Janeway’'s
`
`immuno
`
`biologyEDITION
`
`
`
`Kenneth Murphy+Paul Travers»Mark Walport
`
`Miltenyi Ex. 1029 Page 1
`
`

`

`Janeway's 1mmuno
`
`SEV ENTH EDITION
`
`Kenneth Murphy
`Washington University School of Medicine, St. Louis
`
`Paul Travers
`Anthony Nolan Research Institute, London
`Mark Wolport
`The Wellcome Trust, London
`
`With contributions by:
`Michael Ehrenstein
`University College London, Division of Medicine
`Claudia Mauri
`University College London, Division of Medicine
`Allan Mowat
`University of Glasgow
`Andrey Shaw
`Washington University School of Medicine, St. Louis
`
`GS Garland Science
`
`Taylor & Francis Group
`NEWYORKAND LONOON
`
`Miltenyi Ex. 1029 Page 2
`
`

`

`Vice President:
`Assistant Editor:
`Text Editor:
`Production Editor and Layout:
`Copy Editor:
`lltu1tratlon and Design:
`Permissions Coordinator:
`Indexer:
`
`Denise Schanck
`Sigrid Masson
`Eleanor Lawrence
`Georgina Lucas
`Bruce Goetly
`Matthew McClements, Blink Stucio, Ltd.
`Mary Dispenza
`Merrall-Ross International Ltd.
`
`lmmunobiology, Seventh Edition Interactive:
`Storyboards by:
`Kenneth Murphy, Paul Travers, and Peter Walter
`Narrated by:
`Julie Theriot
`Animations, Interface Design,
`and Programming:
`Senior Meda Editor:
`
`Matthew McClements, Blink Studio, Ltd.
`Michael Morales
`
`© 2008 by Garland Science, Taylor & Francis Group, LLC
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted
`material is quoted with permission, and sources are indicated. A wide variety of references are
`listed. Reasonable efforts have been made to publish reliable data and information, but the author
`and the publisher cannot assume responsibility for the validity of all materials or for the
`consequences of their use.
`
`All rights reserved. No part of this book covered by the copyright heron 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.
`
`10-dlgit ISBN 0-8153-4123-7
`0-8153-4290-X (International Student Edition)
`13-digit ISBN 978-0-8153-4123-9
`978-0-8153-4290-8 (International Student Edition)
`
`Library of Congress Cataloging-in-Publication Data
`Janeway, Charles.
`Janeway's immunobiology. - - 7th ed. / Kenneth Murphy, Paul Travers, Mark Walport.
`p. cm.
`Includes index.
`ISBN 0-8153-4 123-7 (978-0-8153-4123-9)
`I. Murphy, Kenneth. II. Travers, Paul. Ill. Walport, Mark. IV. TIiie.
`QR181J37 2008
`616.07'9--dc22
`
`2007002499
`
`Published by Garland Science, Taylor & Francis Group, LLC, an inforrna business
`270 Madison Avenue, New York, NY 10016, US, and
`2 Park Square, Milton Park, Abingdon, OX14 4RN, UK
`
`Printed in the United States of America
`15 14 13 12 11 10 9 8 7 6 5 4 3 2
`
`lli1nforma]
`
`T aytor & Francis Group. an informa business
`
`Visit our web site at http://www.garlandscience.com
`
`Miltenyi Ex. 1029 Page 3
`
`

