The immune system consists of an intricately linked
network of cells, proteins and lymphoid organs that are
strategically placed to ensure maximal protection against
infection. Immune defences are normally categorised
into the innate immune response, which provides immediate
protection against an invading pathogen, and the
adaptive or acquired immune response, which takes
more time to develop but confers exquisite specificity
and long-lasting protection.
The innate immune system
Innate defences against infection include anatomical
barriers, phagocytic cells, soluble molecules, such as
complement and acute phase proteins, and natural killer
cells. The innate immune system recognises generic
microbial structures present on non-mammalian tissue
and can be mobilised within minutes. A specific stimulus
will elicit essentially identical responses in different
individuals (in contrast with antibody and T-cell
responses, which vary greatly between individuals).
Constitutive barriers to infection
The tightly packed, highly keratinised cells of the skin
constantly undergo renewal and replacement, which
physically limits colonisation by microorganisms.
Microbial growth is inhibited by physiological factors,
such as low pH and low oxygen tension, and sebaceous
glands secrete hydrophobic oils that further repel water
and microorganisms. Sweat also contains lysozyme, an
enzyme that destroys the structural integrity of bacterial
cell walls; ammonia, which has antibacterial properties;
and several antimicrobial peptides such as defensins.
Similarly, the mucous membranes of the respiratory,
gastrointestinal and genitourinary tract provide a constitutive
barrier to infection. Secreted mucus acts as
a physical barrier to trap invading pathogens, and
immunoglobulin A (IgA) prevents bacteria and viruses
attaching to and penetrating epithelial cells. As in the
skin, lysozyme and antimicrobial peptides within
mucosal membranes can directly kill invading pathogens,
and additionally lactoferrin acts to starve invading
bacteria of iron. Within the respiratory tract, cilia directly
trap pathogens and contribute to removal of mucus,
assisted by physical manoeuvres, such as sneezing and
coughing. In the gastrointestinal tract, hydrochloric acid
and salivary amylase chemically destroy bacteria, while
normal peristalsis and induced vomiting or diarrhoea
assist clearance of invading organisms.
Endogenous commensal bacteria provide an additional
constitutive defence against infection .
They compete with pathogenic microorganisms for
space and nutrients, and produce fatty acids and bactericidins
that inhibit the growth of many pathogens. In
addition, commensal bacteria help to shape the immune
response by inducing specific regulatory T cells within
the intestine .
These constitutive barriers are highly effective, but if
external defences are breached by a wound or pathogenic
organism, the specific soluble proteins and cells of
the innate immune system are activated.
Phagocytes (‘eating cells’) are specialised cells which
ingest and kill microorganisms, scavenge cellular and
infectious debris, and produce inflammatory molecules
which regulate other components of the immune system.
They include neutrophils, monocytes and macrophages,
and are particularly important for defence against bacterial
and fungal infections.
Phagocytes express a wide range of surface receptors
that allow them to identify microorganisms. These
pattern recognition receptors include the Toll-like
receptors, NOD (nucleotide-oligomerisation domain
protein)-like receptors and mannose receptors. They recognise
generic molecular motifs not present on mammalian
cells, including bacterial cell wall components,
bacterial DNA and viral double-stranded RNA. While
phagocytes can recognise microorganisms through
pattern recognition receptors alone, engulfment of
microorganisms is greatly enhanced by opsonisation.
Opsonins include acute phase proteins such as
C-reactive protein (CRP), antibodies and complement.
They bind both to the pathogen and to phagocyte receptors,
acting as a bridge between the two to facilitate
Opsonisation. Phagocytosis of microbial products may be augmented by several opsonins. A C-reactive protein. B Antibody.
C Complement fragments.
Neutrophils, also known as polymorphonuclear leucocytes,
are derived from the bone marrow (Fig.). They
are short-lived cells with a half-life of 6 hours in the
blood stream, and are produced at the rate of approximately
1011 cells daily. Their functions are to kill microorganisms
directly, facilitate the rapid transit of cells
through tissues, and non-specifically amplify the immune
response. This is mediated by enzymes contained in
granules which also provide an intracellular milieu for
the killing and degradation of microorganisms.
