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

`

`Garland
`Vice President: Denise Schanck
`Managing Editor: Sarah Gibbs
`Senior Editorial Assistant: Kirsten Jenner
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`Proofreader and Layout: Emma Hunt
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`
`Bruce Alberts received his Ph.D. from Harvard University and is
`President of the National Academy of Sciences and Professor of
`Biochemistry and Biophysics at 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 Research Institute of
`Cancer Research UK. Martin Raffreceived his MD. from McGill
`University and is 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 PhD. from the University of Cambridge and is Associate
`Research Director at the John Innes Centre, Norwich. PeterWalter
`received his Ph.D. from The Rockefeller University in NewYork and
`is Professor and Chairman of the Department of Biochemistry and
`Biophysics at the University of California, San Francisco, and an
`Investigator of the Howard Hughes Medical Institute.
`
`© 2002 by Bruce Alberta, Alexander Johnson, Iulianilewis,
`Martin Raff, Keith Roberts, and Peter Walter.
`© 1983, 1989, 1994 by Bruce Alberts, Dennis Bray, Julian Lewis,
`Martin Raff, Keith Reberts, and James D. Watson.
`
`All rights reserved. No part of this book covered by the copyright
`hereon may be reproduced or used in any format in any form or
`by any means—graphic, electronic, or mechanical, including
`photocopying, recording, taping, or information storage and
`retrieval systems—without permission of the publisher.
`
`Library of Congress Cataloging-in-Publicatlon Data
`Molecular biology of the cell / Bmce Alberta
`[et al.].-- 4th ed.
`p. cm
`Includes bibliographical references and index.
`ISBN 0'8153—3218-1 (hardbound) -- ISBN 0-8153-4072-9 (pbk.)
`1. Cytology 2. Molecular biology. l. Aiberts, Bruce.
`[DNLM: 1. Cells. 2. Molecular Biology. 1
`01-15812 .M64 2002
`571 .6--dc21
`
`2001054471 CIP
`
`Published by Garland Science, a member of the Taylor & Francis Group,
`29 West 35th Street, NewYork, NY 100012299
`
`Printed in the United States of America
`
`15141312111098765432
`
`Cell Biology In tel-active
`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, NI-JGRI;
`Jim Kent, UCSC: Ewan Bimey, EB]; and Darryl Leia,
`NHGRI; showing a portion of Chromosome 1 from the
`initial sequencing of the human genome.
`
`Chapter opener Portion of chromosome 2 from the
`genome of the fruit fly Drowpliila melanogrtsrei:
`(Reprinted with permission from MI). Adams et a1.,
`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 produced an 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.
`Drosophlla,Arabidopsls, Dolly and the assembled
`company tempt you to dip inside where, as in the
`original, "a splendid time is guaranteed for all.”
`(Gunter Blobel, courtesy ofThe Rockefeller University; Marie
`Curie, Keystone Press Agency Inc: Daann 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; James Joyce,
`etching by Peter Blake: Robert Johnson, photo booth
`self-portrait early 19305, © 1985 Delta Haze Corporation all
`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 Helen and Linus Pauling
`Papers, Special Collections, Oregon Stale University; Nicholas
`Poussin, courtesy ofArtToday.com: Barbara McClintock,
`iii) David Micklos, 1983; Andrei Sakharov, courtesy of Elena
`Bonner; Frederick Sanger, © The Nobel Foundation, 1958.)
`
`Lassen — Exhibit 1042, p. 2
`
`Lassen - Exhibit 1042, p. 2
`
`

