MOLECULAR BIOLOGY OF
`
`THE CELL
`
`fourth
`
`edition
`
`Lassen - Exhibit 1042, p. 1
`
`Lassen - Exhibit 1042, p. 1
`
`

`

`Garland
`Vice President: Denise Schanck
`ManagingEditor: Sarah Gibbs
`Senior Editorial Assistant: Kirsten Jenner
`Managing Production Editor: Emma Hunt
`Proofreader and Layout: Emma Hunt
`Production Assistant; Angela Bennett
`Text Editors: Marjorie Singer Anderson andBetsy Dilernia
`CopyEditor: Bruce Goatly
`Word Processors: Fran Dependahl, Misty Landers and Carol Winter
`Designer: Blink Studio, London
`Illustrator: Nigel Orme
`Indexer: Janine Ross and Sherry Granum
`Manufacturing: Nigel Eyre and Marion Morrow
`
`Bruce Alberts received his Ph.D. from Harvard University and is
`President of the National Academyof Sciences and Professor of
`Biochemistry and Biophysicsat the University of California, San
`Francisco. Alexander Johnson received his Ph.D. from Harvard
`University and is a Professor of Microbiology and Immunology
`and Co-Director of the Biochemistry and Molecular Biology
`Program at the University of California, San Francisco.
`Julian Lewis received his D.Phil. from the University of Oxford
`and {is a Principal Scientist at the London ResearchInstitute of
`CancerResearch UK. Martin Raff received his M.D. from McGill
`University andis at the Medical Research Council Laboratory for
`Molecular Cell Biology and Cell Biology Unit and in the Biology
`Department at University College London.Keith Roberts received
`his Ph.D, from the University of Cambridge andis Associate
`Research Director at the John Innes Centre, Norwich. Peter Walter
`received his Ph.D. from The Rockefeller University in New York and
`is Professor and Chairmanof the Departmentof Biochemistry and
`Biophysicsat the University of California, San Francisco, and an
`Investigator of the Howard Hughes MedicalInstitute.
`
`© 2002 by Bruce Alberts, Alexander Johnson, JulianLewis,
`Martin Raff, Keith Roberts, and Peter Walter.
`© 1983, 1989, 1994 by Bruce Alberts, Dennis Bray, Julian Lewis,
`Martin Raff, Keith Roberts, and James D. Watson,
`
`All rights reserved. No part of this book covered by the copyright
`hereon maybe reproducedorused in any formatin any form or
`by any means—graphic, electronic, or mechanical, including
`photocopying,recording, taping, or information storage and
`retrieval systems—without permission ofthe publisher.
`
`Library of Congress Cataloging-in-Publication Data
`Molecular biology of the cell / Bruce Alberts... [et al.].-- 4th ed.
`p.cm
`Includesbibliographical references and index.
`ISBN 0-8153-3218-1 (hardbound) -- ISBN 0-8153-4072-9 (pbk.)
`1. Cytology. 2. Molecularbiology. I. Alberts, Bruce.
`(DNLM:1. Cells. 2. Molecular Biology.}
`QH581.2 .M64 2002
`571.6--de21
`
`2001054471 CIP
`
`Published by Garland Science, a memberofthe Taylor & Francis Group,
`29 West 35th Street, New York, NY 10001-2299
`
`Printed in the United States of America
`
`16 14 13 12 111098765432
`
`Cell Biology Interactive
`Artistic and Scientific Direction: Peter Walter
`Narrated by: Julie Theriot
`Production, Design, and Development: Mike Morales
`
`Front cover Human Genome:Reprinted by permission
`from Nature, International Human Genome Sequencing
`Consortium, 409:860-921, 2001 © Macmillan Magazines
`Ltd. Adapted from an image by Francis Collins, NHGRI;
`Jim Kent, UCSC; EwanBirney, EBI; and Darryl Leja,
`NHGRI; showinga portion of Chromosome 1] from the
`initial sequencing of the human genome.
`
`Chapter opener Portion of chromosome2 from the
`genome ofthefrult fly Drosophila melanogaster.
`(Reprinted with permission from M.D, Adams et al.,
`Science 287:2185-2195, 2000. © AAAS.)
`
`In 1967, the British artist Peter Blake
`Back cover
`created a design classic. Nearly 35 years later Nigel
`Orme(illustrator), Richard Denyer (photographer), and
`the authors have together producedan affectionate
`tribute to Mr Blake's image. With its gallery of icons and
`influences, its assembly created almost as much
`complexity, intrigue and mystery as the original.
`Drosophila, Arabidopsis, Dolly and the assembled
`companytemptyou to dip inside where,as in the
`original, “a splendid time is guaranteedforall.”
`(Gunter Blobel, courtesy ofThe Rockefeller University; Marie
`Curie, Keystone Press Agency Inc; Darwin bust, by permission
`of the President and Council of the Royal Society; Rosalind
`Franklin, courtesy of Cold Spring Harbor Laboratory Archives;
`Dorothy Hodgkin, © The Nobel Foundation, 1964; JamesJoyce,
`etching by Peter Blake; Robert Johnson, photo booth
`self-portrait early 1930s, © 1986 Delta Haze Corporationall
`rights reserved, used by permission; Albert L. Lehninger,
`(unidentified photographer) courtesy ofThe Alan Mason
`Chesney Medical Archives of The Johns Hopkins Medical
`Institutions; Linus Pauling, from Ava Helenand Linys Pauling
`Papers, Special Collections, Oregon State University; Nicholas
`Poussin, courteay of ArtToday.com; Barbara McClintock,
`© David Micklos, 1983; Andre{ Sakharov, courtesy of Elena
`Bonner; Frederick Sanger, © The Nobel Foundation, 1958.)
`
`Lassen - Exhibit 1042, p. 2
`
`Lassen - Exhibit 1042, p. 2
`
`