`

`Principles of iMale and adaptive Immunity I
`
`3
`
`Principles of innate and adaptive immunity.
`
`U1e body is protected from infectious agents and the damage they cause, and
`from other harmful substances such as insect toxins, by a variety of effector
`cells and molecules that together make up the immune system. In this part
`of the chapter we discuss the main principles underlying immune responses
`and introduce the cells and tissues of the immune system on which an
`immune response depends.
`
`1-1
`
`Functions of the immune response.
`
`To protect the individual effectively against disease, the immune system
`must fulfill four main tasks. The first is immunological recognition: the pres(cid:173)
`ence of an infection must be detected. This task is carried out both by the
`white bJood cel1s oft.he innate immune system, which provide an immediate
`response, and by the lymphocytes of the adaptive immune system. The sec(cid:173)
`ond task is to contain the infection and if possible eliminate it completely,
`which brings into play immune effector functions such as the complement
`system of blood proteins, antibodies, and the destructive capacities of lym(cid:173)
`phocytes and the other white blood cells. At the same time the immune
`response must be kept under control so that it does not Itself do damage to
`the body. Immune regulation, or the ability of the immune system to self(cid:173)
`regulate, is thus an important feature of immune responses, and failUJe of
`such regulation contributes to conditions stLch as allergy and autoimmune
`disease. The fourth task is to protect the individual against recurring disease
`due to the same pathogen, A unique feature of the adaptive immune system
`'is that it is capable of generating immunological memory, so that having
`been exposed once to an infectious agent, a person will make an immediate
`and stronger response against any subsequent exposure lo it; that is, they will
`have protective immunity against it. Finding ways of generating long-lasting
`immunity to pathogens that do not naturally provoke it is one of the b'Teatest
`challenges facing immunologists today.
`
`When an individual first encounters an infectious agent. the initial defenses
`against infection are physical and chemical baniers thal prevent microbes
`from entering the body; these are not generally considered as part of the
`immune system proper and it is only when these barriers are overcome or
`evaded that the immune system comes into play. The first cells that respond
`are phagocytic while blood cells, such as macrophages, that fonn part of the
`innate immune system. These ceUs are able to ingest and kill microbes by
`producing a variety of toxic chemicals and powerful degradative enzyrnes.
`Innate immunity is of ancient origin-some form of innate defense against
`disease is found in all animals and plants. The macrophages of humans and
`other vertebrates, for example, are presumed to be the direct evolutionary
`descendants of the phagocytic cells present in simpler animals, such as those
`that Metchnikoft' observed in the invertebrate sea stars.
`
`Innate immune responses occur rapidly on exposure to an infectious organ(cid:173)
`ism. Overlapping with the .innate immune response, but taking days rather
`than hours to develop, the adaptive immune system is capable of eliminating
`infections more effi:cien,tly than the jnnate immune response. It is present
`only in vertebrates and depends on the exquisitely specific recognition func(cid:173)
`tions of lymphocytes, wmioh have t!he ability rto distinguish the particU!lar
`pathogen and focus the immune response more strongly on it. These cells can
`recognize and respond ro individual antigens by means of highly spectahzed
`antigen .receptors on the lymphocyte surface. The blllions of lymphocytes
`
`Miltenyi Ex. 1029 Page 4
`
`