`

`T'—
`
`Contents
`
`Special Features
`List of Topics
`Acknowledgments
`A Note to the Reader
`
`PART I
`
`INTRODUCTION TO THE CELL
`
`1.
`
`2.
`3.
`
`Cells and Genomes
`
`Cell Chemistry and Biosynthesis
`Proteins
`
`PART II
`
`BASIC GENETIC MECHANISMS
`
`4. DNA and Chromosomes
`
`5. DNA Replication, Repair, and Recombination
`6. How Cells Read the Genome: From DNA to Protein
`7. Control of Gene Expression
`
`PART III
`
`METHODS
`
`8. Manipulating Proteins, DNA, and RNA
`9. Visualizing Cells
`
`PART IV
`
`INTERNAL ORGANIZATION OF THE CELL
`
`10. Membrane Structure
`
`1 1. Membrane Transport of Small Molecules and the Electrical
`Properties of Membranes
`Intracellular Compartments and Protein Sorting
`Intracellular Vesicular Traffic
`
`12.
`13.
`
`14. Energy Conversion: Mitochondria and Chloroplasts
`15. Cell Communication
`
`16. The Cytoskeleton
`17. The Cell Cycle and Programmed Cell Death
`18. The Mechanics of Cell Division
`
`PARTV
`
`CELLS IN THEIR SOCIAL CONTEXT
`
`19. Cell Junctions, Cell Adhesion, and the Extracellular Matrix
`20. Germ Cells and Fertilization
`
`21. Development of Multicellular Organisms
`22. Histology: The Lives and Deaths of Cells 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
`xxxiit
`
`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—I
`[—1
`T—1
`
`
`
`.—
`
`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 immune system will soon die
`unless extraordinary measures are taken to isolate 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 irmate immune responses as a 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 immune responses, the adaptive responses are highly specific to
`the particular pathogen that induced them. They can also provide long-lasting
`protection. A person who recovers from measles, for example, is protected for life
`against measles by the adaptive immune system, although not against other
`common viruses. such as those that cause mumps or chickenpox. In this chap-
`ter, we focus mainly on adaptive immune responses, and, unless we indicate
`otherwise,
`the term immune responses refers to them. We discuss innate
`immune responses in 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 made only in response to molecules that are
`foreign to the host and not to the molecules of the host itself. The ability to dis-
`tinguish what is foreign from what is selfin this way is a fundamental feature of
`the adaptive immune system. Occasionally, the system fails to make this dis-
`tinction and reacts destructively against the host‘s own molecules. Such autoim-
`Mune diseases can be fatal.
`
`Of course, many foreign molecules that enter the body are harmless, and it
`Would be pointless and potentially dangerous to mount adaptive immune
`re-‘iponses against them. Allergic conditions such as hayfever and asthma are
`eiterrlples of deleterious adaptive immune responses against apparently harm-
`1855 foreign molecules. Such inappropriate responses are normally avoided
`use the innate immune system calls adaptive immune responses into play
`Only when it recognizes molecules characteristic of invading pathogens called
`
`-
`
`
`
`Lassen — Exhibit 1042, p. 4
`
`Lassen - Exhibit 1042, p. 4
`
`

