THE IMMUNE SYSTEM
`
`Peter Parham
`
`Stanford University
`
`The Immune System is derived from
`lmmunobio/ogy by Charles A. Janeway, Jr., Paul
`Travers and Mark Walport; also published by
`Garland Publishing and Current Trends.
`
`Garland Publishing
`New York and London
`
`CURRENT
`TRENDS
`
`Current Trends
`London
`
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`

`
`© 2000 by Garland Publishing/Elsevier Science Ltd.
`
`All rights reserved. No part of this publication may be reproduced, stored in a
`retrieval system or transmitted in any form or by any means-electronic,
`mechanical, photocopying, recording, or otherwise-without the prior written
`permission of the copyright holders.
`
`Distributors:
`
`Inside North America: Garland Publishing, a member of the Taylor & Francis
`Group, 29West 35th Street, New York, NY 10001-2299, US.
`Outside North America: Garland Publishing, a member of the Taylor & Francis
`Group, 11, New Fetter Lane, London EC4P 4EE, UK.
`
`ISBN: 0 8153 3043 X
`ISBN: 0 8153 3848 1
`
`(paperback) Garland
`(paperback) International Student Edition
`
`A catalog record for this book is available from the British Library.
`
`Library of Congress Cataloging-in-Publication Data
`
`Parham, Peter, 1950-
`The immune system I Peter Parham
`p.cm.
`
`Includes index.
`ISBN 0-8153-3043-X (pbk.)
`1. Immune system.
`2. Immunopathology.
`
`I. Title.
`
`QR181 .P335 2000
`616.07'9 21--dc21
`
`99-042006
`
`This book was produced using QuarkXpress 4.0 and Adobe Illustrator 7.0.
`
`Printed in United States of America.
`
`Published by Current Trends, part of Elsevier Science London, 84 Theo balds
`Road, London, WClX BRR, UK and Garland Publishing, a member of the
`Taylor & Francis Group, 29 West 35th Street, New York, NY 10001-2299, US.
`
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`

`
`Elements of the Immune
`System and their
`Roles in Defense
`
`Immunology is the study of the physiological mechanisms that humans and other
`animals use to defend their bodies from invasion by other organisms. The origins
`of the subject lie in the practice of medicine and in historical observations that
`people who survived the ravages of epidemic disease were untouched when faced
`with that same disease again-they had become immune to infection. Infectious
`diseases are caused by microorganisms, which have the advantage of reproducing
`and evolving much more rapidly than do their human hosts. During the course of
`an infection, the microorganism can pit enormous populations of its species
`against an individual Homo sapiens. In response, the human body invests heavily
`in cells dedicated to defense, which collectively form the immune system.
`
`The immune system is crucial to human survival. In the absence of a working
`immune system, even minor infections can take hold and prove fatal. Without
`intensive treatment, children born without a functional immune system die in
`early childhood from the effects of common infections. However, in spite of their
`immune systems, all humans suffer from infectious disease, especially when
`young. This is because the immune system takes time to build up a strong
`response to an invading microorganism, time during which the invader can mul(cid:173)
`tiply and cause disease. To provide protective immunity for the future, the
`immune system must first do battle with the microorganism. This places people
`at highest risk during their first infection with a microorganism and, in the
`absence of modern medicine, leads to substantial child mortality as witnessed in
`the developing world. When entire populations face a completely new infection,
`the outcome can be catastrophic, as experienced by indigenous Americans whose
`populations were decimated by European diseases to which they were suddenly
`exposed after 1492.
`
`In medicine the greatest triumph of immunology has been vaccination, or
`immunization, a procedure whereby severe disease is prevented by prior exposure
`to the infectious agent in a form that cannot cause disease. Vaccination provides
`the opportunity for the immune system to gain the experience needed to make a
`protective response with little risk to health or life. Vaccination was first used
`against smallpox, a viral scourge that once ravaged populations and disfigured the
`survivors. In Asia, small amounts of smallpox virus had been used to induce pro(cid:173)
`tective immunity for hundreds of years before 1721, when Lady Mary Wortley
`Montagu introduced the method into western Europe. Subsequently, in 1796,
`Edward Jenner, a doctor in rural England, showed how inoculation with cowpox
`virus offered protection against the related smallpox virus with less risk than the
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`2
`
`Chapter 1: Elements of the Immune System and their Roles in Defense
`
`earlier methods. Jenner called his procedure vaccination, after vaccinia, the name
`given to the mild disease produced by cowpox, and he is generally credited with
`its invention. Since his time, vaccination dramatically reduced the incidence of
`smallpox worldwide with the last cases being seen by physicians in the 1970s
`(Figure 1.1).