`

`I Chapter 1; Basic Concepts in Immunology
`___ _,
`
`4
`
`Bone marrow
`
`0
`
`pluripotent hema!Of)oietic slam cell
`
`'
`
`"7
`
`I
`I
`
`Bone marrow
`
`@ lt @ @
`
`ri
`common
`gran,Jloeytel
`~ macroe:,iage
`piogeMOr
`progenitor
`
`111egal!a')'OCYte.'
`el)thr~
`progeni or
`
`J
`
`Blood
`
`Graoulocytes (or polymorphonuclear leukocytes)
`
`ri.
`'
`
`megakaryocyto
`
`aryt/ilolllast
`
`I
`
`•
`
`common
`l'fmpl-,oid
`progenitor
`
`J
`
`l
`
`•
`
`I
`
`1
`
`- ,_
`
`V
`
`Bcell
`
`T CEii
`
`~~ ....
`
`"7
`
`NKcelt
`....
`...,
`
`lt g 0
`,_ , - - - ...__ ----
`-
`-
`~ L J
`- - ~
`' .
`""' ~,, 0
`'~ Q ¥ 1ft ~®~@e
`· .. ·· .
`••'
`- ...,
`L.y· --
`.o. @)
`~oo
`~ Q ¥ ~ " cfft
`Q "' ~
`
`Immature
`dendrftic cell
`
`neutrophi( e06inophil
`
`basophil
`
`unknown
`pre<:ursor monocyte
`olmastcell
`
`... -.,
`
`ri..a
`
`platelets
`
`erythrocyte
`
`'
`
`'~
`
`immature
`derorilicceU
`
`• -✓ Q
`o e o ~
`C>9 C>
`
`Q
`
`mast cell
`
`macrophage
`
`B cell
`
`i='vc.
`
`Teel!
`
`-' ...
`Effector cell•
`
`NKceU
`
`malure
`dendnlic cell
`~
`
`'}.) A1t·
`
`plasma cell
`
`aaivated
`Teel!
`
`.
`l
`acllvated
`NK~t
`
`Fig. 1.3 All the cellular elements of the blood, including the cells
`of the Immune system, arise from pluripotent hematopoietio
`stem cells in the bone marrow. These pluripotent cells divide to
`produce two types of stem cells. A common lymphoid progenitor
`gives rise to the lymphoid lfneage (blue baci<gro1.11d) of white blood
`cells or leukocytes-the natl.Kai klNer (NI<} cells atld the T and B
`lymphocytes. A common myeloid progenitor gives rise to the
`myeloid lineage (pink and yellow backgrounds), which comprises
`the rest of the leukocytes, the eiythrocytes (red blood cells), and the
`megakaryocytes that produce platelets important in blood clotting.
`T and B lymphocytes are distinguished from the other leukocytes by
`
`the possession of antigen receptors, and from each other by their
`sites of differentiation-the thymus and bone marrow, respectively.
`After encounter with antigen, B cells differentiate into antibody-
`secreting plasma cells, while T cells differentiate into effector T cells
`with a variety of functions. Unlike T and B cells, NK cells lack
`antigen specificity. The remaining leukocytes are the monocytes, the
`dendritic cells, and the neutrophils, eosinophils, and basophils. The
`latter three circulate in the blood and are termed granulocytes,
`because of the cytoplasmic granules whose staining gives these
`cells a distinctive appearance in blood smears, or
`polymorphonuclear leukocytes, because of their irregularly shaped
`nuclei. Immature dendritic cells (yellow background) are phagocytic
`cells that enter the tissues; they mature after they have encountered
`a potential pathogen. The common lymphoid progenitor also gives
`rise to a minor subpopulation of dendritic cells, but for simplicity this
`developmental pathway has not been IAostrated. However, as there
`are more common myeloid progenitor cells than there are oonmon
`lymphoid progenitors, the majority of the dendrrtic cells in the body
`develop from common myeloid progenitors. Mooocytes enter
`tissues, where they differentiate Into phagocytic macrophages. The
`precursor ceU that gives rise to mast cells is still unknown. Mast
`cells also enter tissues and complete their maturation there.
`
`Miltenyi Ex. 1029 Page 5
`
`

