Appendix II. CD Antigens.
`
`Appendix III. Cytokines and Their Receptors.
`
`Appendix IV. Chemokines and Their Receptors.
`
`Appendix V. Immunological Constants.
`
`Biographies
`
`Glossary
`
`
`7 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Immunobiology
`
`
`Charles A. Janeway Jr.
`Yale University School of Medicine
`
`Paul Travers
`Anthony Nolan Research Institute, London
`
`Mark Walport
`Imperial College School of Medicine, London
`
`Mark J. Shlomchik
`Yale University School of Medicine
`
`
`Vice President: Denise Schanck
`
`Text Editors: Penelope Austin, Eleanor Lawrence
`
`Managing Editor: Sarah Gibbs
`
`Editorial Assistant: Mark Ditzel
`
`Managing Production Editor: Emma Hunt
`
`Production Assistant: Angela Bennett
`
`New Media Editor: Michael Morales
`
`Copyeditor: Len Cegielka
`
`Indexer: Liza Furnival
`
`Illustration and Layout: Blink Studio, London
`
`Manufacturing: Marion Morrow, Rory MacDonald
`
`Garland Publishing, New York
`
`ISBN 0 8153 3642 X (paperback) Garland
`
`ISBN 0 4430 7098 9 (paperback) Churchill Livingstone
`
`ISBN 0 4430 7099 7 (paperback) International Student Edition
`
`© 2001 by Garland Publishing
`
`Library of Congress Cataloging-in-Publication Data
`
`Immunobiology : the immune system in health and disease / Charles A. Janeway, Jr. ... [et al.].--
`5th ed.
`
`8 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`p. cm.
`
`Includes bibliographical references and index.
`
`ISBN 0-8153-3642-X (pbk.) 1. Immunology. 2. Immunity. I. Janeway, Charles. II. Title.
`
`QR181 .I454 2001
`
`616.07'9--dc21 2001016039
`
`
`
`
`
`Acknowledgments
`
`Text
`
`We would like to thank the following experts who read parts or the whole of the fourth edition
`chapters indicated and provided us with invaluable advice in developing this fifth edition.
`
`
`Chapter 2: Ivan Lefkovits, Basel Institute for Immunology, Switzerland; Anthony T. Vella,
`Oregon State University.
`
`Chapter 3: Sherie Morrison, University of California, Los Angeles; Michael S. Neuberger,
`MRC Laboratory of Molecular Biology, Cambridge.
`
`Chapter 4: Ian A. Wilson, The Scripps Research Institute, La Jolla; Peter Cresswell, Yale
`University School of Medicine; Mark M. Davis, Stanford University School of Medicine; Paul
`M. Allen, Washington University School of Medicine, St. Louis; John Trowsdale, Cambridge
`University.
`
`Chapter 5: John C. Cambier, National Jewish Medical and Research Center, Denver; Dan R.
`Littman, Skirball Institute of Biomolecular Medicine, New York; Arthur Weiss, The University
`of California, San Francisco.
`
`Chapter 6: Richard R. Hardy, Fox Chase Cancer Center, Philadelphia; John G. Monroe,
`University of Pennsylvania Medical Center; Max D. Cooper, Comprehensive Cancer Center,
`University of Alabama; David Nemazee, The Scripps Research Institute, La Jolla; Michel C.
`Nussenzweig, Rockefeller University, New York.
`
`Chapter 7: Alexander Y. Rudensky, University of Washington School of Medicine; Johnathan
`Sprent, The Scripps Research Institute, La Jolla; Leslie J. Berg, University of Massachusetts
`Medical School; Adrian C. Hayday, Guy's King's St Thomas' Medical School, University of
`London; Mike Owen, Imperial Cancer Research Fund, London; Robert H. Swanborg,
`Washington State University; Steve C. Jameson, University of Minnesota.
`
`Chapter 8: Donna Paulnock, University of Wisconsin; Tim Springer, Center for Blood
`Research, Harvard Medical School; Marc K. Jenkins, University of Minnesota; Jürg Tschopp,
`University of Lausanne; Ralph Steinman, The Rockefeller University, New York.
`
`
`9 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Chapter 9: Michael C. Carroll, The Center for Blood Research, Harvard Medical School; E.
`Sally Ward, University of Texas; Jeffrey Ravetch, Rockefeller University, New York; Garnett
`Kelsoe, Duke University Medical Center, Durham; Douglas Fearon, University of Cambridge.