`

`Contents
`
`Special Features
`List of Topics
`Acknowledgments
`A Note to the Reader
`
`PART |
`INTRODUCTION TO THE CELL
`1.
`Cells and Genomes
`2.
`Cell Chemistry and Biosynthesis
`3.
`Proteins
`
`PART II
`
`BASIC GENETIC MECHANISMS
`
`4. DNAand Chromosomes
`5. DNA Replication, Repair, and Recombination
`6. How Cells Read the Genome: From DNAto Protein
`7. Control of Gene Expression
`
`PARTIl
`
`METHODS
`
`8. Manipulating Proteins, DNA, and RNA
`9. Visualizing Cells
`
`PART IV
`
`INTERNAL ORGANIZATION OF THE CELL
`
`10. MembraneStructure
`11, Membrane Transport of Small Molecules and the Electrical
`Properties of Membranes
`Intracellular Compartments and Protein Sorting
`12.
`Intracellular Vesicular Traffic
`13.
`14. Energy Conversion: Mitochondria and Chloroplasts
`15. Cell Communication
`16. The Cytoskeleton
`17. The Cell Cycle and ProgrammedCell Death
`18. The Mechanicsof Cell Division
`
`PART V
`
`CELLS IN THEIR SOCIAL CONTEXT
`
`19. Cell Junctions, Cell Adhesion, and the Extracellular Matrix
`20. Germ Cells andFertilization
`21. Developmentof Multicellular Organisms
`22. Histology: The Lives and DeathsofCells in Tissues
`23. Cancer
`24. The Adaptive Immune System
`25. Pathogens, Infection, and Innate Immunity
`
`Glossary
`Index
`Tables: The Genetic Code, Amino Acids
`
`ix
`xi
`xxix
`KXXML
`
`3
`47
`129
`
`191
`235
`299
`375
`
`469
`547
`
`583
`
`615
`659
`711
`767
`831
`907
`983
`1027
`
`1065
`1127
`1157
`1259
`1313
`1363
`1423
`
`G-1
`Fl
`T-1
`
`
`
`igI|
`
`Lassen - Exhibit 1042, p. 3
`
`Lassen - Exhibit 1042, p. 3
`
`