`

`Figure 24-I Innate and adaptive immune responses. Innate Immune
`responses are activated directly by pathogens and defend all multicellular
`organisms against Infection. In vertebrates, pathogens. together with the
`innate immune responses they activate, stimulate adaptive immune
`responses, which then help fight the Infection.
`
`pathogen-associated immunostimulants (discussed in Chapter 25). Moreover,
`the innate immune system can distinguish between different classes of
`pathogens and recruit the most effective form of adaptive immune response to
`eliminate them.
`
`Any substance capable of eliciting an adaptive immune response is referred
`to as an antigen (antibody generator). Most of what we know about such
`responses has come from studies in which an experimenter tricks the adaptive
`immune system of a laboratory annual [usually a mouse] into responding to a
`harmless foreign molecule. such as a foreign protein. The trick involves injecting
`the harmless molecule together with lmmunostimulants (usually microbial in
`origin) called adjuvam‘s, which activate the innate immune system. This process
`is called immunization. If administered in this was almost any macromolecule.
`as long as it Is foreign to the recipient, can induce an adaptive immune response
`that is specific to the administered macromolecule. Remarkably, the adaptive
`immune system can distinguish between antigens that are very similar—such as
`between two proteins that differ in only a single amino acid, or between two
`optical isomers of the same molecule.
`Adaptive immune responses are carried out by white blood cells called lym-
`phocytes. There are two broad classes of such responses—antibody responses
`and cell—mediated immune responses, and they are carried out by 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
`immunogiobulins. The antibodies circulate in the bloodstream and permeate
`the other body fluids, 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 host cells. Antibody binding also marks
`invading pathogens for destruction, mainly by making it easier for phagocytic
`cells of the innate immune system to ingest them.
`In cell-mediated immune responses, the second class of adaptive immune
`response, activated T cells react direcrly against a foreign antigen that is pre-
`sented to them on the surface of a host cell. The T cell, for example, might kill a
`virus~infected host cell that has viral antigens on its surface, thereby eliminating
`the infected cell before the virus has had a chance to replicate (see Figure 24-2).
`In other cases, the T cell produces signal molecules that activate macrophages
`to destroy the invading microbes that they have phagocytosed.
`We begin this chapter by discussing the general properties of lymphocytes.
`We then consider the functional 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-
`ber of different 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 host cells and either kill
`the infected cells or help other cells to eliminate the microbes.
`
`LYMPHOCYTES AND THE CELLULAR BASIS OF
`ADAPTIVE IMMUNITY
`
`Lymphocytes are responsible for the astonishing specificity of adaptive immune
`responses. They occur in large numbers in the blood and lymph (the colorless
`fluid in the lymphatic vessels that connect the lymph nodes in 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).
`
`|364
`
`Chapter 24 :THE ADAPTIVE IMMUNE SYSTEM
`
`
`
`INNATE
`IMMUNE
`RESPONSES
`
`
`
`
`
`I
`
`0
`
`.— virus
`
`virus-Infected
`
`J
`
`host cell
`
`innate immune
`r§aponses
`
`* m
`
`.
`.
`
`-n .od
`flames
`
`56::
`
`' "1':
`
`IGI-T ‘
`.
`iLr-
`
`.
`
`
`(:3
`
`dead virus-Infected cell
`
`Figure 24-2 The two main classes of
`adaptive immune responses.
`Lymphocytes carry out borh classes of
`responses. Here. the lymphocytes are
`responding so a viral Infection. In one ch55
`of response. B cells secrete antibodies that
`neutralize the virus. In the otherna
`
`cell-mediated response,T cells kill the
`virus-Infected cells.
`
`
`
`|
`
`.
`
`'
`
`
`
`Lassen — Exhibit 1042, p. 5
`
`Lassen - Exhibit 1042, p. 5
`
`

`

`thymus
`
`Peyer‘s patches in
`small Intestine
`
`appendix
`
`bone marrow
`
`adenoid
`
`
`
`lymphatic vessels
`
`lymph nodes
`
`spleen
`
`
`
`
`
`
`
`
`
`
`
`
`[n this section, we discuss the general properties of lymphocytes that apply
`_a both B cells and T cells. We shall see that each lymphocyte is committed to
`.5.'- pond to a specific antigen and that its response during its first encounter with
`1': antigen ensures that a more rapid and effective response occurs on subse-
`:i'uent encounters with the same antigen We consider how lymphocytes avoid
`
`f. ,Lpondlng to self antigens and how they continuously reclrculate between the
`
`
`
`
`
`"
`
`__aptive immune responses of irradiated animals, indicating that lymphocytes
`‘ required for these responses (Figure 24—4).
`
`Figure 243-3 Human lymphoid
`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
`Iymphocytes.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
`showlng that lymphocytes are
`required for adaptive immune
`responses to foreign antigens. An
`Important requirement of all such
`cell-transfer experiments is 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
`against the "foreign" antigens of the host
`and can 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
`
`NORMAL ADAPTIVE
`—- hhgglFl’im-ZSES
`
`NO ADAPTIVE IMMUNE
`RESPONSES
`
`irradiated
`animal
`
`CONTROL
`
`: PHOCYTES AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`andgen
`
`ADAPTIVE
`—-> IMMUNE
`l
`RESPONSES
`d
`d
`irra late anima
`HESTORED
`given lymphocytes
`from a normal
`animal
`
`
`
`
`antigen
`
`irradiated animal
`
`given other cells
`from a normal
`animal
`
`NO ADAPTIVE
`IMMUNE
`RESPONSES
`
`Lassen — Exhibit 1042, p. 6
`
`Lassen - Exhibit 1042, p. 6
`
`