`
`Chapter 10: Alan Ezekowitz, Massachusetts General Hospital, Harvard Medical School; Eric
`Pamer, Yale University School of Medicine; Adrian C. Hayday, Guy's King's St Thomas'
`Medical School, University of London.
`
`Chapter 11: Fred Rosen, Center for Blood Research, Harvard Medical School; Robin A. Weiss,
`Royal Free and University College Medical School, London.
`
`Chapter 12: Raif S. Geha, Children's Hospital, Harvard Medical School; Hugh A. Sampson,
`Mount Sinai Medical Center, New York; Philip W. Askenase, Yale University School of
`Medicine; Jeffrey Ravetch, The Rockefeller University, New York.
`
`Chapter 13: Diane Mathis, Harvard Medical School; Christopher C. Goodnow, John Curtin
`School of Medical Research, Canberra; Jeffrey Ravetch, The Rockefeller University, New York;
`Kathryn Wood, University of Oxford; Hugh Auchincloss, Massachusetts General Hospital,
`Harvard Medical School; Joseph E. Craft, Yale University School of Medicine; Jan Erikson, The
`Wistar Institute, University of Pennsylvania; Keith Elkon, Cornell University, New York; Fiona
`Powrie, University of Oxford.
`
`Chapter 14: Thierry Boon, Ludwig Institute for Cancer Research, Brussels; Gerry Crabtree,
`Stanford University School of Medicine; Jeffrey A. Bluestone, University of Chicago.
`
`Appendix II: Joost J. Oppenheim, National Cancer Institute Frederick Cancer Research and
`Development Center, Maryland.
`
`Appendix III: Jason Cyster, University of California, San Francisco; Craig Gerard, Children's
`Hospital, Harvard Medical School.
`
`Immunobiology Animations
`
`We would like to thank Hung-Sia Teh of the University of British Columbia and David A.
`Lawlor of the Rochester Institute of Technology, for reviewing these animations.
`
`Photographs
`
`The following photographs have been reproduced with the kind permission of the journal in
`which they originally appeared.
`
`
`Chapter 1
`
`Fig. 1.1 courtesy of Yale University Harvey Cushing/John Hay Whitney Medical Library.
`
`Fig. 1.9 photo from The Journal of Experimental Medicine 1972, 135:200-214. © 1972 The
`Rockefeller University Press.
`
`
`
`Chapter 2
`
`10 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Fig. 2.10 photo from FEBS Letters 1989, 250:78-84. © 1989 Elsevier Science.
`
`Fig. 2.13 photo from The Journal of Immunology 1990, 144:2287-2294. © 1990 The American
`Association of Immunologists.
`
`Fig. 2.24 photos from Blut 1990, 60:309-318. © 1990 Springer-Verlag.
`
`Fig. 2.39 photo from Nature 1994, 367:338-345. © 1994 Macmillan Magazines Limited.
`
`
`
`Chapter 3
`
`Fig. 3.1 photo from Nature 1992, 360:369-372. © 1992 Macmillan Magazines Limited.
`
`Fig. 3.4 photo from Advances in Immunology 1969, 11:1-30. © 1969 Academic Press.
`
`Fig. 3.8 panel a from Science 1990, 248:712-719. © 1990 American Association for the
`Advancement of Science; panel b from Structure 1993, 1:83-93 © 1993 Current Biology.
`
`Fig. 3.10 from Science 1986, 233:747-753. © 1986 American Association for the Advancement
`of Science.
`
`Fig. 3.13 photos from Science 1996, 274:209-219. © 1996 American Association for the
`Advancement of Science.
`
`Fig. 3.14 panel a from Journal of Biological Chemistry 1998, 263:10541-10544. © 1998
`American Society for Biochemistry and Molecular Biology.
`
`Fig. 3.18 from Nature 1997, 387:630-634. © 1997 Macmillan Magazines Limited.
`
`Fig. 3.27 from Science 1996, 274:209-219. © 1996 American Association for the Advancement
`of Science.
`
`Fig 3.28 from Science 1999, 286:1913-1921. © 1999 American Association for the
`Advancement of Science.
`
`
`
`Chapter 4
`
`Fig. 4.23 top photo from the European Journal of Immunology 1988, 18:1001-1008. © 1988
`Wiley-VCH.