`
`Number 30
`of
`countries
`with one or
`more cases
`permonth 15
`
`smallpox
`officially
`eradicated
`
`o-i-.-....-.-..-........ -.-........ ...,.....,,.........,.....~
`1980
`1965
`1970
`1975
`Year
`
`Figure 1.1 The eradication of
`smallpox by vaccination. In 1979,
`after 3 years in which no case of
`smallpox was recorded, the World
`Health Organization announced that
`the virus had been eradicated. Since
`then there has been debate as to
`whether all laboratory stocks of the
`virus should be destroyed. One view is
`that the stocks could be used for
`nefarious purposes and should therefore
`be destroyed. The other view is that the
`virus might not have been eradicated
`and that if the disease returns, well
`characterized laboratory stocks will be
`required to renew study of the disease
`and its prevention.
`
`Effective vaccines have been made from only a fraction of the agents that cause
`disease and of those some are of limited availability because of their cost. Most of
`the widely used vaccines were first developed many years ago by processes of
`trial and error, before very much was known about the workings of the immune
`system. That approach is no longer so successful for making new vaccines, perhaps
`because all the easily won vaccines have been obtained. But deeper understand(cid:173)
`ing of the mechanisms of immunity is spawning new ideas for vaccines against
`infectious diseases and even against other types of disease such as cancer. Much
`is now known about the molecular and cellular components of the immune system
`and what they can do in the laboratory. Current research aims at understanding
`their contributions to fighting infections in the world at large. The new knowl(cid:173)
`edge is also being used to find better ways of manipulating the immune system
`to prevent the unwanted immune responses that cause allergies, autoimmune
`diseases, and rejection of organ transplants.
`
`In the first part of this chapter we consider the microorganisms that infect human
`beings and the defenses they must overcome to start an infection. These include
`physical barriers, chemical barriers, and the fixed defenses of innate immunity
`that are ready and waiting to halt infections before they can barely start. Also
`described are the individual cells and tissues of the immune system and how
`they integrate their functions with the rest of the human body. The second part
`of the chapter focuses on the more flexible and forceful defenses of adaptive
`immunity. These mechanisms are only brought into play if and when an infection
`is established. The adaptive response is always targeted to the specific problem at
`hand and is made and refined during the course of the infection. When success(cid:173)
`ful, it clears the infection and provides long-lasting immunity that prevents its
`recurrence.
`
`Defenses facing invading pathogens
`
`The purpose of the vertebrate immune system is to recognize invading foreign
`organisms, to prevent their spread, and ultimately to clear them from the body. It
`consists of billions of cells of various types, which interact with the infectious
`agent and with each other to fight the infection. With very few exceptions, the cells
`of the immune system derive originally from the bone marrow, but at some time
`in their life they leave that site to circulate in the blood, to enter other tissues, and
`to form part of specialized lymphoid tissues. This part of the chapter introduces
`the cells and tissues of the immune system and some of the molecules through
`which they carry out their functions. But first we shall consider the organisms and
`infections that the immune system evolved to protect us against.
`
`1-1 Pathogens are infectious organisms that cause disease
`
`Numerous species of microorganism colonize the human body in large numbers
`and rarely produce symptoms of disease, for example the benign strains
`of the bacterium Escherichia coli that normally inhabit the gastrointestinal tract.
`However, for some microorganisms, such as the influenza virus or the typhoid
`bacillus, infection habitually causes a disease. Any organism with the potential to
`cause disease is known as a pathogen. This definition includes not only microor(cid:173)
`ganisms that generally cause disease if they enter the body, but also ones that can
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`Defenses facing invading pathogens
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`3
`
`Figure 1.2 The four kinds of
`pathogen that cause human disease.
`Examples of the types of pathogen are
`listed, along with the diseases they
`cause.