`

`Principles of innate and adaptive invnunity ~
`
`present in the body collectively possess a vast repertoire of antigen receptors,
`which enables the immune system to recognize and respond to virtually any
`antigen a person is likely to be exposed to. By making recognition and
`response specific for a particular pathogen, the adaptive immune response
`focuses the resources of the immune system on combating that pathogen,
`enabling the body to overcome pathogens that have evaded or overwhelmed
`innate immunity. Antibodies and activated lymphocytes produced in this
`phase of the response also persist after the original infection has been elimi(cid:173)
`nated and prevent immediate reinfection. Lymphocytes are also responsible
`for the long-lasting immunity that is generated after a successful adaptive
`immune response to many pathogens, so that the response to a second expo(cid:173)
`sure to the same microbe is both faster and greater in magnitude, even when
`it occurs many years later.
`
`1-2
`
`The cells of the immune system derive from precursors in the
`bone marrow.
`
`Both innate and adaptive immune responses depend upon the activities of
`white blood cells or leukocytes. These cells all originate in the bone marrow,
`and many of them also develop and mature there. They then migrate to guard
`the peripheral tissues-some of them residing within tissues, others circulat(cid:173)
`ing in the bloodstream and in a specialized system of vessels called the lym(cid:173)
`phatic system, which drains extracellular fluid and free cells from tissues,
`transports them through the body as lymph, and eventually empties back
`into the blood system.
`
`All the cellular elements of blood, including the red blood cells that transport
`oxygen, the platelets that trigger blood clotting in damaged tissues, and the
`white blood cells of the immune system, derive from the hematopoietic stem
`cells of the bone marrow. As these stem cells can give rise to all the different
`types of blood cells, they are often known as pluripotent hematopoietic stem
`cells. They give rise to stem cells of more limited developmental potential,
`which are the immediate progenitors of red blood cells, platelets, and the two
`main categories of white blood cells, the lymphoid and myeloid lineages. The
`different types of blood cells and their lineage relationships are summarized
`in Fig. 1.3.
`
`1-3 The myeloid lineage comprises most of the cells of the innate
`immune system.
`
`The common myeloid progenitor is the p recursor of the macrophages, gran(cid:173)
`ulocytes, mast cells and dendritic cells of the innate immune system, and also
`of megakaryocytes and red blood cells, which we will not be concerned with
`here. The cells of the myeloid lineage are shown in Fig. 1.4.
`
`Macrophages are resident in almost all tissues and are the mature form of
`monocytes, which circulate in the blood and continually migrate into tissues,
`where they differentiate. Together, monocytes and macrophages make up
`one of the three types of phagocytes in the immune system: the others are the
`granulocytes (the collective term for the white blood cells called neutrophils,
`eosinophils, and basophils) and the dendritic cells. Macrophages are rela(cid:173)
`tively long-lived cells and perform several different functions throughout the
`innate immune response and rthe subsequent adaptive immune ,response.
`One is to engulf and kill invading microorganisms. In this phagocytic role
`they are an important first defense in innate immunity and also dispose of
`p athogens and infected cells targeted by an adaptive immune response. Both
`monocytes and macrophages are phagocytic, but most infections occur in
`the tissues, and so it is primarily macrophages that perform this important
`iproteotive function. An addi~ional an<!l .cruoia1 role of macroph~es is to
`
`Miltenyi Ex. 1029 Page 6
`
`

`

`·~
`
`Chapter 1: Basic Concepts in Immunology
`
`Fig. 1.4 Mye!oid cells in innate and
`adaptive immunity. Cells of the myeloid
`lineage perform various important
`functions in the immune response. In the
`rest of the book these cells will be
`represented in the schematic form shown
`on the left. A photomicrograph of each
`cell type is shown in the center panels.
`Macrophages and neutrophils are
`primarily phagocytic cells that engulf
`pathogens and destroy them in
`intracellular vesicles, a function they
`perform in both innate and adaptive
`immune responses. Dendritic cells are
`phagocytic when they are immature and
`can take up pathogens; after maturing,
`they function as specialized cells that
`present pathogen antigens to
`T lymphocytes in a form they can
`recognize, thus activating T lymphocytes
`and initiating adaptive immune
`responses. Macrophages can also
`present antigens to T lymphocytes and
`can activate them. The other myeloid
`cells are primarily secretory cells that
`release the contents of their prominent
`granules upon activation via antibody
`during an adaptive immune response.
`Eosinophils are thought to be involved in
`attacking large antibody-coated parasites
`such as worms, whereas the function of
`basophils is less clear. Mast cells are
`tissue cells that trigger a local
`inflammatory response to antigen by
`releasing substances that act on local
`blood vessels; they are also important in
`allergic responses. Photographs courtesy
`of N. Rooney, R. Steinman, and D. Friend.
`
`Ctll
`
`j Actlveted function I
`
`Phagocytosis
`and activation ol
`bactericidal
`mechanisms
`
`Antigen
`presentation
`
`Antigen uptake
`in peripheral
`sites
`
`Antigen
`presentation
`
`Phagocytosis
`and activation
`of bactericidal
`mechanisms
`
`Kllllng oi
`antibody-coated
`parasites
`
`Unknown
`
`Release of
`granules
`containing
`histamine
`and active
`agents
`
`Q
`
`Neutrophll
`
`Eoelnophll
`
`Basophll
`
`Masi cell
`
`Miltenyi Ex. 1029 Page 7
`
`