`
`
`
`Chapter 5
`
`Fig. 5.4 from Science 1995, 268:533-539. © 1995 American Association for the Advancement of
`Science.
`
`Fig. 5.7 model structure from Cell 1996, 84:505-507. © 1996 Cell Press.
`
`11 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Fig. 5.18 photo from Nature 1996, 384:188-192. © 1996 Macmillan Magazines Limited.
`
`
`
`Chapter 7
`
`Fig. 7.3 panel b from the European Journal of Immunology 1987, 17:1473-1484. © 1987 VCH
`Verlagsgesellschaft mbH.
`
`Fig. 7.10 photos from Nature 1994, 372:100-103. © 1994 Macmillan Magazines Limited.
`
`Fig. 7.32 photos from International Immunology 1996, 8:1537-1548. © 1996 Oxford University
`Press.
`
`
`
`Chapter 8
`
`Fig. 8.2 bottom panel from Nature 1997, 388:787-792. © 1997 Macmillan Magazines Limited.
`
`Fig. 8.29 panel c from Second International Workshop on Cell Mediated Cytoxicity. Eds. P.A.
`Henkart, and E. Martz. © 1985 Plenum Press.
`
`Fig. 8.37 panels a and b from Second International Workshop on Cell Mediated Cytoxicity . Eds.
`P.A. Henkart, and E. Martz. © 1985 Plenum Press; panel c from Immunology Today 1985, 6:21-
`27. © 1985 Elsevier Science.
`
`
`
`Chapter 9
`
`Fig. 9.15 left panel from The Journal of Immunology 1989, 134:1349-1359. © 1989 The
`American Association of Immunologists. Middle and right panels from Annual Reviews of
`Immunology 1989, 7:91-109. © 1989 Annual Reviews.
`
`Fig. 9.21 from Nature 1994, 372:336-343. © 1994 Macmillan Magazines Limited.
`
`Fig. 9.27 planar conformation from the European Journal of Immunology 1988, 18:1001-1008.
`© 1988 Wiley-VCH.
`
`
`
`Chapter 11
`
`Fig. 11.6 top panels from International Reviews of Experimental Pathology 1986, 28:45-78,
`edited by M.A. Epstein and G.W. Richter. © 1986, Academic Press.
`
`Fig. 11.26 from Cell 1998, 93:665-671. © 1998 Cell Press Limited.
`
`Fig. 11.27 from the Nature 1995, 373:117-122. © 1995 Macmillan Magazines Limited.
`
`12 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`
`
`Chapter 13
`
`Fig. 13.20 photo from Cell 1989, 59:247-255. © Cell Press.
`
`Fig. 13.34 photos from The Journal of Experimental Medicine 1992, 176:1355-1364. © 1992
`The Rockefeller University Press.
`
`
`
`Chapter 14
`
`Fig. 14.16 photos from Mechanisms of Cytoxicity by Natural Killer Cells, edited by R.B.
`Herberman and D.M. Callewaert © 1985 Academic Press.
`
`
`
`Appendix I
`
`Fig. A.39 from Nature 2000, 403:503-511. © 2000 Macmillan Magazines Limited.
`
`
`
`13 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`Immunobiology Part I. An Introduction to Immunobiology and Innate Immunity
`
`CHAPTER 1. Basic Concepts in Immunology
`
` Introduction to Chapter 1
`
` (cid:198)
`
`(cid:198) The components of the immune system
`
`(cid:198) Principles of innate and adaptive immunity
`
`(cid:198) The recognition and effector mechanisms of adaptive immunity
`
`(cid:198) Summary to Chapter 1
`
`
`
`Introduction to Chapter 1
`
`Immunology is a relatively new science. Its origin is usually attributed to Edward Jenner (Fig. 1.1), who discovered
`in 1796 that cowpox, or vaccinia, induced protection against human smallpox, an often fatal disease. Jenner called his
`procedure vaccination, and this term is still used to describe the inoculation of healthy individuals with weakened or
`attenuated strains of disease-causing agents to provide protection from disease. Although Jenner's bold experiment
`was successful, it took almost two centuries for smallpox vaccination to become universal, an advance that enabled
`the World Health Organization to announce in 1979 that smallpox had been eradicated (Fig. 1.2), arguably the
`greatest triumph of modern medicine.
`
`
`Figure 1.1. Edward Jenner. Portrait by John Raphael Smith. Reproduced courtesy of Yale University, Harvey
`Cushing/John Hay Whitney Medical Library.