`

`
`
`
`
`THE ADAPTIVE IMMUNE
`SYSTEM
`
`LYMPHOCYTES AND THE
`CELLULAR BASIS OF ADAPTIVE
`IMMUNITY
`
`B CELLS AND ANTIBODIES
`
`
`THE GENERATION OF ANTIBODY
`
`DIVERSITY
`
`
`T CELLS AND MHC PROTEINS
`
`HELPERT CELLS AND
`
`LYMPHOCYTE ACTIVATION
`
`Our adaptive immune system saves us from certain death by infection. An
`infant born with a severely defective adaptive immunesystem will soon die
`unless extraordinary measures are taken toisolate it from a host of infectious
`agents, including bacteria, viruses, fungi, and parasites. Indeed, all multicellular
`organisms need to defend themselves against infection by such potentially
`harmful invaders, collectively called pathogens. Invertebrates use relatively
`simple defense strategies that rely chiefly on protective barriers, toxic molecules,
`and phagocytic cells that
`ingest and destroy invading microorganisms
`(microbes) and larger parasites (such as worms). Vertebrates, too, depend on
`such innate immune responeesasa first line of defense (discussed in Chapter
`25), but they can also mount much more sophisticated defenses,called adaptive
`immune responses. The innate responses call the adaptive immune responses
`into play, and both work together to eliminate the pathogens (Figure 24-1).
`Unlike innate immuneresponses, the adaptive responses are highly specific to
`the particular pathogen that induced them. They can also provide long-lasting
`protection. A person whorecovers from measles, for example, is protectedforlife
`against measles by the adaptive immunesystem, although not against other
`commonviruses, such as those that cause mumpsor chickenpox. In this chap-
`ter, we focus mainly on adaptive immuneresponses, and, unless we indicate
`otherwise,
`the term immune responses refers to them. We discuss innate
`immuneresponsesin detail in Chapter 25.
`The function of adaptive immune responses is to destroy invading
`pathogens and any toxic molecules they produce. Because these responses are
`destructive,it is crucial that they be madeonly in response to moleculesthatare
`foreign to the host andnotto the molecules of the hostitself. The ability to dis-
`tinguish what is foreign from whatis selfin this way is a fundamental feature of
`the adaptive immune system. Occasionally, the system fails to make this dis-
`tinction andreacts destructively against the host's own molecules. Such autoim-
`mune diseases can befatal.
`Of course, many foreign molecules that enter the body are harmless, andit
`Would be pointless and potentially dangerous to mount adaptive immune
`Tesponses against them. Allergic conditions such as hayfever and asthma are
`&xamples of deleterious adaptive immune responses against apparently harm-
`ess foreign molecules, Such inappropriate responses are normally avoided
`use the innate immune system calls adaptive immuneresponsesinto play
`Only when it recognizes molecules characteristic of invading pathogenscalled
`
`
`
`Lassen - Exhibit 1042, p. 4
`
`Lassen - Exhibit 1042, p. 4
`
`