`

`Principles of innate and adaptive immunity ~
`
`orchestrate immune responses: they help induce inflammation, which, as we
`shall see, is a prerequisite to a successful immune response, and they secrete
`signaling proteins that activate other immune-system cells and recruit them
`into an immune response. As well as their specialized role in the immune sys(cid:173)
`tem, macrophages act as general scavenger cells in the body, clearing dead
`cells and cell debris.
`The granulocytes are so called because they have densely staining granules
`in their cytoplasm; they are also called polymorphonuclear leukocytes
`because of their oddly shaped nuclei. There are three types of granulocytes(cid:173)
`neutrophils, eosinophils, and basophils- which are distinguished by the dif(cid:173)
`ferent staining properties of the granules. In comparison with macrophages
`they are all relatively short-lived, surviving for only a few days, and are pro(cid:173)
`duced in increased numbers during immune responses, when they leave the
`blood to migrate to sites of infection or inflammation. The phagocytic neu(cid:173)
`trophils are the most numerous and most important cells in innate immune
`responses: they take up a variety of microorganisms by phagocytosis and effi(cid:173)
`ciently destroy them in intracellular vesicles using degradative enzymes and
`other antimicrobial substances stored in their cytoplasmic granules. Their
`role is discussed in more detail in Chapter 2. Hereditary deficiencies in neu(cid:173)
`trophil function lead to overwhelming bacterial infection, which is fatal if
`untreated.
`The protective functions of eosinophils and basophils are less well under(cid:173)
`stood. Their granules contain a variety of enzymes and toxic proteins, which
`are released when the cell is activated. Eosinophils and basophils are thought
`to be important chiefly in defense against parasites, which are too large to be
`ingested by macrophages or neutrophils, but their main medical importance
`is their involvement in allergic inflammatory reactions, in which their effects
`are damaging rather than protective. We discuss the functions of these cells in
`Chapter 9 and their role in allergic inflammation in Chapter 13.
`Mast cells, whose blood-borne precursors are not well defined, differentiate
`in the tissues. Although best known for their role in orchestrating allergic
`responses, which is discussed in Chapter 13, they are believed to play a part
`in protecting the internal surfaces of the body against pathogens and are
`involved in the response to parasitic worms. They have large granules in their
`cytoplasm that are released when the mast cell is activated; these help induce
`inflammation.
`The dendritic cells are the third class of phagocytic cell of the immune sys(cid:173)
`tem. They have long finger-like processes, like the dendrites of nerve cells,
`which gives them their name. Immature dendritic cells migrate through the
`bloodstream from the bone marrow to enter tissues. They both take up par(cid:173)
`ticulate matter by phagocytosis and continually ingest large amounts of the
`extracellular fluid and its contents by a process known as macropinocytosis.
`Like macrophages and neutrophils, they degrade the pathogens they take up,
`but their main role in the immune system is not the clearance of microor(cid:173)
`ganisms. Instead, dendritic cells that have encountered invading microor(cid:173)
`ganisms mature into cells capable of activating a particular class of
`lymphocytes-the T lymphocytes-which are described below. Dendritic
`cells do this by displaying pathogen antigens on their surface in such a way
`that they can be recognized and responded to by this type of lymphocyte. As
`we discuss later in the chapter, recognition of antigen alone is not sufficient
`to activate a T lymphocyte that has never encountered its antigen before.
`Mature dendritic cells, however, have additional properties that enable them
`to activate T lymphocytes. Cells that can present antigens to inactive T lym(cid:173)
`phocytes and activate them for the very first time are known as antigen-pre(cid:173)
`senting cells (APCs), and such cells form a crucial link between the innate
`immune response and the adaptive immune response. Macrophages can also
`
`Miltenyi Ex. 1029 Page 8
`
`

