Really Essential Medical Immunology Arthur Rabson

224 Pages·2006·4.94 MB·English

REALLY ESSENTIAL
MEDICAL
IMMUNOLOGY
Arthur Rabson,Ivan M.Roitt,Peter J.Delves
S E C O N D E D I T I O N
SECOND EDITION
Really Essential
Medical Immunology
Arthur Rabson
MB, BCh, FRCPath
Department of Pathology
Tufts University School of Medicine
Boston
USA
Ivan M. Roitt
DSc, HonFRCP, FRCPath, FRS
Department of Immunology & Molecular Pathology
Royal Free & University College Medical School
London
UK
Peter J. Delves
PhD
Department of Immunology & Molecular Pathology
Royal Free & University College Medical School
London
UK
© 2005 A. Rabson, I.M. Roitt, P.J. Delves
Published by Blackwell Publishing Ltd
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First published 2000
Reprinted 2001
Second edition 2005
Library of Congress Cataloging-in-Publication Data
Rabson, Arthur.
Really essential medical immunology / Arthur Rabson, Ivan M. Roitt,
Peter J. Delves.—2nd ed.
p. ; cm.
Rev. ed. of: Really essential medical immunology / Ivan Roitt and
Arthur Rabson. 2000.
Includes bibliographical references and index.
ISBN 1-4051-2115-7
1. Clinical immunology.
[DNLM: 1. Immunity. QW 540 R116r 2005] I. Roitt, Ivan M. (Ivan
Maurice) II. Delves, Peter J. III. Roitt, Ivan M. (Ivan Maurice). Really
essential medical immunology. IV. Title.
RC582.R65 2005
616.07’9—dc22
200400393
ISBN 1-4051-2115-7
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iii
Contents
Part 1 The Basis of Immunology Part 4 Immunity to Infection
1 Innate Immunity, 1 11 Adversarial Strategies During Infection, 114
2 Specific Acquired Immunity, 17 12 Prophylaxis, 127
Part 2 The Recognition of Antigen Part 5 Clinical Immunology
3 Antibodies, 27 13 Immunodeficiency, 135
4 Membrane Receptors for Antigen, 41 14 Hypersensitivity, 148
5 The Primary Interaction with Antigen, 50 15 Transplantation, 164
Part 3 The Acquired Immune Response 16 Tumor Immunology, 177
6 The Anatomy of the Immune Response, 62 17 Autoimmune diseases, 188
7 Lymphocyte Activation, 75 Glossary, 211
8 The Production of Effectors, 82 Index, 213
9 Control Mechanisms, 97
10 Ontogeny, 105
CHAPTER 1 1
Innate immunity
External barriers against infection, 1 Complement has a range of defensive biological functions, 9
Phagocytic cells kill microorganisms, 2 Complement can mediate an acute inflammatory
The polymorphonuclear neutrophil, 2 reaction, 10
The macrophage, 2 Macrophages can also do it, 10
Pattern recognition receptors (PRRs) on phagocytic cells Humoral mechanisms provide a second defensive
recognize and are activated by pathogen-associated strategy, 11
molecular patterns (PAMPs), 4 Acute phase proteins increase in response to infection, 12
Toll-like receptors (TLRs) recognize PAMPs and cause cytokine Extracellular killing, 13
release, 5 Natural killer (NK) cells are part of the innate immune
Microbes are engulfed by phagocytosis, 5 system, 13
Killing by reactive oxygen intermediates (ROIs), 6 Natural killer cells also produce cytokines which regulate
Other killing mechanisms, 7 inflammation and acquired immune function, 14
Complement facilitates phagocytosis, 7 Eosinophils, 14
Complement and its activation, 7
intact, is impermeable to most infectious agents. When
We live in a potentially hostile world filled with a
there is skin loss, as for example in burns, infection
bewildering array of infectious agents against
becomes a major problem. Additionally, most bacteria
which we have developed a series of defense
fail to survive for long on the skin because of the direct
mechanisms at least their equal in effectiveness
inhibitory effects of lactic acid and fatty acids in sweat
and ingenuity. It is these defense mechanisms that
and sebaceous secretions and the low pH which they
can establish a state of immunity against infection
generate. An exception is Staphylococcus aureus, which
(Latin immunitas, freedom from) and whose
often infects the relatively vulnerable hair follicles and
operation provides the basis for the delightful
glands.
subject called “Immunology.”