`

`Figure 24~| Innate and adaptive immune responses.Innate Immune
`responsesare activated directly by pathogens and defend all multicellular
`organisms against Infection. In vertebrates, pathogens, together with the
`innate immune responses theyactivate, stimulate adaptive immune
`responses, which then helpfight the Infection.
`
`pathogen-assoclated immunostimulants (discussed in Chapter 25). Moreover,
`the innate immune system can distinguish between different classes of
`pathogensandrecruit the mosteffective form of adaptive immuneresponse to
`eliminate them,
`Any substance capable ofeliciting an adaptive immuneresponseis referred
`to as an antigen (antibody generator). Most of what we know about such
`responses has comefrom studies in which an experimentertricks the adaptive
`immunesystem of a laboratory animal (usually a mouse) into respondingto a
`harmless foreign molecule, such as a foreign protein. Thetrick involvesinjecting
`the harmless molecule together with immunostimulants (usually microbial in
`origin) called adjuvants, whichactivate the innate immunesystem.This process
`is called immunization.If administered in this way, almost any macromolecule,
`as longasit is foreign to the recipient, can induce an adaptive immuneresponse
`that is specific to the administered macromolecule. Remarkably, the adaptive
`immunesystem can distinguish between antigens thatare very similar—such as
`between two proteins thatdiffer in only a single amino acid, or between two
`optical isomers of the same molecule.
`Adaptive immuneresponses are carried out by white bloodcells called lym-
`phocytes. There are two broad classes of such responses—antibody responses
`andcell-mediated immuneresponses, and they are carried outby different classes
`of lymphocytes, called B cells and T cells, respectively. In antibody responses,
`B cells are activated to secrete antibodies, which are proteins called
`immunoglobulins. The antibodies circulate in the bloodstream and permeate
`the other bodyfluids, where they bind specifically to the foreign antigen that
`stimulated their production (Figure 24-2). Binding of antibody inactivates virus-
`es and microbial toxins (such as tetanus toxin or diphtheria toxin) by blocking
`their ability to bind to receptors on hostcells, Antibody binding also marks
`invading pathogensfor destruction, mainly by makingit easier for phagocytic
`cells of the innate immunesystem to ingest them,
`In cell-mediated immuneresponses,the second class of adaptive immune
`response,activated T cells react directly against a foreign antigen that is pre-
`sented to them on the surface ofa hostcell. The T cell, for example, mightkill a
`virus-infected hostcell that hasviral antigens onits surface, thereby eliminating
`the infectedcell before the virus has had a chanceto replicate (see Figure 24-2).
`In other cases, the T cell producessignal molecules that activate macrophages
`to destroy the invading microbesthat they have phagocytosed.
`Webegin this chapter by discussing the general properties of lymphocytes.
`We then consider the fictional and structural features of antibodies that
`enable them to recognize and neutralize extracellular microbes and the toxins
`they make. Next, we discuss how B cells can produce a virtually unlimited num-
`berofdifferent antibody molecules. Finally, we consider the special features of
`T cells and the cell-mediated immune responses they are responsible for.
`Remarkably, T cells can detect microbes hiding inside hostcells and either kill
`the infected cells or help othercells to eliminate the microbes.
`
`LYMPHOCYTES AND THE CELLULAR BASIS OF
`ADAPTIVE IMMUNITY
`
`Lymphocytesare responsiblefor the astonishing specificity of adaptive immune
`responses. They occur in large numbers in the blood and lymph(thecolorless
`fluid in the lymphatic vessels that connect the lymph nodesin the body to each
`other and to the bloodstream) and in lymphoid organs, such as the thymus,
`lymph nodes,spleen, and appendix (Figure 24-3).
`
`
`
`INNATE
`IMMUNE
`
`RESPONSES
`
`
`
`®
`
`@— virus
`
`e
`
`:virus-infected
`
`host cell
`
`innate immune
`réaponses
`
`i {virus
`
`response
`
`respon
`
`
`T call
`e.. ©
`.
`F
`
`antibody
`
`:.
`
`dead virus-Infacted cell
`
`Figure 24-2 The two main classes of
`adaptive immuneresponses.
`Lymphocytes carry out both classes of
`responses, Here, the lymphocytes are
`responding to a viralinfection. In one class
`of response, B cells secrete antibodies that
`neutralize the virus, In the other, a
`cell-mediated response,T cells kill the
`virus-infected cells,
`
`
`
`|
`
`|
`
`
`
`1364=Chapter 24 : THE ADAPTIVE IMMUNE SYSTEM
`
`Lassen - Exhibit 1042, p. 5
`
`Lassen - Exhibit 1042, p. 5
`
`

`

`edenoid
`
`
`
`thymus
`
`Peyer's patches in
`small Intestine
`
`appendix
`
`Bone marrow
`
`lymphatic vessels
`
`lymph nodes
`
`spleen
`
`
`
`
`
`
`animal
`
`
`Figure 24-3 Human lymphold
`organs. Lymphocytes develop in the
`thymus and bone marrow(yellow), which
`are therefore called central (or primary)
`lymphoid organs. The newly formed
`lymphocytes migrate from these primary
`organs to peripheral (or secondary)
`lymphoid organs(blue), where they can
`react with foreign antigen, Only some of
`the peripheral lymphoid organs and
`lymphatic vessels are shown; many
`lymphocytes, for example, are found in the
`skin and respiratory tract.As we discuss
`later, the lymphatic vessels ultimately
`empty Into the bloodstream (not shown).
`
`Figure 24-4 A classic experiment
`showing that lymphocytes are
`required for adaptive immune
`responsesto foreign antigens. An
`important requirementof all such
`cell-transfer experimentsis that cells are
`transferred between animals of the same
`inbred strain, Members of an inbred strain
`are genetically Identical,If lymphocytes are
`transferred to a genetically different
`animal that has been Irradiated, they react
`agalnst the foreign” antigens of the host
`and ean kill the animal, In the experiment
`shown, the Injection of lymphocytes
`restores both antibody and cell-mediated
`adaptive immune responses,indicating that
`lymphocytes are required for both types
`of responses,
`
`antigen
`
`ADAPTIVE
`a IMMUNE
`RESPONSES
`RESTORED
`
`irradiated animal
`given lymphocytes
`from a normal
`animal
`
`antigen
`
`irradiated animal
`given othercells
`fram a normal
`animal
`
`NO ADAPTIVE
`IMMUNE
`RESPONSES
`
`
`
`
`In this section, we discuss the general properties of lymphocytes that apply
`fo both B cells and T cells. We shall see that each lymphocyte is committed to
`yespondto a specific antigen andthatits response duringits first encounter with
`an antigen ensures that a morerapid and effective response occurs on subse-
`Iguent encounters with the same antigen. We consider how lymphocytes avoid
`
`
`1esFane to selfantigens andhowtheycontinuouslyrecirculate between the
`
`iirradiatedtokillmostoftheirwhitebloodcells, includinglymphocytes,This
`Then,by makes the animals unable to mount adaptive immune responses,
`
`
`aicaptive immuneresponsesofirradiated animals, indicating that lymphocytes
`
`
`ale required for these responses (Figure 24-4),
`
` normal
`
`NORMAL ADAPTIVE
`—_——— IMMUNE
`RESPONSES
`
`
`Irradiated
`anlmal
`
`NO ADAPTIVE IMMUNE
`RESPONSES
`
`Ca
`CONTROL
`SEEPEMENTY
`
`EP HOCYTES AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`1365
`
`Lassen - Exhibit 1042, p. 6
`
`Lassen - Exhibit 1042, p. 6
`
`