`
`
`
`
`Figure 1.2. The eradication of smallpox by vaccination. After a period of 3 years in which no cases of smallpox
`were recorded, the World Health Organization was able to announce in 1979 that smallpox had been eradicated.
`
`
`
`When Jenner introduced vaccination he knew nothing of the infectious agents that cause disease: it was not until late
`in the 19th century that Robert Koch proved that infectious diseases are caused by microorganisms, each one
`
`14 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`responsible for a particular disease, or pathology. We now recognize four broad categories of disease-causing
`microorganisms, or pathogens: these are viruses, bacteria, pathogenic fungi, and other relatively large and complex
`eukaryotic organisms collectively termed parasites.
`
`The discoveries of Koch and other great 19th century microbiologists stimulated the extension of Jenner's strategy of
`vaccination to other diseases. In the 1880s, Louis Pasteur devised a vaccine against cholera in chickens, and
`developed a rabies vaccine that proved a spectacular success upon its first trial in a boy bitten by a rabid dog. These
`practical triumphs led to a search for the mechanism of protection and to the development of the science of
`immunology. In 1890, Emil von Behring and Shibasaburo Kitasato discovered that the serum of vaccinated
`individuals contained substances which they called antibodies
`that specifically bound to the relevant pathogen.
`
`A specific immune response, such as the production of antibodies against a particular pathogen, is known as an
`adaptive immune response, because it occurs during the lifetime of an individual as an adaptation to infection with
`that pathogen. In many cases, an adaptive immune response confers lifelong protective immunity to reinfection with
`the same pathogen. This distinguishes such responses from innate immunity, which, at the time that von Behring and
`Kitasato discovered antibodies, was known chiefly through the work of the great Russian immunologist Elie
`Metchnikoff. Metchnikoff discovered that many microorganisms could be engulfed and digested by phagocytic cells,
`which he called macrophages. These cells are immediately available to combat a wide range of pathogens without
`requiring prior exposure and are a key component of the innate immune system. Antibodies, by contrast, are
`produced only after infection, and are specific for the infecting pathogen. The antibodies present in a given person
`therefore directly reflect the infections to which he or she has been exposed.
`
`Indeed, it quickly became clear that specific antibodies can be induced against a vast range of substances. Such
`substances are known as antigens because they can stimulate the generation of antibodies. We shall see, however,
`that not all adaptive immune responses entail the production of antibodies, and the term antigen is now used in a
`broader sense to describe any substance that can be recognized by the adaptive immune system.
`
`Both innate immunity and adaptive immune responses depend upon the activities of white blood cells, or leukocytes.
`Innate immunity largely involves granulocytes and macrophages. Granulocytes, also called polymorphonuclear
`leukocytes, are a diverse collection of white blood cells whose prominent granules give them their characteristic
`staining patterns; they include the neutrophils, which are phagocytic. The macrophages of humans and other
`vertebrates are presumed to be the direct evolutionary descendants of the phagocytic cells present in simpler animals,
`such as those that Metchnikoff observed in sea stars. Adaptive immune responses depend upon lymphocytes, which
`provide the lifelong immunity that can follow exposure to disease or vaccination. The innate and adaptive immune
`systems together provide a remarkably effective defense system. It ensures that although we spend our lives
`surrounded by potentially pathogenic microorganisms, we become ill only relatively rarely. Many infections are
`handled successfully by the innate immune system and cause no disease; others that cannot be resolved by innate
`immunity trigger adaptive immunity and are then overcome successfully, followed by lasting immunological
`memory.
`
`The main focus of this book will be on the diverse mechanisms of adaptive immunity, whereby specialized classes of
`lymphocytes recognize and target pathogenic microorganisms or the cells infected with them. We shall see, however,
`that all the cells involved in innate immune responses also participate in adaptive immune responses. Indeed, most of
`the effector actions that the adaptive immune system uses to destroy invading microorganisms depend upon linking
`antigen-specific recognition to the activation of effector mechanisms that are also used in innate host defense.
`
`In this chapter, we first introduce the cells of the immune system, and the tissues in which they develop and through
`which they circulate or migrate. In later sections, we outline the specialized functions of the different types of cells
`and the mechanisms by which they eliminate infection.
`
`
`
`
`The components of the immune system.
`
`The cells of the immune system originate in the bone marrow, where many of them also mature. They then migrate to
`guard the peripheral tissues, circulating in the blood and in a specialized system of vessels called the lymphatic
`system.