Mucus secreted by the membranes lining the inner
Anumber of nonspecific antimicrobial systems
surfaces of the body acts as a protective barrier to block
(e.g. phagocytosis) have been recognized which
the adherence of bacteria to epithelial cells. Microbial
are innatein the sense that they are not intrinsically
and other foreign particles trapped within the ad-
affected by prior contact with the infectious agent
hesive mucus are removed by mechanical stratagems
and are usually present before the onset of the
such as ciliary movement, coughing and sneezing.
infectious agent. The innate response is not
Among other mechanical factors that help protect the
enhanced by previous exposure to the foreign
epithelial surfaces, one should also include the wash-
organism and the response time is very rapid
ing action of tears, saliva and urine. Many of the secret-
usually occurring in minutes or hours. We shall
ed body fluids contain bactericidal components, such
discuss these systems and examine how, in the
as acid in gastric juice, spermine and zinc in semen,
state of specific acquired immunity, their
lactoperoxidase in milk, and lysozyme in tears, nasal
effectiveness can be greatly increased.
secretions and saliva.
Atotally different mechanism is that of microbial an-
tagonism where the normal bacterial flora of the body
suppresses the growth of many potentially pathogenic
bacteria and fungi. This is due to competition for
EXTERNAL BARRIERS AGAINST INFECTION
essential nutrients or by the production of microbici-
The simplest way to avoid infection is to prevent the dal substances. For example, pathogen invasion of the
microorganisms from gaining access to the body. The vagina is limited by lactic acid produced by commen-
major line of defense is of course the skin which, when sal organisms which metabolize glycogen secreted by
2 PART 1—The basis of immunology
Figure 1.1 Ultrastructure of neutrophil.
The multilobed nucleus and two main
types of cytoplasmic granules are well dis-
played. (Courtesy of Dr D. McLaren.)
the vaginal epithelium. When protective commensals much of the lysozyme, alkaline phosphatase (figure
are disturbed by antibiotics, susceptibility to oppor- 1.2c) and membrane-bound cytochrome b .
558
tunistic infections such as Candida albicansand Clostrid-
ium difficileis increased.
The macrophage
If microorganisms do penetrate the body, two fur-
ther innate defensive operations come into play, the These cells derive from bone marrow promonocytes
destructive effect of soluble chemical factors such as which, after differentiation to blood monocytes
bactericidal enzymes and the mechanism of phagocy- (figure 1.2a), finally settle in the tissues as mature
tosis—literally “eating” by the cell (Milestone 1.1). macrophages where they constitute the mononuclear
phagocyte system (figure 1.2d). They are present
throughout the connective tissue and around the
PHAGOCYTIC CELLS
basement membrane of small blood vessels and are
KILL MICROORGANISMS
particularly concentrated in the lung (figure 1.2f,
alveolar macrophages), liver (Kupffer cells), and lining
The polymorphonuclear neutrophil
of spleen sinusoids and lymph node medullary si-
This cell shares a common hematopoietic stem cell pre- nuses, where they are strategically placed to filter off
cursor with the other formed elements of the blood and foreign material. Other examples are mesangial cells
is the dominant white cell in the bloodstream. It is in the kidney glomerulus, brain microglia and osteo-
a nondividing, short-lived cell with a multilobed nu- clasts in bone. Unlike the polymorphonuclear neu-
cleus (figures 1.1 & 1.2a,b) and an array of granules trophils, they are long-lived cells with significant
which are of two main types (figure 1.1): (i) the primary rough-surface endoplasmic reticulum and mitochon-
azurophil granule, which develops early and contains dria. Whereas the neutrophils provide the major de-
myeloperoxidase together with most of the nonoxida- fense against pyogenic (pus-forming) bacteria, as a
tive antimicrobial effectors, including defensins, rough generalization it may be said that macrophages
bactericidal/permeability-increasing (BPI) protein are at their best in combating those bacteria (figure
and cathepsin G, and (ii) the peroxidase-negative sec- 1.2e), viruses and protozoa that are capable of living
ondary specific granules, containing lactoferrin and within the cells of the host.
CHAPTER 1—Innate immunity 3
Milestone 1.1—Phagocytosis
a b e
c d
Figure M1.1.1 Reproductions of some of the illustrations in
Metchnikoff’s book, Comparative Pathology of Inflammation
(1893).(a) Four leukocytes from the frog, enclosing anthrax bacilli.