`

`
`
`The Innate and Adaptive Immune Systems Work Together
`As mentionedearlier, lymphocytes usually respondto foreign antigens only if
`the innate immunesystem is first activated. As discussed in Chapter 25, the
`innate immune responses to an infection are rapid. They depend on pattern
`
`recognition receptors that recognize patterns of pathogen-associated molecules
`
`(immunostimulants) that are not presentin the host organism,including micro-
`
`bial DNA,lipids, and polysaccharides, and proteins that form bacterial flagella.
`
`Someofthese receptors are present on the surface of professional phagocytic
`
`cells such as macrophages and neutrophils, where they mediate the uptake of
`
`pathogens, which are then delivered to lysosomes for destruction. Others are
`
`secreted and bindto the surface of pathogens, marking them for destruction by
`
`either phagocytes or the complementsystem.Still others are present on the sur-
`
`face ofvarioustypesofhostcells and activate intracellular signaling pathways in
`
`responseto the binding of pathogen-associated immunostimulants;this leads
`
`to the productionof extracellular signal molecules that promote inflammation
`
`and help activate adaptive immune responses.
`
`Somecells ofthe innate immunesystem directly present microbial antigens
`to T cells to initiate an adaptive immuneresponse. The cells that do this most
`
`efficiently are called dendritic cells, which are presentin mostvertebratetissues.
`
`They recognize and phagocytose invading microbes ortheir products at a site of
`
`infection and then migrate with their prey to a nearby peripheral lymphoid
`
`organ, There they act as antigen-presentingcells, which directly activateTcells
`
`to respond to the microbial antigens, Once activated, some of the T cells then
`
`migrate to thesite of infection, where they help other phagocytic cells, mainly
`
`macrophages, destroy the microbes (Figure 24-5), OtheractivatedTcells remain
`
`
`
`
`- ———_ ©©
`
`ACTIVATED T CELLS MIGRATE TO SITE OF
`INFECTION TO HELP ELIMINATE RESIDUAL MICROBES
`
`antigen-
`presenting
`cell
`
`-
`|
`
`activated T cell
`
`BS
`
`e
`
`°
`a
`
`8
`
`dendritic cell
`
`MICROBES ENTER THROUGH
`BREAK IN SKIN AND ARE
`PHAGOCYTOSED BY
`DENDRITIC CELL
`
`remnants of microhe
`In phagolysasome
`
`
`
`
`
`antigen
`DENDRITIC CELL MATURES
`AND CARRIES MICROBIAL
`ANTIGENS TO LOCAL LYMPH
`NODE TO BECOME AN
`ANTIGEN-PRESENTING CELL
`
`(naMUNERESPONBE ADAPTIVE IMMUNE RESPONEE
`
`Figure 24-5 One way in which the innate immunesystem helps activate the adaptive immune) —
`including macrophages (not shown) nding
`system. Specialized phagocytic cells of the innate immune system,
`
`dendritic calls ingest invading microbes or their products at the site of infection.The dendritic cells then!
`-prasenting—
`mature and migrate in lymphatic vessels to a nearby lymph node, where they serve as antigen
`.
`
`cells.The antigen-presenting cells activaceT cells to respond to the microbial antigens that are displayed on
`
`1 surface (called
`the presenting cells’ surface.The antigen-presenting cells also have special proteins on thei
`4
`co the
`Ip
`costimulotory molecules) that help activate the T cells. Some of the activated T cells then migrate
`re the %
`d cells, thereby helping to alimina
`infection where they either help activate macrophagesorkill infecce
`ly after chese calls
`microbes. As we discuss later, the costimulatory molecules appear on dendritic cells on
`mature in response to invading microbes.
`
`1366
`
`Chapter 24: THE ADAPTIVE IMMUNE SYSTEM
`
`.
`
`‘
`.
`immu
`lymph node
`costimulatory protein
`ANTIGEN-PRESENTING CELL
`ACTIVATES T CELLS TO
`RESPOND TO MICROBIAL
`ANTIGENS
`
`
`
`
`
`Lassen - Exhibit 1042, p. 7
`
`Lassen - Exhibit 1042, p. 7
`
`

