Case 1:18-cv-00924-CFC Document 399-3 Filed 10/07/19 Page 1 of 61 PageID #: 30576
`
`arnino
`
`membrane
`protein - - (cid:173)
`degradation
`function ~
`
`/
`
`-
`acid metabolism
`
`- - - meiosis
`
`fatty-acid and
`sterol metabolism
`
`Summary
`
`Figure 3-78 A map of the
`protein-protein interactions
`observed between different
`functional groups of proteins in the
`yeast 5. cerevisiae. To produce this map,
`more than I 500 proteins were assigned to
`the indicated 3 I functional groups. About
`70 percent of the known protein-pro~ein
`interactions were observed to occur
`between proteins assigned to the same
`functional group. However, as indicated, a
`surpr isingly large number of interactions
`crossed between these groups. Each line
`in this diagram designates that more t han
`I 5 protein-protein interactions were
`observed between proteins in the two
`functional groups that are connected by
`that line. The three functional groups
`highlighted in yellow display at least
`I 5 interactions with IO or more of the
`3 1 functional groups defined in the study.
`(From C.L.Tucker,J.F. Gera, and P.Vetz.,
`Trends Cell Biol. I I: I 02- 106, 200 I.)
`
`I
`
`turnover
`
`Proteins can form enormously sophisticated chemical devices, whose functions
`l~rgely depend on the detailed chemical properties of their surfaces. Binding sites for
`ligands are formed as surface cavities in which precisely positioned amino acid side
`chains are brought together by protein folding. In the same way, normally unreac(cid:173)
`tive amino acid side chains can be activated to make and break covalent bonds.
`Enzymes are catalytic proteins that greatly speed up reaction rates by binding the
`high-energy transition states for a specific reaction path; they also perform acid
`catalysis and base catalysis simultaneously. The rates of enzyme reactions are often
`so fast that they are limited only by diffusion; rates can be further increased if
`enzymes that act sequentially on a substrate are joined into a single multienzyme
`complex, or if the enzymes and their substrates are confined to the same compart(cid:173)
`ment of the cell.
`Proteins reversibly change their shape when ligands bind to their surface. The
`allosteric changes in protein conformation produced by one ligand affect the bind(cid:173)
`ing of a second ligand, and this linkage between two ligand-binding sites provides a
`crucial mechanism for regulating cell processes. Metabolic pathways, for example,
`are controlled by feedback regulation: some small molecules inhibit and other small
`molecules activate enzymes early in a pathway. Enzymes controlled in this way gen(cid:173)
`erally form symmetric assemblies, allowing cooperative conformational changes to
`create a steep response to changes in the concentrations of the ligands that regulate
`them.
`Changes in protein shape can be driven in a unidirectional manner by the expen(cid:173)
`diture of chemical energy. By coupling allosteric shape changes to ATP hydrolysis, for
`example, proteins can do useful work, such as generating a mechanical force or
`moving for long distances in a single direction. The three-dimensional structures of
`proteins, determined by x-ray crystallography, have revealed how a small local
`change caused by nucleoside triphosphate hydrolysis is amplified to create major
`changes elsewhere in the protein. By such means, these proteins can serve as
`input-<Jutput devices that transmit information, as assembly factors, as motors, or
`as membrane-bound pumps. Highly efficient protein machines are formed by incor(cid:173)
`porating many different protein molecules into larger assemblies in which the
`allosteric movements of the individual components are coordinated. Such machines
`are now known to perform many of the most important reactions in cells.
`
`PROTEIN FUNCTION
`
`187
`
`APPX 0159
`
`

`

`Case 1:18-cv-00924-CFC Document 399-3 Filed 10/07/19 Page 2 of 61 PageID #: 30577
`
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`Kyte J ( 1995) Structure in Protein Chemistry. New York: Garland Publish(cid:173)
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`Mathews CK van Holde KE & Ahem K-G (2000) Biochemistry, 3rd edn. San
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`The Shape and Structure of Proteins
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`.
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`.
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`
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`.
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`.
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`.
`the
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`
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`.
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`
`APPX 0160
`
`