`

`The Innate and Adaptive Immune Systems Work Together
`
`As mentioned earlier. lymphocytes usually respond to foreign antigens only if
`the Innate immune system 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 pamogenvassoclated molecules
`(immunoatimulants) that are not present in the host organism. including micro-
`bial DNA. lipids. and polysaccharides. and proteins that form bacterial flagella.
`Some of these receptors are present on the surface of professional phagocytic
`cells such as macrophages and neotrophils. where they mediate the uptake of
`pathogens. which are then delivered to lysosomes for destruction. Others are
`secreted and bind to the surface of pathogens. marking them for destruction by
`either phagocytes or the complement system. Still others are present on the sur-
`face ofvarious types ofhost cells and activate intracellular signaling pathways in
`response to the binding of pathogen-associated hnmunostirnulants: this leads
`to the production of extracellular signal molecules that promote inflammation
`and help activate adaptive immune responses.
`Some cells of the Innate immune system directly present microbial antigens
`to T cells to initiate an adaptive immune response. The cells that do this most
`efficiently are called dendritic cells, which are present in most vertebrate tissues.
`They recognize and phagocytose invading microbes or their products at a site of
`infection and then migrate with their prey to a nearby peripheral lymphoid
`organ. There they act as antigen-presenting cells. which directly activate T cells
`to respond to the microbial antigens. Once activated. some of the T cells then
`migrate to the site of infection, where they help other phagocytic cells. mainly
`macrophages. destroy the microbes {Figure 24-55). Other activated T cells remain
`
`ACTIVATED T CELLS MIGRATE T0 SITE 0F
`INFECTION TO HELP ELIMINATE RESIDUAL MICROBES
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`/@c_.c\©
`
`
`remnants of microbe
`In phagolysosomo
`
`antigen-
`presenting
`_
`cell
`..-‘
`___.. so
`
`_
`
`“Ill/“‘9" T “e”
`
`costimulatory protein
`
`lymph node
`
`Q
`
`'
`
`’
`.
`
`'
`
`..-.,..
`
`dendrl ccell
`
`
`
`MICROBES ENTER THROUGH
`BREAK IN SKIN AND ARE
`PHAGOCYTOSED BY
`DENDRITIC CELL
`
`DENDRITIC CELL MATURES
`AND CARRIES MICROBIAL
`ANTIGENS T0 LOCAL LYMPH
`NODE TO BECOME AN
`ANTIGEN-PRESENTING CELL
`
`ANTIGEN-PRESENTING CELL
`ACTIVATES T CELLS T0
`RESPOND TO MICROBIAL
`ANTIGENS
`
`— th
`Figure 24—5 One way in which the innate Immune system helps activate the adaptive Immilflfi -
`system. Specialized phagocytlt cells of the Innate Immune system. Including nucrcphages (no: show") ”'5:
`.
`de’ndrltit cells ingest invading microbes or their products at. the sire of inlsttlcnfl'he dandriric tells thall'
`
`mum and migrate In lymphatic vessels no a nearby lymph notinwhem they serve as anflgw-PF"°"""5_. ._
`
`callaTha antigen-presenting «III strivauT cells to rupand to the microbial antigens that are display“ T '
`the presenting cellr' rurhse'l’he anew-presenting cells also have special pmmlns on their will“ (all! .
`
`tostlmulcrory molecules} that help actlvau meT calls. Some 01' the nttlvaudT cells than migrate to III. 91M- -
`Infection where they althlr help atrivau macrophages or kill Initiated cells. thereby helping to ‘Ilmlflmhf "
`”kW-A5 we discuss law. the coadmulatory molecule: appear on dendrirlc tails only after we “I -'
`'
`mature In response to invading microbes.
`
`l3“
`
`Chapter 24 :THE ADAPTIVE IMMUNE SYSTEM
`
`
`
`
`
`Lassen — Exhibit 1042, p. 7
`
`Lassen - Exhibit 1042, p. 7
`
`