`

`
`
`
`
`Tcelt
`precursor
`
`‘
`
`)
`
`Figure 24-6 The development and
`activation of T and B cells. The
`central lymphoid organs, where
`lymphocytes develop from precursorcells,
`are labeled In yellow boxes. Lymphocytes
`respond to antigen in peripheral lymphoid
`organs, such as lymph nodesorspleen.
`
`CELL-MEDIATED
`IMMUNE
`RESPONSE
`
`
`
` lymphocyte |
`
`f
`
`@)
`
`hemopoietic <|
`stem calls @
`ANTIBODY
`RESPONSE
`
`bone marrow
`
`
`
`©
`
`in the lymphoid organ andhelp B cells respond to the microbial antigens. The
`activated B cells secrete antibodies that circulate in the body and coat the
`microbes, targeting them forefficient phagocytosis.
`Thus, innate immune responsesare activated mainlyatsites of infection,
`whereas adaptive immune responses are activated in peripheral lymphoid
`organs. The two types of responses work together to eliminate invading
`pathogens,
`
`B Lymphocytes Develop in the Bone Marrow;T Lymphocytes
`Develop in the Thymus
`T cells andBcells derive their names from the organs in which they develop, T
`cells develop in the thymus, and B cells, in mammals, develop in the bone marrow
`in adults or theliver in fetuses,
`Despite their different origins, both T and B cells develop from the same
`pluripotent hemopoietic stem cells, which give rise to all of the blood cells,
`including red blood cells, white blood cells, and platelets, These stem cells (dis-
`cussed in Chapter 22) are located primarily in hemopoietic tissues—mainly the
`liver in fetuses and the bone marrow in adults. Tcells develop in the thymus
`_
`from precursor cells that migrate there from the hemopoietic tissues via the
`_
`| blood, In most mammals, including humans and mice, B cells develop from
`| stem cells in the hemopoietic tissues themselves (Figure 24-6), Because they are
`_
`sites where lymphocytes develop from precursor cells,
`the thymus and
`_ hemopoietic tissues are referred to as central (primary) lymphoid organs(see
`_ Figure 24-3),
`As we discuss later, most lymphocytes die in the central lymphoid organ
`soonafter they develop, without ever functioning, Others, however, mature and
`Migrate via the blood to the peripheral (secondary) lymphoid organs—mainly,
`the lymph nodes, spleen, and epithelium-associated lymphoid tissues in the
`_ §astrointestinal tract, respiratory tract, and skin (see Figure 24-3). As mentioned
`_ Sarlier, it is in the peripheral lymphoid organs that T cells and B cells react with
`foreign antigens (see Figure 24-6),
`T and B cells become morphologically distinguishable from each other only
`after they have been activated by antigen. Nonactivated T andB cells look very
`Similar, even in an electron microscope. Both are small, only marginally bigger
`than red blood cells, and containlittle cytoplasm (Figure 24-7A). Both are acti-
`Vated by antigen to proliferate and mature into effector cells, Effector B cells
`secrete antibodies. In thelr most mature form, called plasma cells, they arefilled
`With an extensive rough endoplasmic reticulum (Figure 24-7B). In contrast,
`effector T cells (Figure 24-7C) contain very little endoplasmic reticulum and do
`Not secrete antibodies.
`There are two main classes of T cells—cytotoxic Tcells and helperTcells.
`Otoxic T cells kill infected cells, whereas helper T cells help activate
`
`UMPHocyTEs AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`1367
`
`Lassen - Exhibit 1042, p. 8
`
`
`
`Lassen - Exhibit 1042, p. 8
`
`