`
`15 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`1-1. The white blood cells of the immune system derive from precursors in the bone marrow.
`
`All the cellular elements of blood, including the red blood cells that transport oxygen, the platelets that trigger blood
`clotting in damaged tissues, and the white blood cells of the immune system, derive ultimately from the same
`the hematopoietic stem cells in the bone marrow. As these stem cells can give rise to
`progenitor or precursor cells
`all of the different types of blood cells, they are often known as pluripotent hematopoietic stem cells. Initially, they
`give rise to stem cells of more limited potential, which are the immediate progenitors of red blood cells, platelets, and
`the two main categories of white blood cells. The different types of blood cell and their lineage relationships are
`summarized in Fig. 1.3. We shall be concerned here with all the cells derived from the common lymphoid progenitor
`and the myeloid progenitor, apart from the megakaryocytes and red blood cells.
`
`
`
`
`Figure 1.3. All the cellular elements of blood, including the lymphocytes of the adaptive immune system, arise
`from hematopoietic stem cells in the bone marrow. These pluripotent cells divide to produce two more specialized
`types of stem cells, a common lymphoid progenitor that gives rise to the T and B lymphocytes responsible for
`adaptive immunity, and a common myeloid progenitor that gives rise to different types of leukocytes (white blood
`cells), erythrocytes (red blood cells that carry oxygen), and the megakaryocytes that produce platelets that are
`important in blood clotting. The existence of a common lymphoid progenitor for T and B lymphocytes is strongly
`supported by current data. T and B lymphocytes are distinguished by their sites of differentiation T cells in the
`thymus and B cells in the bone marrow and by their antigen receptors. Mature T and B lymphocytes circulate
`between the blood and peripheral lymphoid tissues. After encounter with antigen, B cells differentiate into antibody-
`secreting plasma cells, whereas T cells differentiate into effector T cells with a variety of functions. A third lineage of
`lymphoid-like cells, the natural killer cells, derive from the same progenitor cell but lack the antigen-specificity that
`is the hallmark of the adaptive immune response (not shown). The leukocytes that derive from the myeloid stem cell
`are the monocytes, the dendritic cells, and the basophils, eosinophils, and neutrophils. The latter three are collectively
`
`16 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`termed either granulocytes, because of the cytoplasmic granules whose characteristic staining gives them a distinctive
`appearance in blood smears, or polymorphonuclear leukocytes, because of their irregularly shaped nuclei. They
`circulate in the blood and enter the tissues only when recruited to sites of infection or inflammation where neutrophils
`are recruited to phagocytose bacteria. Eosinophils and basophils are recruited to sites of allergic inflammation, and
`appear to be involved in defending against parasites. Immature dendritic cells travel via the blood to enter peripheral
`tissues, where they ingest antigens. When they encounter a pathogen, they mature and migrate to lymphoid tissues,
`where they activate antigen-specific T lymphocytes. Monocytes enter tissues, where they differentiate into
`macrophages; these are the main tissue-resident phagocytic cells of the innate immune system. Mast cells arise from
`precursors in bone marrow but complete their maturation in tissues; they are important in allergic responses.
`
`
`
`The myeloid progenitor is the precursor of the granulocytes, macrophages, dendritic cells, and mast cells of the
`immune system. Macrophages are one of the three types of phagocyte in the immune system and are distributed
`widely in the body tissues, where they play a critical part in innate immunity. They are the mature form of
`monocytes, which circulate in the blood and differentiate continuously into macrophages upon migration into the
`tissues. Dendritic cells are specialized to take up antigen and display it for recognition by lymphocytes. Immature
`dendritic cells migrate from the blood to reside in the tissues and are both phagocytic and macropinocytic, ingesting
`large amounts of the surrounding extracellular fluid. Upon encountering a pathogen, they rapidly mature and migrate
`to lymph nodes.
`
`Mast cells, whose blood-borne precursors are not well defined, also differentiate in the tissues. They mainly reside
`near small blood vessels and, when activated, release substances that affect vascular permeability. Although best
`known for their role in orchestrating allergic responses, they are believed to play a part in protecting mucosal surfaces
`against pathogens.