`
`The immune system protects against four classes of pathogen
`
`Type of pathogen
`
`Examples
`
`Bacteria
`
`Viruses
`
`Fungi
`
`Parasites
`
`Salmonella enteritidis
`Mycobacterium tuberculosis
`
`Variola
`Influenza
`HIV
`
`Epidermophyton floccosum
`Candida albicans
`
`I
`
`I
`
`11
`
`11
`
`Diseases
`
`Food poisoning
`Tuberculosis
`
`Smallpox
`Flu
`AIDS
`
`Ringworm
`Thrush, systemic candidiasis
`
`protozoa
`
`worms
`
`Trypanosoma brucei
`Leishmania donovani
`Plasmodium falciparum
`Ascaris lumbricoides
`Schistosoma mansoni
`
`Sleeping sickness
`Leishmaniasis
`Malaria
`Ascariasis
`Schistosomiasis
`
`colonize the human body to no ill effect for much of the time but cause illness if
`the body's defenses are weakened or if the organism gets into the 'wrong' place.
`The latter kinds of microorganism are known as opportunistic pathogens.
`
`Pathogens can be divided into four kinds: bacteria, viruses, and fungi, which are
`each a group of related microorganisms, and internal parasites, a less precise
`term used to embrace a heterogeneous collection of unicellular protozoa and
`multicellular invertebrates, mainly worms (Figure 1.2). In this book we consider
`the functions of the human immune system principally in the context of control(cid:173)
`ling infections. For some pathogens, this necessitates their complete elimination,
`but for others it is sufficient to limit the size and location of the pathogen popula(cid:173)
`tion within the host. Figure 1.3 gives examples of pathogens from the four classes.
`
`Over evolutionary time, the relationship between a pathogen and its human hosts
`can change, affecting the severity of the disease produced. Most pathogenic
`organisms have evolved special adaptations that enable them to invade their
`hosts, replicate in them and be transmitted. However, the rapid death of its host is
`rarely in a microbe's interest, because this destroys both its home and its source of
`food. Consequently, those organisms with the potential to cause severe and rapidly
`fatal disease often tend to evolve towards an accommodation with their hosts. In
`complementary fashion, host populations have evolved a degree of in-built
`genetic resistance to common disease-causing organisms, as well as acquiring
`lifetime immunity to endemic diseases as a result of infection in childhood.
`Because of the interplay between host and pathogen, the nature and severity of
`infectious diseases in the human population are always changing.
`
`Influenza is a good example of a common viral disease that, although severe in its
`symptoms, is usually overcome successfully by the immune system. The fever,
`aches, and lassitude that accompany infection can be overwhelming, and it is dif(cid:173)
`ficult to imagine overcoming foes or predators at the peak of a bout of influenza.
`However, despite the severity of the symptoms, most strains of influenza do not
`pose any great danger to healthy people in populations in which influenza is
`endemic. Warm, well-nourished, and otherwise healthy individuals usually
`recover in a couple of weeks and take it for granted that their immune systems will
`accomplish this task. Pathogens new to the human population, in contrast, often
`cause high mortality-between 60% and 75% in the case, of the Ebola virus.
`
`I
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`4
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`Chapter 1: Elements of the Immune System and their Roles in Defense
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`Defenses facing invading pathogens
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`5
`
`Figure 1.3 (opposite) The diversity of human pathogens. Panel
`a: light micrograph of Schistosoma mansoni, the helminth worm that
`causes schistosomiasis. The adult intestinal blood fluke form is shown:
`the male is thick and bluish, the female white and thread-like.
`Magnification x 5. Panel b: false-color scanning electron micrograph
`of red blood cells and Trypanosoma brucei, a protozoan of the type
`that causes African sleeping sickness. Magnification x 1750.
`Panel c: false-color scanning electron micrograph of Pneumocystis
`carinii, the fungus that causes opportunistic infections in patients
`whose immune system is suppressed by disease or drugs. The view is
`of a lung alveolus from a monkey who is immunosuppressed because
`of infection with a simian virus that causes an acquired
`immune deficiency syndrome (AIDS). The fungal cells have been
`colored green. Magnification x 720. Panel d: scanning electron
`micrograph of Epidermophyton floccosum, the dermatophyte fungus
`that causes ringworm. Pear-shaped spore-producing structures
`(macronidia) are seen connected by filaments (hyphae). Magnification
`x 500. Panel e: false-color transmission electron micrograph of
`human immunodeficiency virus (HIV), the cause of AIDS.