Some are alive and unstained; others, which have been killed,
have taken up the vesuvine dye and have been colored. (b) Draw-
ing of an anthrax bacillus, stained by vesuvine, in a leukocyte of
the frog. The two figures represent two phases of movement of the
same frog leukocyte which contains stained anthrax bacilli within
its phagocytic vacuole. (c and d) Aforeign body (colored) in a
starfish larva surrounded by phagocytes which have fused to
form a multinucleate plasmodium, shown at higher power in (d).
(e) This gives a feel for the dynamic attraction of the mobile mes-
enchymal phagocytes to a foreign intruder within a starfish larva.
The perceptive Russian zoologist, Elie Metchnikoff (1845–
1916), recognized that certain specialized cells mediate de-
fenseagainst microbial infections, so fathering the whole
concept of cellular immunity. He was intrigued by the
motile cells of transparent starfish larvae and made the
critical observation that a few hours after the introduction
of a rose thorn into these larvae these motile cells sur-
rounded it. Ayear later, in 1883, he observed that fungal
spores can be attacked by the blood cells of Daphnia, a tiny
metozoan which, also being transparent, can be studied
directly under the microscope. He went on to extend his
investigations to mammalian leukocytes, showing their
ability to engulf microorganisms, a process which he
termed phagocytosis.
Because he found this process to be even more effective
in animals recovering from infection, he came to a some-
what polarized view that phagocytosis provided the main,
if not the only, defense against infection. He went on to de-
fine the existence of two types of circulating phagocytes:
Figure M1.1.2 Caricature of Professor Metchnikoff (from
the polymorphonuclear leukocyte, which he termed a
Chanteclair, 1908, 4, p. 7).(Reproduction kindly provided by The
“microphage,” and the larger “macrophage.” Wellcome Institute Library, London.)
4 PART 1—The basis of immunology
(a) (b) (c)
(d) (e) (f)
(g) (h) (i)
Figure 1.2 Cells involved in innate immunity.(a) Monocyte, show- (Giemsa). (e) Macrophages in monolayer cultures after phagocytosis
ing “horseshoe-shaped” nucleus and moderately abundant pale of mycobacteria (stained red) (Carbol-Fuchsin counterstained with
cytoplasm. Note the three multilobed polymorphonuclear neu- Malachite Green.) (f) Numerous plump alveolar macrophages
trophils and the small lymphocyte (bottom left) (Romanowsky). (b) within air spaces in the lung. (g) Basophil with heavily staining
Four polymorphonuclear neutrophils and one eosinophil. The mul- granules compared with a neutrophil (below). (h) Mast cell from
tilobed nuclei and the cytoplasmic granules are clearly shown, those bone marrow. Round central nucleus surrounded by large darkly
of the eosinophil being heavily stained. (c) Polymorphonuclear staining granules. Two small red cell precursors are shown at the bot-
neutrophil showing cytoplasmic granules stained for alkaline phos- tom (Romanowsky). (i) Tissue mast cells in skin stained with Tolui-
phatase. (d) Inflammatory cells from the site of a brain hemorrhage dine Blue. The intracellular granules are metachromatic and stain
showing the large active macrophage in the center with phagocy- reddish purple. (The slides for (a), (c), (d), (g) and (h) were very kind-
tosed red cells and prominent vacuoles. To the right is a monocyte ly provided by Mr M. Watts. (b) was kindly supplied by Professor
with horseshoe-shaped nucleus and cytoplasmic bilirubin crystals J.J. Owen; (e) by Professors P. Lydyard and G. Rook; (f) by Dr Meryl
(hematoidin). Several multilobed neutrophils are clearly delineated Griffiths and (i) by Professor N. Woolf.)
recognizing PAMPs expressed on the surface of infec-
Pattern recognition receptors (PRRs) on
tious agents. These PAMPs are essentially polysaccha-
phagocytic cells recognize and are activated
rides and polynucleotides that differ minimally from
by pathogen-associated molecular patterns
one pathogen to another but are not found in the host.
(PAMPs)
By and large the PRRs are lectin-like and bind multiva-
Phagocytes must have mechanisms to enable them to lently with considerable specificity to exposed micro-
distinguish friendly self-components from unfriendly bial surface sugars. Engagement of the PRR generates
and potentially dangerous microbial agents. Phago- a signal through a NFkB (nuclear factor-kappa B) tran-
cytic cells have therefore evolved a system of receptors scription factor pathway which alerts the cell to danger
called pattern recognition receptors(PRRs) capable of and initiates the phagocytic process.