`

`Case 1:18-cv-00924-CFC Document 399-3 Filed 10/07/19 Page 3 of 61 PageID #: 30578
`
`THE ADAPTIVE IMMUNE
`SYSTEM
`
`?ur adaptive ~mune system saves us from certain death by infection. An
`mfant born WI~ a severely defective adaptive immune system will soon die
`unless extraordmary 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 innate 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 p~ovide long-lasti?g
`protection. A person who recovers from measles, for example, is protec~ed for hfe
`against measles by the adaptive immune system, alth~ugh not agam~t other
`common viruses such as those that cause mumps or chickenpox. In this chap(cid:173)
`ter, we focus m~inly on adaptive immune responses, and, unles~ we in_dicate
`otherwise, the term immune responses refers to the~. We discuss mnate
`itnmune responses in detail in Chapter 25.
`.
`.
`.
`The function of adaptive immune responses is to destroy mvadmg
`Pathogens and any toxic molecules they produce. Because these responses are
`·a1 th t they be made only in response to molecules that are
`destru t·
`· ·
`ct·
`c 1ve, it IS cruc1
`a
`•
`lf Th
`b"l"
`foreign to the host and not to the molecules of the h?st 1tse .
`e a 1 1ty to 1s-
`· fi
`·
`hat 1·s se/Fin this way is a fundamental feature of
`tingu· h h
`f
`Is w at 1s oreign rom w
`:1
`•
`•
`•
`the ad
`·
`•
`Occasionally the system fails to make this d1s-
`t
`aptive immune sys em.
`'
`,
`h
`·
`• 1 gainst the hosts own molecules. Sue autoim-
`tinct·
`1on and reacts destructive Ya
`rnune diseases can be fatal.
`the body are harmless and it
`t
`th
`i
`· molecules at en er
`,
`Of
`w
`·a11 dangerous to mount adaptive immune
`course, many oreign
`re~uld be poi?tless and pote~~I co:ditions such as hayfever and asthma are
`.
`onses against apparently harm-
`Ponses agamst them. Allerg
`ex::in-. 1
`.
`d
`f ve immune resp
`1 ... ,,p es of deletenous a ap 1.
`. te responses are normally avoided
`bess foreign molecules. Such mappr:n:daptive immune responses into play
`ecause the innate immune syStem ~ s cteristic of invading pathogens called
`OnJy When it recognizes molecules c ara
`
`LYMPHOCYTES AND THE
`CELLULAR BASIS OF ADAPTIVE
`IMMUNITY
`
`B CELLS AND ANTIBODIES
`
`THE GENERATION OF ANTIBODY
`DIVERSITY
`
`T CELLS AND MHC PROTEINS
`
`HELPER T CELLS AND
`LYMPHOCYTE ACTIVATION
`
`1363
`
`APPX 0161
`
`

`

`Case 1:18-cv-00924-CFC Document 399-3 Filed 10/07/19 Page 4 of 61 PageID #: 30579
`
`PATHOGENS
`
`INNATE
`IMMUNE
`RESPONSES
`
`ADAPTIVE IMMUNE RESPONSES
`
`•
`
`._ virus
`
`•
`
`innate immune +
`responses
`
`virus
`
`/
`
`antibody
`response
`
`cell-mediated
`response
`
`24 I
`ce immune
`I
`F•
`Innate and adaptive immune responses. nna
`•gure
`-
`responses are activated dire ctly 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 Infectio n.
`
`pathogen-associated immunostlmulants (discussed in Chapter 25). Moreover,
`the innate immune system can distinguish between differen t 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 s~ch
`responses has come from studies in which an experimenter tricks the adapttve
`immune system of a laboratory animal (usually a mouse) into responding t? a
`harmless foreign molecule, such as a foreign protein. The trick involves inje~lli!g
`the harmless molecule together with immunostimulants (usually microbial m
`origin) called adjuuants, which activate the innate immune system. This process
`is called immunization. If administered in this way, 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(cid:173)
`phocytes. There are t\vo 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
`immunoglobulins. 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(cid:173)
`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 directly against a foreign antigen that is pre(cid:173)
`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 tl1e 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 ch ap ter 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(cid:173)
`ber of different antibody molecules. FinalJy, 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.
`
`B ce ll
`
`hr _,
`
`Tcell
`
`(!j
`\~ · . .,
`1
`~ dead virus-infected cell
`
`,otiOO~
`
`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).
`
`Figure 24-2 The two main classes of
`adaptive immune responses.
`Lymphocytes carry out both classes of
`responses. Here, the lymphocytes are
`responding to a viral infection. In one class
`of response, 8 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
`
`APPX 0162
`
`