`

`act as antigen-presenting cells, and they are important in particular situa(cid:173)
`tions. Dendritic cells, however, are the cells that specialize in presenting anti(cid:173)
`gens to lymphocytes and initiating adaptive immune responses.
`
`1-4
`
`The lymphoid lineage comprises the lymphocytes of the adaptive
`Immune system and the natural killer cells of innate Immunity •
`
`The common lymphoid progenitor in the bone marrow gives rise lo the anti(cid:173)
`gen-specific lymphocytes of the adaptive immune system and also to a type
`of lymphocyte that responds to the presence of infection but is nol specific for
`antigen, and is thus considered to be part of the innate immune system. This
`latter is a large cell with a distinctive granular cytoplasm and is called a natu(cid:173)
`ral killer ceU (NK cell) (Fig. 1.5). These cells are able to recognize and.kill some
`abnormal cells, for ex.ample some tumor cells and cells infected with herpes
`viruses. Their functions in innate immunity are described in Chapter 2.
`We come finally lo the antigen-specific lymphocytes, with which most of this
`book will be concerned: unless indicated otherwise, we shall use the term
`lymphocyte from now on to refer to the antigen,specific lymphocytes only,
`The immune system must be able to mount an immune response against
`any of the wide variety of different pathogens a person is likely to encounter
`during their lifetime. Lymphocytes collectively make this possible thrnug.h
`the hlghJy variable antigen receptors on their surface, by which they recog(cid:173)
`nize and bind antigens. Each lymphocyte matures bearing a unique valiant
`of a prototype antigen receptor, so that the population of lymphocytes
`expresses a huge repertoire of receptors that are highly diverse in their anti(cid:173)
`gen-binding sites. Among the billion or so lymphocytes circulating in the
`body at any one time there will always be some that can recognize a given
`foreign antigen.
`
`In the absence of ao infection, most lymphocytes circulating in the body are
`small, featureless cells with few cytoplasmic organelles and much of the
`nuclear chromatin inactive, as shown by its condensed state (Fig. 1.6). This
`appearance is typical of inactive cells. lt is hardly surprising that until the
`1960s textbooks described these cell.s, now the central focus of immunology,
`as having no known function. Indeed, these small lymphocytes have no func(cid:173)
`tional activity until they encounter their specific antigen. Lymphocytes that
`have not yet been activated by antigen are known as naive lymphocytes;
`those that have met their antigen, become activated, and have differentiated
`further into fully functional lymphocytes are known as effector lymphocytes.
`
`-~
`
`Chapter 1: Basic Concepts in Immunology
`
`Natural kllllr (NK) cell g . . . . .
`
`Releases lytic granules that kill some
`virus-Infected cells
`
`Fig. 1.5 Natural killer (NK) cells. These
`are large granular lymphoid-like cells with
`important functions In lnnate immunity,
`especially against intracellular infections,
`being able to kill other cells . Unlike
`lymphocytes, they lack antigen-specific
`receptors. Photograph courtesy of
`B. Smith.
`
`Fig. 1.6 Lymphocytes are mostly small
`and inactive cells. The left panel shows
`a light micrograph of a small lymphocyte
`in which the nucleus has been stained
`purple by the hematoxylin and eosin dye,
`surrounded by red blood cells (which
`have no nuclei). Note the darker purple
`patches of condensed chromatin of the
`lymphocyte nucleus, Indicating little
`transcriptional activity, the relative
`absence of cytoplasm, and the small size.
`The right panel shows a transmission
`electron micrograph of a small
`lymphocyte. Again, note the evidence of
`functional lnactivify: the condensed
`chromatin, the scanty cytoplasm, and the
`absenc-,e of rough endoplasmic reticulum.
`Photographs courtesy of N. Rooney.
`
`Miltenyi Ex. 1029 Page 9
`
`