`Magnification x 80,000. Panel f: false-color transmission electron
`micrograph of influenza virus, an orthomyxovirus that causes
`influenza. Magnification x 40,000. Panel g: false-color scanning
`electron micrograph of the fungus Candida albicans, a normal
`inhabitant of the human body that occasionally causes thrush and
`more severe systemic infections. Pseudohyphae are visible in a row.
`At the junctions of the hyphae, rounded yeast-like cells (blastospores)
`are budded off into colonies. Magnification x 1400. Panel h:
`false-color scanning electron micrograph of Staphylococcus aureus, a
`Gram-positive bacterium that colonizes human skin and is the
`common cause of pimples and boils. Some strains, however, cause
`food poisoning. The small spherical cells (cocci) typically form
`grape-like clusters. Magnification x 5000. Panel i: false-color scanning
`electron micrograph of Mycobacterium tuberculosis, the bacterium
`that causes tuberculosis. Magnification x 15,000. Panel j: false-color
`transmission electron micrograph of a human cell (colored green) and
`bacteria of the species Listeria monocytogenes, a Gram-positive
`coccobacillus that can contaminate processed food, causing disease
`(listeriosis) in immunocompromised individuals and pregnant women.
`Magnification x 1250. Panel k: false-color scanning electron
`micrograph of Salmonella enteritidis, a Gram-negative, rod-shaped
`bacterium that is a common cause of food poisoning. The hair-like
`flagella enable the bacteria to move. Magnification x 6500.
`Panel I: false-color scanning electron micrograph of Streptococcus
`pyogenes, a Gram-positive bacterium that is the principal cause of
`tonsilitis and scarlet fever, and can also cause ear infections. It has
`rounded or spherical cells that sometimes form chains as seen here.
`Magnification x 6500.
`
`1-2 The skin and mucosa! surfaces form physical barriers
`against infection
`
`The skin is the human body's first defense against infection. It forms a tough
`impenetrable barrier of epithelium protected by layers of keratinized cells. This
`barrier can be breached by physical damage, such as wounds, burns, or surgical
`procedures, which exposes soft tissues and renders them vulnerable to infection.
`Until the adoption of antiseptic procedures in the nineteenth century, surgery
`was a very risky business, principally because of the life-threatening infections
`that the procedures introduced. For the same reason, far more soldiers have died
`from infection acquired on the battlefield than from the direct effects of enemy
`action. Ironically, the need to conduct increasingly sophisticated and wide(cid:173)
`ranging warfare has been the major force driving improvements in surgery and
`medicine. As an example from immunology, the burns suffered by fighter pilots
`during World War II stimulated studies on skin transplantation that led directly to
`the understanding of the cellular basis of the immune respo{se.
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`6
`
`Chapter 1: Elements of the Immune System and their Roles in Defense
`
`r
`
`I
`
`skin
`
`nails
`
`~----eyes
`
`'il>i-----oral
`cavity
`
`respiratory tract
`
`I
`mammary -l------tt--""I::.
`\
`glands
`<+ - - - - - - - esophagus
`. - - ->T - - - - - stomach
`
`gastrointestinal tract
`
`kidneys}
`urogenital tract
`
`MH•'-------+-+-i- bla~der
`,.,._ __ ~--+- vagina
`
`;
`\
`\
`
`Figure 1.4 The physical barriers that
`separate the body from its external
`environment. In these images of a
`woman, the strong barriers to infection
`provided by the skin, hair, and nails are
`colored blue and the more vulnerable
`mucosa! membranes are colored red.
`
`Continuous with the skin are the epithelia lining the respiratory, gastrointestinal,
`and urogenital tracts (Figure 1.4). On these internal surfaces, the impermeable
`skin gives way to tissues that are specialized for communication with their envi(cid:173)
`ronment and are more vulnerable to microbial invasion. Such surfaces are known
`as mucosa! surfaces or mucosa as they are continually bathed in the mucus that
`they secrete. This thick fluid layer contains glycoproteins, proteoglycans, and
`enzymes that protect the epithelial cells from damage and help to limit infection.