`

`Case 1:18-cv-00924-CFC Document 399-3 Filed 10/07/19 Page 5 of 61 PageID #: 30580
`
`Payer's patches in
`small intestine
`
`......,,..........,...- t-l-\-\s1-\\-le----spleen
`
`In this section, we discuss the general properties of lymphocytes that apply
`to both B cells ~d T ce~s. We shall see that each lymphocyte is committed to
`respon_d to a specific antigen and that its response during its first encounter with
`an antigen ensures ~at a more rapid and effective response occurs on subse(cid:173)
`quent e~counters Wl~
`the same antigen. We consider how lymphocytes avoid
`responding to self antigens and how they continuously recirculate between the
`blood and lymphoid organs, ensuring that a lymphocyte will find its specific
`foreign antigen no matter where the anitgen enters the body.
`
`Lymphocytes A re Required for Adaptive Immunity
`There are about 2 x 1012 lymphocytes in the human body, making the immune
`system comparable in cell mass to the liver or brain. Despite their abundance,
`their central role in adaptive immunity was not demonstrated until the late
`1950s. The crucial experiments were performed in mice and rats that were heav(cid:173)
`ily irradiated to kill m ost of their white blood cells, including lymphocytes. This
`treatment makes the animals unable to mount adaptive immune responses.
`Then, by transferring various types of cells into th e animals it was possible to
`determine which cells reversed the deficiency. Only lymphocytes restored the
`adaptive immune responses of irradiated animals, indicating that lymphocytes
`are required for these responses (Figure 24-4).
`
`~~n t ig e-n- --
`-
`(cid:141) NORMAL ADAPTIVE
`~ IMMUNE
`normal
`RESPONSES
`animal
`
`irrad~'ation
`
`,,
`
`.
`antigen
`
`® ·
`
`___ __ NO ADAPTIVE IMMUNE
`RESPONSES
`
`irradiated
`animal
`
`CONTROL
`
`c'\'Mfll-iocYTES AND THE CELLUlAR BASIS OF ADAPTIVE IMMUNITY
`
`Figure 24-3 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
`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
`s ho wing tha t lymphocytes a re
`require d for adaptive immune
`responses to fore ign 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.
`
`-
`
`- - --
`
`ADAPTIVE
`IMMUNE
`RESPONSES
`RESTORED
`
`_____ NO ADAPTIVE
`IMMUNE
`RESPO NSES
`
`EXPERIMENT
`
`1365
`
`APPX 0163
`
`