`

`Principles of innate and adaptive Immunity ~
`
`There are two types of lymphocytes-B lymphocytes (B cells) and T lympho(cid:173)
`cytes (T cells)-each with quite different roles in the immune system and dis(cid:173)
`tinct types of antigen receptors. After antigen binds to a B-cell antigen
`receptor, or B-cell receptor (BCR), on the B-cell surface, the lymphocyte will
`proliferate and differentiate into plasma cells. These are the effector form of
`B lymphocytes and they produce antibodies, which are a secreted form of the
`B-cell receptor and have an identical antigen specificity. Thus the antigen
`that activates a given B cell becomes the target of the antibodies produced by
`that cell's progeny. Antibody molecules as a class are known as immunoglob(cid:173)
`ulins (lg), and so the antigen receptor of B lymphocytes is also known as
`membrane immunoglobulln (mlg) or surface immunoglobulin (slg).
`
`The T-cell antigen receptor, or T-cell receptor (TCR), is related to
`immunoglobulin but is quite distinct in its structure and recognition proper(cid:173)
`ties. After a T cell is activated by its first encounter with antigen it proliferates
`and differentiates into one of several different functional types of effector
`T lymphocytes. T-cell functions fall into three broad classes-killing, activa(cid:173)
`tion, and regulation. Cytotoxic T cells kill cells that are infected with viruses
`or otber intracellular pathogens. Helper T cells provide essential additional
`signals that activate antigen-stimulated B cells to differentiate and produce
`antibody; some of these T cells can also activate macrophages to become
`more efficient at kiiling engulfed pathogens. We return to the functions of
`cytotoxic and helper T cells later in this chapter, and their actions are
`described in detail in Chapters 8 and 10. Regulatory T cells suppress the
`activity of other lymphocytes and help control immune responses; they are
`discussed in Chapters 8, 10, and 14.
`
`During the course of an immune response, some of the B cells and T cells acti(cid:173)
`vated by antigen differentiate into memory cells, the lymphocytes that are
`responsible for the long-lasting immunity that can follow exposure to disease
`or vaccination. Memory cells will readily differentiate into effector cells on a
`second exposure to their specific antigen. Immunological memory is
`described in Chapter 10.
`
`1-5
`
`Lymphocytes mature in the bone marrow or the thymus and then
`congregate in lymphoid tissues throughout the body.
`
`Lymphocytes circulate in the blood and the lymph and are also found in large
`numbers in lymphoid tissues or lymphoid organs, which are organized
`aggregates of lymphocytes in a framework of nonlymphoid ceUs. Lymphoid
`organs can be divided broadly into central or primary lymphoid organs,
`where lymphocytes are generated, and peripheral or secondary lymphoid
`organs, where mature naive lymphocytes are maintained and adaptive
`immune responses are initiated. The central lymphoid organs are the bone
`marrow and the thymus, an organ in the upper chest. The peripheral lym(cid:173)
`phoid organs comprise the lymph nodes, the spleen and the mucosal lym(cid:173)
`phoid tissues of the gut,"the nasal and respiratory tract, the urogenital tract
`and other mucosa. The location of the main lymphoid tissues is shown
`schematically in Fig. 1. 7, and we shall describe the individual peripheral lym(cid:173)
`phoid organs in more detail later in the chapter. Lymph nodes are intercon(cid:173)
`nected by a system of lymphatic vessels, which drain extracellular fluid from
`tissues, through the lymph nodes, and back into the blood.
`
`Both B and T lymphocytes originate in the bone marrow, but only the B lym(cid:173)
`phocytes mature there. The precursorT lymphocytes migrate to the thymus,
`from which they get their name, and mature there. The 'B' in B lymphocytes
`originally stood for the bursa ofFabricius, a lymphoid organ in young chicks
`in which lymphocytes mature; fortunately, it can stand equally well for
`bone marrow-derived. Once they have completed maturation, both types of
`
`Miltenyi Ex. 1029 Page 10
`
`