`The enzyme lysozyme in tears and saliva is one of a number of anti-bacterial sub(cid:173)
`stances in secretions from mucosal surfaces. In the respiratory tract, mucus is
`continuously removed through the action of epithelial cells bearing beating cilia
`and is replenished by mucus-secreting goblet cells. The respiratory mucosa are
`thus continually cleansed of unwanted material, including infectious microor(cid:173)
`ganisms that have been breathed in. Microorganisms are also deterred by the
`acidic environments of the stomach, the vagina, and the skin. With such defenses,
`skin and mucosa provide a well-maintained physical and chemical barrier that
`prevents most pathogens from gaining access to the cells and tissues of the body.
`When that barrier is breached and pathogens gain entry to the body's soft tissues,
`the defenses of the immune system are brought into play.
`
`1-3 Immune defenses consist of innate and adaptive immunity
`
`The body has two types of response to invasion by a pathogen-the innate
`immune response, or innate immunity, and the adaptive immune response.
`The mechanisms of innate immunity come into play first. They are always pre(cid:173)
`sent and can rapidly be brought into action, but do not always have the power to
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`Defenses facing invading pathogens
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`7
`
`'·iure L'j The principal
`characteristics of innate and
`adaptive immunity.
`
`Recognition mechanisms of innate immunity
`
`Recognition mechanisms of adaptive immunity
`
`I Rapid response (hours)
`I Invariant
`I Limited number of specificities
`I Constant during response
`\_
`
`I Slow response (days to weeks)
`I
`I I Variable
`I I Numerous highly selective specificities
`I I Improve during response
`)
`
`~
`
`,,.l L,
`
`I
`I
`I
`I
`
`Common effector mechanisms for the destruction of pathogens
`
`eliminate the infection. In such circumstances the innate immune response
`contains the infection while the more powerful forces of the adaptive immune
`response are martialled.
`
`Innate immunity uses general molecular recognition mechanisms to detect the
`presence of bacteria and viruses, and it does not lead to long-term immunity to
`that particular pathogen. The adaptive immune response, in contrast, focuses
`specifically on the pathogen at hand and leads to a condition of long-lived pro(cid:173)
`tection called adaptive immunity to that pathogen alone, and no other. Infection
`with the measles virus, for example, results in immunity to measles but not to
`mumps, an infection caused by a different virus. However, although the recogni(cid:173)
`tion mechanisms of innate and adaptive immune responses differ, the means
`used to destroy pathogens after their identification are common to both (Figure
`1.5). Innate immune defenses are present in vertebrates and invertebrates, but
`nnly vertebrates seem to have evolved adaptive immune responses.
`
`The immune system recognizes the presence of a pathogen by the use of so-called
`'recognition molecules'. These are proteins that bind to molecules produced by
`the pathogen or carried on its surface. Some recognition molecules are free in the
`circulation; others are receptor proteins present on cells of the immune system.
`Only a few types of recognition molecule are involved in innate immunity; in gen(cid:173)
`eral, these recognize and distinguish between the major categories of pathogens
`by binding to distinctive shared features on the pathogen surface. These recogni(cid:173)
`tion molecules are always present and can therefore initiate an immediate and
`;-apid response to an invader. In contrast, adaptive immunity has millions of dif(cid:173)
`!'erent recognition proteins at its disposal, but requires time for the most useful
`•Jnes to be selected and mass-produced for use against the particular pathogen.
`
`,i White blood cells are responsible for immune responses
`
`f'he cells responsible for both innate and adaptive immune responses are princi(cid:173)
`pally the white blood cells or leukocytes, and the tissue Lells related to them
`'·Figure 1.6). They all originate in the bone marrow, from where they migrate to
`Jevelop further and perform their functions. Cells of the immune system are
`:)resent throughout the body. Some are resident within tissues, where they
`espond to local trauma and sound the alarm; others circulate in body fluids,
`>ram where they are recruited to sites of infection. In defending the body against
`•Jathogens, white blood cells cooperate with each other first to recognize the
`·nicroorganism as an invader and then to destroy it.