`

`Lot
`
`
`(A) resting T or B cell
`
`(C) effectorT cell
`
`macrophages,B cells, and cytotoxic T cells. Effector helper T cells secrete a vari-
`Figure 24-7 Electron micrographs of
`nonactivated andactivated
`ety of signal proteins called cytokines, which act as local mediators. Theyalso
`display a variety of costimulatory proteins on their surface. By meansof these
`lymphocytes,(A)Aresting lymphacyte,
`which could be aT cell or a B cell, as
`cytokines and membrane-boundcostimulatory proteins, they can influence the
`these cells are difficult to distinguish
`behaviorofthe variouscell types they help. Effector cytotoxic T cells kill infected
`morphologically until they have been
`target cells also by meansofproteins that they either secrete or display on their
`activated to becomeeffectorcells, (B) An
`surface, Thus, whereasBcells can act over long distancesby secreting antibod-
`effector B cell (a plasma call). It Is filled
`ies that are distributed by the bloodstream,T cells can migrate to distantsites,
`with an extensive rough endoplasmic
`but there they actonly locally on neighboringcells.
`reticulum (ER), which Is distended with
`antibody molecules. (C) An effector T cell,
`which has relatively JIttle rough ER butIs
`The Adaptive Immune System Works by Clonal Selection
`filled with free ribosomes, Note that the
`three cells are shown at the same
`The most remarkable feature of the adaptive immune system is that it can
`magnification. (A, courtesy of Dorothy
`respondto millionsofdifferent foreign antigens in a highly specific way. B cells,
`Zucker-Franklin; B, courtesy of Carlo
`for example, make antibodies that react specifically with the antigen that
`Grossi;A and B,from D. Zucker-Franklin
`induced their production. How doBcells produce such a diversity of specific
`et al.,Aclas of Blood Calls: Funetion and
`antibodies? The answer began to emergein the 1950s with the formulation of the
`Pathology, 2nd edn, Milan,Italy: Edi. Ermes,
`clonal selection theory. Accordingto this theory, an animal first randomly gen-
`1988; C, courtesy of Stefanello de Petris,)
`erates a vast diversity of lymphocytes, and then those lymphocytes that can
`react againstthe foreign antigensthat the animal actually encounters are specif-
`ically selected for action. As each lymphocyte develops in a central lymphoid
`organ, it becomes committedto react with a particular antigen before ever being
`exposedto the antigen. It expresses this commitmentin the form of cell-surface
`receptor proteins that specifically fit the antigen. When a lymphocyte encoun-
`ters its antigen in a peripheral lymphoid organ, the binding of the antigen to the
`receptors activates the lymphocyte, causingit both to proliferate and to differ-
`entiate into an effector cell. An antigen therefore selectively stimulates those
`cells that express complementary antigen-specific receptors and are thus
`already committed to respondto it. This arrangement is what makes adaptive
`immuneresponsesantigen-specific.
`The term “clonal” in clonal selection theory derives from the postulate that
`the adaptive immunesystem is composed of millions of different families, or
`clones, of lymphocytes, each consisting of T or B cells descended from a com-
`monancestor, Each ancestralcell was already committed to make one particu-
`lar antigen-specific receptor protein, andsoall cells in a clone have the same
`antigen specificity (Figure 24-8). According to the clonal selection theory, then,
`the immune system functions on the “ready-made” principle rather than the
`“made-to-order” one,
`
`1368
`
`Chapter 24 : THE ADAPTIVE IMMUNE SYSTEM
`
`
`
`Lassen - Exhibit 1042, p. 9
`
`Lassen - Exhibit 1042, p. 9
`
`