CHAPTER 1—Innate immunity 5
LBP LPS
LBP LPS Toll-like
TLR
CD14 receptor
Adaptor
MyD88
Serine/threonine
IRAK
kinase
INGESTION
TNF receptor associated
TRAF
factor
NFkB inducing
L NFkB IkB NIK kinase
L
E
C
C
YTI IKK Kinase
C
O
G
HA NFkB IkB P
P
Translocation to Ubiquitin
nucleus degradation
Transcription
factor
Expression of
proinflammatory
genes
Figure 1.3 Activation of a phagocytic cell by a Gram-negative nucleus, where it upregulates genes encoding defensive factors such
lipopolysaccharide (LPS) (endotoxin) danger signal. Circulating as tumor necrosis factor (TNF), antibiotic peptides and the nicoti-
LPS is complexed by LPS-binding protein (LBP) and captured by the namide adenine dinucleotide phosphate (NADPH) oxidase which
CD14 surface scavenging receptor. This signals internalization of the generates reactive oxygen intermediates (ROIs). The TLR appears to
complex and activates the Toll-like receptor (TLR), which then initi- control the type of defensive response to different microbes. Thus
ates a phosphorylation cascade mediated by different kinase en- TLR4 engineers the response to Gram-negative bacteria and LPS
zymes. As a result the transcription factor nuclear factor-kappa B while TLR2 plays a key role in yeast and Gram-positive infections.
(NFkB) is released from its inhibitor IkB and translocates to the
Toll-like receptors (TLRs) recognize PAMPs and Microbes are engulfed by phagocytosis
cause cytokine release
Before phagocytosis can occur, the microbe must
Toll-like receptors are a family of at least 10 trans- first adhere to the surface of the polymorph or
membrane proteins that recognize various microbial macrophage through recognition of a PAMP. The
products. For example TLR2 recognizes Gram- resulting signal initiates the ingestion phase by
positive bacterial peptidoglycan, TLR4 is specialized activating an actin–myosin contractile system which
for the recognition of Gram-negative bacterial results in pseudopods being extended around the
lipopolysaccharide (LPS) (endotoxin) and TLR3 and particle (figures 1.4 & 1.5a). As adjacent receptors
TLR5 are important in the recognition of virus derived sequentially attach to the surface of the microbe, the
double-stranded RNA. When the TLRs are activated plasma membrane is pulled around the particle just
they trigger a biochemical cascade with activation of like a “zipper” until it is completely enclosed in a
NFkB and ultimately synthesis of proinflammatory vacuole called a phagosome (figures 1.4 & 1.5b).
cytokines and other antimicrobial peptides that lead Within 1min the cytoplasmic granules fuse with the
to the development of adaptive immunity (figure phagosome and discharge their contents around the
1.3). imprisoned microorganism (figure 1.5c), which is now
6 PART 1—The basis of immunology
1 2 3 4
BACTERIUM
PHAGOCYTE
Adherence through Membrane activation Initiation of
Chemotaxis
PAMP recognition through ‘danger’ signal phagocytosis
5 6 7 8
GRANULES
Phagosome Fusion Killing and Release of degradation Figure 1.4 Phagocytosis and killing of a
formation digestion products
bacterium.
(a) (b) (c)
Figure 1.5 Adherence and phagocytosis. (a) Phagocytosis of Candi- degranulated and two lysosomal granules (arrowed) are fusing with
da albicansby a polymorphonuclear neutrophil. Adherence to the the phagocytic vacuole. Two lobes of the nucleus are evident (¥5000).
surface initiates enclosure of the fungal particle within arms of cyto- (c) Higher magnification of (b) showing fusing granules discharging
plasm (¥15000). (b) Phagolysosome formation by a neutrophil their contents into the phagocytic vacuole (arrowed) (¥33000).
30min after ingestion of C. albicans. The cytoplasm is already partly (Courtesy of Dr H. Valdimarsson.)
subject to a formidable battery of microbicidal ating reduced nicotinamide adenine dinucleotide
mechanisms. phosphate (NADPH). Electrons pass from the
NADPH to a unique plasma membrane cytochrome
(cyt b ), which reduces molecular oxygen directly to
Killing by reactive oxygen 558
superoxide anion (figure 1.6). Thus, the key reaction
intermediates (ROIs)
catalysed by this NADPH oxidase, which
Trouble starts for the invader from the moment initiates the formation of ROIs, is:
phagocytosis is initiated. There is a dramatic increase
in activity of the hexose monophosphate shunt gener- NADPH+O æoæxidæaseÆNADP++◊O-(superoxide anion)
2 2