`
`i:"he lymphocytes provide cells of both innate and adaptive immunity. Small
`ymphocytes are the cells responsible for adaptive immune responses and carry
`he recognition molecules of adaptive immunity on their surface. Recognition of
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`
`8
`
`Chapter 1: Elements of the Immune System and their Roles in Defense
`
`Small lymphocyte
`
`Eosinophil
`
`Production of antibodies (B cells) or cytotoxic
`and helper functions (T cells)
`
`Killing of antibody-coated parasites through release
`of granule contents
`
`Plasma cell
`
`Basophil
`
`b
`
`Fully differentiated form of B cell that secretes antibodies
`
`g
`
`Unknown
`
`Natural killer cell
`
`Mast cell
`
`c
`
`Kills cells infected with certain viruses
`
`h
`Expulsion of parasites from body through release of granules
`containing histamine and other active agents
`
`Dendritic cell
`
`Monocyte
`
`Activation of T cells and initiation of adaptive
`immune responses
`
`Circulating precursor cell to macrophage
`
`Neutrophil
`
`e
`
`Phagocytosis and killing of microorganisms
`
`Macrophage
`
`@ 0
`
`0
`
`Phagocytosis and killing of microorganisms.
`Activation of T cells and initiation of immune responses
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`Defenses facing invading pathogens
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`9
`
`:1ure 1.5 (opposite) Types of white blood cell. The different
`types of white blood cell are depicted in schematic diagrams, which
`indicate their characteristic morphological features, and in accompa(cid:173)
`nying light micrographs. Their main functions are indicated. Red
`blood cells are also seen in most of the pictures. They are smaller than
`the white blood cells and have no nucleus. Photographs courtesy of
`N. Rooney (a, d, e, f, g, j) and D. Friend (b, c, h, i).
`
`1 pathogen by small lymphocytes drives a process of lymphocyte selection and
`iifferentiation that after 1-2 weeks produces a powerful immune response tailored
`o the invading organism.
`
`The small lymphocytes, although morphologically indistinguishable from each
`other, are divided into various classes with respect to their recognition molecules
`:ind the functions that they are programmed to perform. The most important
`:lifference is between B lymphocytes or B cells, and T lymphocytes or T cells.
`The recognition molecules of B cells are immunoglobulins carried on the B-cell
`surface; whereas those of T cells are known as T-cell receptors. On activation by
`infection, B cells divide and differentiate into plasma cells, which make antibod(cid:173)
`:es-soluble forms of immunoglobulins that are released into the blood and
`3Xtracellular fluid. T cells have more diverse functions, which they perform on
`~nreraction with other cells of the immune system and cells infected with intra(cid:173)
`·:ellular pathogens such as viruses. When activated by infection, T cells differentiate
`into effector T cells with various functions. In addition to small lymphocytes, the
`blood contains large granular lymphocytes called natural killer cells or NK cells.
`They function in innate immunity and are important in the defense against viral
`infections. In the rest of this book the term 'lymphocyte' will be used to denote the
`small lymphocytes-B cells and T cells.
`
`The principal cell that cooperates with lymphocytes to initiate adaptive immune
`,·espouses is the dendritic cell; this has a distinctive star-shaped morphology and
`'s found in many tissues as well as in the blood.
`
`The job of destroying pathogenic organisms rests largely with two types of
`;hagocytic cell, the macrophage and the neutrophil. Macrophages are widely
`distributed in tissues and they derive from circulating white blood cells called
`monocytes. Tissue macrophages are large cells characterized by an extensive
`cytoplasm with numerous vacuoles, often containing engulfed materials. They are
`che general scavenger cells of the body, phagocytosing and disposing of dead cells
`and cell debris. In both innate and adaptive immune responses, one of their roles
`is to engulf, kill, and break down microorganisms. Macrophages have mecha(cid:173)
`nisms for recognizing and reacting to pathogens, which makes them important
`cells of innate immunity. They also cooperate with lymphocytes to develop adaptive
`immune responses.
`
`The neutrophil is smaller than the macrophage and is by far the most abundant
`.vhite blood cell. Unlike the macrophage, it is not resident in healthy tissues but
`capidly migrates to sites of tissue damage, and is at the front line of innate
`:mmune defenses, where it is the principal phagocytic and microbicidal cell. Like
`•he macrophage, it possesses general pathogen-recognition mechanisms, and is
`;pecialized to engulf and kill microorganisms.