`

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`antibody-secreting
`B calla of single clone
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`secretedantibodies
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`There is compelling evidence to support the main tenets ofthe clonal selec-
`tion theory. For example, when lymphocytes from an animal that has not been
`| {mmunized are incubated in a test tube with a numberof radioactively labeled
`antigens, only a very smal proportion (less than 0.01%) bind each antigen, sug-
`}
`gesting that only a few cells are committed to respondto these antigens. More-
`over, when one antigen is made so highly radioactive that it kills any cell thatit
`binds to, the remaining lymphocytes can no longer produce an immune
`responseto that particular antigen, even though theycanstill respond normally
`to other antigens. Thus, the committed lymphocytes must have receptors on
`their surface that specifically bind that antigen. Although most experiments of
`this kind have involved B cells and antibody responses, other experiments indi-
`cate that T cells, like B cells, operate by clonal selection.
`How can the adaptive immunesystem produce lymphocytes that collectively
`display such an enormousdiversity of receptors, including ones that recognize
`synthetic molecules that never occur in nature? We shall see later that the anti-
`gen-specific receptors on both T and B cells are encoded by genes that are
`assembled from a series of gene segments by a unique form of genetic recom-
`bination that occurs early in a lymphocyte’s development, before it has
`encountered antigen. This assembly process generates the enormous diversity
`of receptors and lymphocytes, thereby enabling the immune system to respond
`to an almost unlimited diversity of antigens.
`
`Figure 24-8 The clonal selection
`theory. An antigen activates only those
`lymphocyte clones (represented here by
`single cells) that are alraady committed to
`respondto ic.A cell committed to
`respond to a particular antigen displays
`cell-surface receptors that specifically
`recognize the antigen, andall cells within
`a clone display the same receptor, Tha
`Immune system |s thought to consist of
`millions of different lymphocyte clones.
`A particular antigen may activate hundreds
`ofdifferent clones. Although only B cells
`are shownhere,T cells operate in a
`slmilar way.
`
`amino acid
`
` lyalne
`
`
`
`NO,
`
`Most Antigens Activate Many Different Lymphocyte Clones
`Mostlarge molecules, includingvirtuallyall proteins and manypolysaccharides,
`Can serve as antigens, Those parts of an antigen that combinewith the antigen-
`dinitrophenyl
`bindingsite on either an antibody molecule or a lymphocyte receptorare called
`group (DNP}
`antigenic determinants (or epitopes), Most antigens haveavariety of antigenic
`polypeptide
`determinants that can stimulate the production of antibodies, specific T cell
`backbone of
`Tesponses, or both. Some determinants of an antigen produce a greater
`Protein
`tesponse than others, so that the reaction to them may dominate the overall
`Tesponse, Such determinants are said to be immunodominant.
`The diversity of lymphocytes is such that even a single antigenic determi-
`Nantis likely to activate many clones, each of which produces an antigen-bind-
`a8site with its own characteristic affinity for the determinant.Evenarelatively
`simple structure, like the dinitrophenyl (DNP) group in Figure 24-9, can be
`Ooked at” in manyways. Whenitis coupled to a protein, as shown in thefig-
`Ure, it usually stimulates the production of hundreds of species of anti-DNP
`
`Figure 24-9 The dinltropheny!
`(DONP) group.AlthoughIt is too small to
`induce an immune response onits own,
`whenIt Is coupled covalently to a lysine
`side chain on a protein,asIllustrated,
`DNPstimulates the production of
`hundreds ofdifferent species of antibodies
`thatall bind specifically to It.
`
`LYMPHOCYTES ANDTHE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`1369
`
`Lassen - Exhibit 1042, p. 10
`
`Lassen - Exhibit 1042, p. 10
`
`

`

`
`
`observed in T-cell-mediated responses.
`
`Figure 24-10 Primary and secondary
`antibody responses. The secondary
`response Induced by a second exposure
`to antigen A is faster and greater than the
`primary response andis specific for A,
`indicating that the adaptive immune
`system has specifically remembered
`encountering antigen A before. The same
`type of immunological memoryis
`
`Lassen - Exhibit 1042, p. 11
`
`1370=Chapter 24: THE ADAPTIVE IMMUNE SYSTEM
`
`antibodies, each madebya different B cell clone. Such responsesare said to be
`polyclonal, Whenonly a few clonesare activated, the responseis said to be oligo-
`clonal; and whenthe response involves only a single B or T cell clone,it is said
`to be monocional. Monoclonal antibodies are widely usedastools in biology and
`medicine, but they haveto be producedina special way(see Figure 8-6), as the
`responses to most antigens are polyclonal.
`
`Immunological Memory Is Due to Both Clonal Expansion
`and Lymphocyte Differentiation
`The adaptive immune system,like the nervous system, can rememberprior
`experiences. This is why we develop lifelong immunity to many common
`infectious diseases after ourinitial exposure to the pathogen, andit is why vac-
`cination works. The same phenomenon can be demonstrated in experimental
`animals. If an animal is immunized once with antigen A, an immuneresponse
`{either antibody or cell-mediated) appearsafter several days, rises rapidly and
`exponentially, and then, more gradually, declines. This is the characteristic
`course of a primary immuneresponse, occurring on an animal's first exp