`

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`
`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 pathogen-associated ~ole~ules
`(immunostimulants) that are not present in the host organism, includmg micro(cid:173)
`bial DNA, lipids, and polysaccharides, and proteins that form bacterial flagell~.
`Some of these 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 bind to the surface of pathogens, marking them for destruction by
`either phagocytes or the complement system. Still others are present on the su_r(cid:173)
`face of various types of host cells and activate intracellular signaling pathways m
`response to the binding of pathogen-associated immunostimulants; 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 24-5). Other activated T cells remain
`
`-
`
`skin
`
`ACTIVATED T CELLS MIGRATE TO SITE OF
`INFECTION TO HELP ELIMINATE RESIDUAL MICROBES
`
`remnants of microbe
`in phagolysosome
`
`antigen(cid:173)
`presenting
`cell
`
`-
`
`microbes
`
`dendritic cell
`
`M ICROBES ENTER THROUGH
`BREAK IN SKIN AND ARE
`PHAGOCYTOSED BY
`DENDRITIC CELL
`
`DENDRITIC CELL MATURES
`AND CARRIES MICROBIAL
`ANTIGENS TO LOCAL LYMPH
`NODE TO BECOME AN
`ANTIGEN-PRESENTING CELL
`
`costimulatory protein
`
`\
`
`lymph node
`
`ANT IGEN-PRESENTING CELL
`ACTIVATES T CELLS TO
`RESPOND TO MICROBIAL
`ANTIGENS
`
`INNATE IMMUNE RESPONSE
`
`ADAPTIVE IMMUNE RESPONSE
`
`Figure 24-5 One way in which the innate immune system hel s acti
`.
`.
`system. Specialized phagocytic cells of the inn t
`P
`vate the adaptive immune
`.
`a e immune system includin
`h
`d
`dendritic cells ingest invading microbes or their products at th
`.
`g macrop ages (not shown) an
`. '
`e site of infection Th d d . .
`II
`h
`mature and migrate in lymphatic vessels to a nearby I
`h
`d
`·
`e en rit1c ce s t en
`•
`ymp no e , where they s
`.
`cells. The antigen-presenting cells activate T cells to resp nd
`erve as antigen-presenting
`h
`.
`0
`to t e microbial
`·
`h
`•
`the presenting cells' surface.The antigen-presenting cells als h
`antigens t at are displayed on
`.
`o ave special prot .
`h .
`.
`d
`costJmulatory molecules) that help activate the T cells Som
`f h
`ems on t e1r surface (calle
`.
`e O t e activated T
`f
`II h
`.
`.
`.
`.
`·
`infection where they either help activate macrophages or k"II . f
`ce s t en migrate to the site o
`in ected cells the b h I .
`.
`.
`h
`I
`•
`•
`re Y e ping to eliminate t e
`microbes.As we discuss later, the costimulatory molecule
`•
`s appear on dend . .
`I
`mature in response to invading microbes.
`ritic ce Is only after these cells
`
`1366
`
`Chapter 24 : THE ADAPT IVE IMMUNE SYST EM
`
`APPX 0164
`
`

`

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`
`h emopoietic
`tissue
`
`thymus
`
`peripheral
`lymphoid organs
`
`;cell
`precursor
`
`hemopoietic
`stem cells
`
`CELL(cid:173)
`-+-- MEDIATED
`IMMUNE
`RESPONSE
`
`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.
`
`in ~e lymphoid organ and h~lp B_ cells respond to the microbial antigens. The
`acnvated B cell~ secrete antibodies that circulate in the body and coat the
`[Ilicrobes, ~argetu~g them for efficient phagocytosis.
`Thus, mna~e m:imune 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 m the thymus, and B cells, in mammals, develop in th,e 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(cid:173)
`cussed in Chapter 22) are located primarily in hemopoietic tissues- mainly the
`liver in fetuses and the bone marrow in adults. T cells 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
`so?n 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
`foreign antigens (see Figure 24-6).
`T and B cells become morphologically distinguishable from each other only
`~er they have been activated by antigen. Nonactivated T and B cells look very
`sunuar, 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(cid:173)
`vated by antigen to proliferate and mature into effector cells. Effector B cells
`!e_crete antibodies. In their most matu_re for_m, called f!lasma cells, they are filled
`Vith an extensive rough endoplaslllic 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 T cells and helper T cells.
`Cytotoxic T cells kill infected cells, whereas helper T cells help activate
`
`LYMPHocn-Es AND THE CELLULAR BASIS OF ADAPTIVE IMMUNITY
`
`1367
`
`APPX 0165
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`

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`
`(A) resting T or B cell
`
`l__J
`1 µm
`
`(C) effector T cell
`
`LJ
`1 µm
`
`Figure 24-7 Electron micrographs of
`nonactivated and activated
`lymphocytes. (A) A resting lymphocyte,
`which could be a T cell or a B cell, as
`these cells are difficult to distinguish
`morphologically until they have been
`activated to become effector cells. (8) 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 effector T 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 al.,Atlas of Blood Cells: Function and
`Pathology, 2nd edn. Milan, Italy: Edi. Ermes,
`1988; C, courtesy of Stefanello de Petris.)
`
`(BJ effector B cell (plasma cell)
`
`[_J
`1 µm
`
`macrophages, B cells, and cytotoxic T cells. Effector helper T cells secrete a vari(cid:173)
`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(cid:173)
`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 1950s with the formulation of the
`clonal selection theory. According to this theory, an animal first randomly gen(cid:173)
`erates a vast diversity of lymphocytes, and then those lymphocytes that can
`react against the foreign antigens that the animal actually encounters are specif(cid:173)
`ically selected for action. As each lymphocyte develops in a central lymphoid
`organ, it becomes committed to react with a particular antigen befor