`
`iMated to the neutrophil are two other kinds of white blood cell, the eosinophil
`;md the basophil. Neutrophils, eosinophils, and basophils are collectively called
`~ranulocytes because of their prominent cytoplasmic granules, which contain
`,·eactive substances that kill microorganisms and enhance inflammation. Because
`:;ranulocytes have irregularly shaped nuclei with two to five lobes they are
`:dso called polymorphonuclear leukocytes. The eosinophil is the second most
`
`Luitpold Pharmaceuticals, Inc., Ex. 2008, p. 11
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
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`

`
`1 O
`
`Chapter 1: Elements of the Immune System and their Roles in Defense
`
`abundant granulocyte in the blood and provides defense against parasites such as
`helminth worms. The least abundant granulocyte is the basophil. They are so rare
`that little is known of their contribution to the immune response. Mast cells are
`bone-marrow derived cells found in connective tissues. They contain granules
`containing substances that contribute to inflammation.
`
`1-5 The cells of the immune system derive from precursors in
`the bone marrow
`
`All the cells that circulate in the blood are derived from a common progenitor or
`precursor cell in the bone marrow. This pluripotent precursor is called the
`
`Bone marrow
`
`hematopoietic stem cell
`
`common
`lymphoid progenitor
`
`Bone marrow
`
`@
`
`myeloid
`progenitor
`
`@
`
`erythroid
`progenitor
`
`I I
`
`Blood
`
`erythroblast
`
`Polymorphonuclear leukocytes
`
`B cell
`
`T cell
`
`basophil
`
`eosinophil
`
`neutrophil
`
`I I
`I I
`I I
`I I
`
`I I @8
`
`0
`0 ~'C)
`\J
`0
`0uoG
`platelets
`
`0
`
`erythrocyte
`
`Effector cells
`
`Tissues
`
`plasma
`cell
`
`effector
`T cell
`
`NKcell
`
`~ @ 0
`
`dendritic cell
`
`mast cell
`
`macrophage
`
`Figure 1. 7 Circulating blood cells and certain tissue cells
`derive from a common hematopoietic stem cell in the
`bone marrow. The pluripotent stem cell (brown) divides and
`differentiates into more specialized progenitor cells that give
`rise to the lymphoid lineage, the myeloid lineage, and the
`erythrocyte/megakaryocyte lineage. The common lymphoid
`progenitor divides and differentiates to give B cells (yellow),
`T cells (blue), and NK cells (purple). On activation by infection,
`B cells divide and differentiate into plasma cells, whereas T cells
`
`differentiate into various types of activated effector T cell. The
`myeloid progenitor cell divides and differentiates to produce at
`least six cell types. These are: the three types of granulocyte(cid:173)
`the neutrophil, the eosinophil, and the basophil; the mast cell,
`which takes up residence in connective and mucosal tissues; the
`circulating monocyte, which gives rise to the macrophages
`resident in tissues; and the dendritic cell. The erythroid
`progenitor gives rise to erythrocytes and megakaryocytes.
`
`Luitpold Pharmaceuticals, Inc., Ex. 2008, p. 12
`Pharmacosmos A/S v. Luitpold Pharmaceuticals, Inc., IPR2015-01495
`
`

`
`hematopoietic stem cell. The developmental pathways by which blood cells are
`produced are outlined in Figure 1.7. As hematopoietic stem cells mature in the
`bone marrow they give rise to different kinds of stem cells with more limited
`developmental potential. One kind of stem cell, called the erythroid progenitor,
`gives rise to the erythroid lineage of blood cells-the oxygen-carrying red blood
`cells (erythrocytes) and the megakaryocytes. The latter remain resident in the
`bone marrow; platelets are formed from them and released into the blood. A
`second stem cell gives rise to the monocyte/macrophage lineage, dendritic cells,
`the granulocytes (neutrophils, eosinophils, and basophils), and mast cells. These
`cells are known as the myeloid lineage of white blood cells and their progenitor
`stem cell as the myeloid progenitor. The third type of stem cell is the common
`lymphoid progenitor. It gives rise to white blood cells of the lymphoid lineage,
`which are the small lymphocytes and the larger NK cells.
`
`1-6 Lymphocytes are found in specialized lymphoid tissues
`
`As well as circulating in the blood, lymphocytes congregate in specialized tissues
`known as lymphoid tissues or lymphoid