`

`Figure 24—6 The development and
`activation of T and B cells. The
`central lymphoid organs, where
`lymphocytes develop from precursor cells.
`are labeled In yellow boxes. Lymphocytes
`respond to antigen in peripheral lymphoid
`organs. such as lymph nodes or spleen.
`
`CELL-MEDIATED
`RESPONSE
`IMMUNE
`
`ANTIBODY
`RESPONSE
`
`bone marrow
`lymphocyte
`
`
`
`in the lymphoid organ and help B cells respond to the microbial antigens. The
`activated B cells secrete antibodies that circulate in the body and coat the
`microbes, targeting them for efficient phagocytosis.
`Thus, innate immune responses are activated mainly at sites 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 and B cells 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 the liver 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 inhemopoierie tissue%mainly the
`liver in fetuses and the bone marrow in adults. '1' cells develop in the thymus
`‘
`from precursor cells that migrate there from the hemopoietic tissues via the
`-'
`a; 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
`soon after 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
`-. gastrointestinal tract, respiratory tract, and skin (see Figure 24—3). As mentioned
`. earlier, it is in the peripheral lymphoid organs that T cells and B cells react with
`'
`fureign 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 and B cells look very
`SiInilar, even in an electron microscope. Both are small, only marginally bigger
`than red blood cells, and contain little cytoplasm (Figure 24—7A). Both are acti-
`vated by antigen to proliferate and mature into effector cells. Effector B cells
`SeCrete antibodies. In their most mature form. called plasma cells, they are filled
`with an extensive rough endoplasmic reticulum (Figure 24—7B). In contrast,
`'9lfectorT cells (Figure 24—7C) contain very little endoplasmic reticulum and do
`“0! secrete antibodies.
`There are two main classes of T cells—cytotoxic T cells and helper T cells.
`Cylomxic T cells kill infected cells, whereas helper T cells help activate
`
`
`
`'LYMPHOCYTES AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`I367
`
`Lassen — Exhibit 1042, p. 8
`
`
`
`
`precursor
`
`{
`
`I
`
` I Tcell
`
`I
`
`
`O
`
`
`
`hemopoistlc ‘
`stem cells 0
`
`
`
` l o
`
`
`
`
`
`
`Lassen - Exhibit 1042, p. 8
`
`

`

`
`|——l
`
`(Al resting T or B cell
`
`
`
`(C) effector T cell
`
`L___]
`
`macrophages, B cells, and cytotoxic T cells. Effector helper T cells secrete a vari-
`ety of signal proteins called cytokines, which act as local mediators. They also
`display a variety of costimulatory proteins on their surface. By means of these
`cytokines and membrane-bound costimulatory proteins, they can influence the
`behavior of the various cell types they help. Effector cytotoxic T cells kill infected
`target cells also by means of proteins that they either secrete or display on their
`surface. Thus, whereas B cells can act over long distances by secreting antibod-
`ies that are distributed by the bloodstream, T cells can migrate to distant sites,
`but there they act only locally on neighboring cells.
`
`The Adaptive Immune System Works by Clonal Selection
`
`The most remarkable feature of the adaptive immune system is that it can
`respond to millions of different foreign antigens in a highly specific way. B cells,
`for example, make antibodies that react specifically with the antigen that
`induced their production. How do B cells produce such a diversity of specific
`antibodies? The answer began to emerge in the 195th with the formulation of the
`clonal selection theory. According to this theory, an animal first randomly gen—
`erates a vast diversity of lymphocytes, and then those lymphocytes that can
`react against the foreign antigens that the animal actually encounters are specif-
`ically selected for action. As each lymphocyte develops in a central lymphoid
`organ, it becomes committed to react with a particular antigen before ever being
`exposed to the antigen. It expresses this commitment in 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, causing it 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 respond to it. This arrangement is what makes adaptive
`immune responses antigen-specific.
`The term "clonal" in clonal selection theory derives from the postulate that
`the adaptive immune system is composed of millions of different families, or
`clones, of lymphocytes, each consisting of T or B cells descended from a com-
`mon ancestor. Each ancestral cell was already committed to make one particu-
`lar antigen-specific receptor protein, and so all 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.
`
`I368
`
`Chapter 24 :THE ADAPTIVE IMMUNE SYSTEM
`
`Figure 24-7 Electron micrographs of
`nonactivated and activated
`
`lymphocytes. (A) A resting lymphocyte,
`which could be aT cell or a B cell, as
`these cells are difficult to distinguish
`morphologically until they have been
`activated to become effector cells. (B) An
`effector B cell (a plasma cell). It is filled
`with an extensive rough endoplasmic
`reticulum (ER), which is distended with
`antibody molecules. (C) An effectorT cell,
`which has relatively little rough ER but Is
`filled with free ribosomes. Note that the
`three cells are shown at the same
`magnification. (A, courtesy of Dorothy
`Zucker—Franklin: B, courtesy of Carlo
`Grossi;A and B, from D. Zucker-Franklin
`et ai.,Atlas of Blood Cells: Function and
`Pathology, 2nd edn. Milan, Italy; Edi. Ermes.
`I988; C, courtesy of Stefanelio de Petris.)
`
`
`
`Lassen — Exhibit 1042, p. 9
`
`Lassen - Exhibit 1042, p. 9
`
`