`
`The granulocytes are so called because they have densely staining granules in their cytoplasm; they are also
`sometimes called polymorphonuclear leukocytes because of their oddly shaped nuclei. There are three types of
`granulocyte, all of which are relatively short lived and are produced in increased numbers during immune responses,
`when they leave the blood to migrate to sites of infection or inflammation. Neutrophils, which are the third
`phagocytic cell of the immune system, are the most numerous and most important cellular component of the innate
`immune response: hereditary deficiencies in neutrophil function lead to overwhelming bacterial infection, which is
`fatal if untreated. Eosinophils are thought to be important chiefly in defense against parasitic infections, because their
`numbers increase during a parasitic infection. The function of basophils is probably similar and complementary to
`that of eosinophils and mast cells; we shall discuss the functions of these cells in Chapter 9 and their role in allergic
`inflammation in Chapter 12. The cells of the myeloid lineage are shown in Fig. 1.4.
`
`17 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`
`
`
`Figure 1.4. Myeloid cells in innate and adaptive immunity. Cells of the myeloid lineage perform various important
`functions in the immune response. The cells are shown schematically in the left column in the form in which they will
`be represented throughout the rest of the book. A photomicrograph of each cell type is shown in the center column.
`Macro-phages and neutrophils are primarily phagocytic cells that engulf pathogens and destroy them in intracellular
`vesicles, a function they perform in both innate and adaptive immune responses. Dendritic cells are phagocytic when
`they are immature and take up pathogens; after maturing they act as antigen-presenting cells to T cells, initiating
`adaptive immune responses. Macrophages can also present antigens to T cells and can activate them. The other
`
`18 of 884
`
`OnCusp
`Ex. 1010
`
`

`

`myeloid cells are primarily secretory cells that release the contents of their prominent granules upon activation via
`antibody during an adaptive immune response. Eosinophils are thought to be involved in attacking large antibody-
`coated parasites such as worms, whereas the function of basophils is less clear. Mast cells are tissue cells that trigger
`a local inflammatory response to antigen by releasing substances that act on local blood vessels. Photographs
`courtesy of N. Rooney and B. Smith.
`
`The common lymphoid progenitor gives rise to the lymphocytes, with which most of this book will be concerned.
`There are two major types of lymphocyte: B lymphocytes or B cells, which when activated differentiate into plasma
`cells that secrete antibodies; and T lymphocytes or T cells, of which there are two main classes. One class
`differentiates on activation into cytotoxic T cells, which kill cells infected with viruses, whereas the second class of T
`cells differentiates into cells that activate other cells such as B cells and macrophages.
`
`Most lymphocytes are small, featureless cells with few cytoplasmic organelles and much of the nuclear chromatin
`inactive, as shown by its condensed state (Fig. 1.5). This appearance is typical of inactive cells and it is not surprising
`that, as recently as the early 1960s, textbooks could describe these cells, now the central focus of immunology, as
`having no known function. Indeed, these small lymphocytes have no functional activity until they encounter antigen,
`which is necessary to trigger their proliferation and the differentiation of their specialized functional characteristics.
`
`
`Figure 1.5. Lymphocytes are mostly small and inactive cells. The left panel shows a light micrograph of a small
`lymphocyte surrounded by red blood cells. Note the condensed chromatin of the nucleus, indicating little trans-
`criptional activity, the relative absence of cytoplasm, and the small size. The right panel shows a transmission
`electron micrograph of a small lymphocyte. Note the condensed chromatin, the scanty cytoplasm and the absence of
`rough endoplasmic reticulum and other evidence of functional activity. Photographs courtesy of N. Rooney.
`
`
`
`Lymphocytes are remarkable in being able to mount a specific immune response against virtually any foreign antigen.
`This is possible because each individual lymphocyte matures bearing a unique variant of a prototype antigen receptor,
`so that the population of T and B lymphocytes collectively bear a huge repertoire of receptors that are highly diverse
`in their antigen-binding sites. The B-cell antigen receptor (BCR) is a membrane-bound form of the antibody that the
`B cell will secrete after activation and differentiation to plasma cells. Antibody molecules as a class are known as
`immunoglobulins, usually shortened to Ig, and the antigen receptor of B lymphocytes is therefore also known as
`membrane immunoglobulin (mIg). The T-cell antigen receptor (TCR) is related to immunoglobulin but is quite
`distinct from it, as it is specially adapted to detect antigens derived from foreign proteins or pathogens that have
`entered into host cells. We shall describe the structures of these lymphocyte antigen receptors in detail in Chapter