`

`to7 Chapter 1: !Basic Concepts lo lmmundlogy
`
`Fig. 1. 7 11he distribution of lymphoid
`tissues in the body. Lymphocytes arise
`from stem cells in bone marrow and
`differentiate in the central lymphoid organs
`(yellow)- B cells in the bone marrow arnd
`T cells in the thymus, They migrate from
`these tissues and are carried in the
`bloodstream to the peripheral lymphoid
`organs (blue) These includ.e lymph
`nodes, spleen, and lymphoid tissues
`associated with mucosa, such as the gut(cid:173)
`associated tonsils, Payer's pa1ches, and
`appendix. The peripheral lymphoid
`organs are the sites of lymphocyte
`activation by antigen, and lymphocytes
`recirculate between the blood and these
`organs until they encounter their specific
`antigen, lymphatics drain extracellular
`ftuld from the peripheral tissues, through
`the lymph nodes and Into the thoracic
`duct, which empties into the left
`subclavian vein. This fluid, known as
`lymph, carries antigen taken up by
`dendiitic cells and macrophages to the
`lymph nodes and recirculating
`lymphocytes from the lymph nodes back
`lnto the blood. Lymphoid tissue Is also
`associated with otlier mucosa such as
`the bronchial lfnings (not shown).
`
`adenoid
`Lonsll
`
`nght subclavian vein - - --p,.....;~,!!IN ~ - -\"---
`-=~---- -
`
`J - - -- - 4 - --
`
`lett slbdavlan vein
`thymus
`heart
`
`,,,.~ -11--+-- - spleen
`Peyer's patch in
`small Intestine
`-=-----;---~-;-- large intestine
`
`lymphocytes enter the bloodstream as mature naive lymphocytes. They cir(cid:173)
`culate through the peripheral lymphoid tissue$, in which an adaptive
`immune response is initiated if a lymphocyte meets its corresponding anti(cid:173)
`gen. Before this, however, an innate immune response to the infection has
`usually occurred, and we now look at how this alerts the rest of the immune
`system. to the presence of a pathogen.
`
`1-6 Most infectious agents actlvalte the Innate immune system and
`Induce an Inflammatory respcmse.
`
`The skin and the mucosa] epithe lia lining the airways and gut are the first
`defense against invading pathogens , forming a physicaJ and chemical barrier
`against infection. Microorganisms tlltal breach these defenses are met by cells
`and m o lecules that mount an i mmediate innate immune response.
`Macrophages resident In the tissues are the first line of defense against bac•
`teria, for example, which they reco,gnize by means of receptors tha t bind
`common constituents of many batcterial surfaces. Engagement of these
`receptors ttiggers the m acrophage b,oth to engulf the bacterium and degrade
`.it internally, and to secrete proteins called cytok:ines and chemotines, as well
`as other bioJogicaJly active molecules. Similar responses occur to viruses,
`fungi, and parasites. Cytoldne is a general name for aoy protein that is
`secreted by cells and affects the behavior of nearby cells bearing appropriate
`receptors. Chemc,.ldo.es are secreted proleins tha1 attract ceils bearing
`chemok:ine receptors, such as neutmphils and m onocytes, out of the blood(cid:173)
`stream and into the infected tissue (Fig. 1.8). The cyto.kines and cbemoldnes
`
`Miltenyi Ex. 1029 Page 11
`
`

`

`Principles of innate and adaptive Immunity ~
`
`Fig. 1.8 Infection triggers an
`inflammatory response. Macrophages
`encountering bacteria or other types of
`microorganisms in tissues are triggered to
`release cytokines that increase the
`penneabillty of blood vessels, allowing
`fluid and proteins to pass into the tissues.
`They also produce chemokines, which
`direct the migration of neutrophiis to the
`site of infection. The stickiness of the
`endothelial cells of the blood vessel wall
`is also changed, so that cells adhere to
`the wall and are able to crawl through it;
`first.neutrophils W1d then monocytes are
`shown entering the tissue from a blood
`vessel. The accumulation of fluid and
`cells at the site of infec.tion causes the
`redness, swelling, heat, and pain known
`collectively as inflammation. Neutrophils
`and macrophages are the principal
`inflammatory cells. Later in an immune
`response, activated lymphocytes can also
`contribute to Inflammation.
`
`eactarla trtgga,
`macrophages to rfltaff
`cy1oldnl1 "ll!ld ct111mokln11
`
`Viiaoelllatlon 1111d lnCl'llbleli
`meuhu Ptfflltlbllity oautt
`rvdn1111, ll■lt, .,d •w•llng
`
`ll'lllln111111loty cella Mlgr.(cid:173)
`lnto If Hue, Njea.ln9
`Jrilanlmatorv medlalo,.
`that CA\lN IHdll
`
`0
`
`..
`
`cy1oldnes
`
`.,, oo ..
`' ~o
`+
`•
`•
`
`chemokil11lS
`
`released by activated macrophages initi