`

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`Figure 24-8 The clonal selection
`theory. An antigen activates only those
`lymphocyte clones (represented here by
`single cells) that are already committed to
`respond to it.A cell committed to
`respond to a particular antigen displays
`cell-surface receptors that specifically
`recognize the antigen. and all cells within
`a clone display the same receptor.Tho
`immune system Is thought to consist of
`millions of different lymphocyte clones.
`A particular antigen may activate hundreds
`of different clones.Although only B cells
`are shown here.T cells operate in a
`similar way.
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`There is compelling evidence to support the main tenets of the clonal selec-
`tion theory. For example, when lymphocytes from an animal that has not been
`immunized are incubated in a test tube with a number of radioactively labeled
`antigens, only a very small proportion (less than 0.01%) bind each antigen, sug-
`gesting that only a few cells are committed to respond to these antigens. More-
`over, when one antigen is made so highly radioactive that it kills any cell that it
`binds to, the remaining lymphocytes can no longer produce an immune
`response to that particular antigen, even though they can still 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 immune system produce lymphocytes that collectively
`display such an enormous diversity 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.
`
`Most Antigens Activate Many Different Lymphocyte Clones
`
`Most large molecules, including virtually all proteins and many polysaccharides,
`Can serve as antigens. Those parts of an antigen that combine with the antigen-
`hinding site on either an antibody molecule or a lymphocyte receptor are called
`lllltlgenic determinants (or epitapes). Most antigens have a variety of antigenic
`determinants that can stimulate the production of antibodies, specific T cell
`re“liponses, or both. Some determinants of an antigen produce a greater
`reElponse than others, so that the reaction to them may dominate the overall
`rialsponse. Such determinants are said to be immunodomimznt.
`The diversity of lymphocytes is such that even a single antigenic determi-
`nant is likely to activate many clones, each of which produces an antigen-bind-
`1“5 site with its own characteristic affinity for the determinant. Even a relatively
`flmple structure, like the dinitrophenyl (DNP) group in Figure 24-9, can be
`llInked at" in many ways. When it is coupled to a protein, as shown in the fig-
`u'E. it usually stimulates the production of hundreds of species of anti-DNP
`
`LYMPHOCYTES AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`amino acid
`
`
`
` ivslne
`
` dinitrophenyl
`
`group (DNP)
`
`polypeptide
`backbone of
`protein
`
`Figure 24-9 The dinltrophenyl
`(DNP) group. Although It is too small to
`induce an immune response on its own,
`when it is coupled covalently to a lysine
`side chain on a protein, as illustrated,
`DNP stimulates the production of
`hundreds of different species of antibodies
`that all bind specifically to it.
`
`l369
`
`Lassen — Exhibit 1042, p. 10
`
`Lassen - Exhibit 1042, p. 10
`
`

`

`antibodies, each made by a different B cell clone. Such responses are said to be
`polyclonal.When onlya few clones are activated, the response is said to be oliga-
`clorml: and when the response involves only a single B or T cell clone, it is said
`to be monoclonal. Monoclonal antibodies are widely used as tools in biology and
`medicine, but they have to be produced in a special way (see Figure 845), as the
`responses to most antigens are polyclonal.
`
`Immunological Memory ls Due to Both Clonal Expansion
`and Lymphocyte Differentiation
`
`The adaptive immune system, like the nervous system, can remember prior
`experiences. This is why we develop lifelong immunity to many common
`infectious diseases after our initial exposure to the pathogen, and it is why vac-
`cination works. The same phenomenon can be demonstrated in experimental
`animals. If an animal is immunized once with antigen A, an immune response
`(either antibody or cell-mediated) appears after several days, rises rapidly and
`exponentially, and then, more gradually, declines. This is the characteristic
`course of a primary immune response, occurring on an animal’s first exposure
`to an antigen. If, after some weeks, months, or even years have elapsed, the ani-
`mal is reinjected with antigen A, it will usually produce a secondary immune
`response that is very different from the primary response: the lag period is
`shorter