The two main types of granule are primary
or azurophil granules, and the more numerous secondary
or specific granules. Primary granules contain
myeloperoxidase and other enzymes important for
Neutrophil function and dysfunction (green boxes).
intracellular killing and digestion of ingested microbes.
Secondary granules are smaller and contain lysozyme,
collagenase and lactoferrin, which can be released into
the extracellular space. Granule staining becomes more
intense in response to infection (‘toxic granulation’),
reflecting increased enzyme production.
When tissues are changed or damaged, they trigger
the local production of inflammatory molecules and
cytokines. These stimulate the production and maturation
of neutrophils in the bone marrow, and their release
into the circulation. The neutrophils are recruited to the
inflamed site by chemotactic agents and by activation of
local endothelium. Transit of neutrophils through the
blood stream is responsible for the rise in leucocyte
count that occurs in early infection. Once within infected
tissue, activated neutrophils seek out and engulf invading
microorganisms. These are initially enclosed within
membrane-bound vesicles which fuse with cytoplasmic
granules to form the phagolysosome. Within this
protected compartment, killing of the organism occurs
through a combination of oxidative and non-oxidative
killing. Oxidative killing, also known as the respiratory
burst, is mediated by the NADPH (nicotinamide
adenine dinucleotide phosphate) oxidase enzyme complex.
This converts oxygen into reactive oxygen species
such as hydrogen peroxide and superoxide that are
lethal to microorganisms. When combined with myeloperoxidase,
hypochlorous ions (HOCl−, analogous to
bleach) are produced, which are highly effective oxidants
and antimicrobial agents. Non-oxidative (oxygenindependent)
killing occurs through the release of
bactericidal enzymes into the phagolysosome. Each
enzyme has a distinct antimicrobial spectrum, providing
broad coverage against bacteria and fungi.
The process of phagocytosis depletes neutrophil glycogen
reserves and is followed by neutrophil cell death.
As the cells die, their contents are released and lysosomal
enzymes degrade collagen and other components
of the interstitium, causing liquefaction of closely adjacent
tissue. The accumulation of dead and dying neutrophils
results in the formation of pus, which, if
extensive, may result in abscess formation.
Monocytes and macrophages
Monocytes are the precursors of tissue macrophages.
They are produced in the bone marrow and constitute
about 5% of leucocytes in the circulation. From the
blood stream, they migrate to peripheral tissues, where
they differentiate into tissue macrophages and reside for
long periods. Specialised populations of tissue macrophages
include Kupffer cells in the liver, alveolar
macrophages in the lung, mesangial cells in the kidney,
and microglial cells in the brain. Macrophages, like neutrophils,
are capable of phagocytosis and killing of
microorganisms but also play an important role in
the amplification and regulation of the inflammatory
response (Box). They are particularly important in
tissue surveillance, monitoring their immediate surroundings
for signs of tissue damage or invading
Dendritic cells are specialised antigen-presenting cells
which are prevalent in tissues in contact with the external
environment, such as the skin and mucosa. They can
also be found in an immature state in the blood. They
sample the environment for foreign particles, and once
activated, carry microbial antigens to regional lymph
nodes, where they interact with T cells and B cells to
initiate and shape the adaptive immune response.
Cytokines are small soluble proteins that act as multipurpose
chemical messengers. Examples are listed in
Box. They are produced by cells involved in immune
responses and by stromal tissue. More than 100 cytokines
have been described, with overlapping, complex roles in
intercellular communication. Their clinical importance
is demonstrated by the efficacy of ‘biological’ therapies
(often abbreviated to ‘biologics’) that target specific
The complement system is a group of more than 20
tightly regulated, functionally linked proteins that act to
promote inflammation and eliminate invading pathogens.
Complement proteins are produced in the liver
and are present in the circulation as inactive molecules.
When triggered, they enzymatically activate other proteins
in a rapidly amplified biological cascade analogous
to the coagulation cascade.
There are three mechanisms by which the complement
cascade may be triggered (Fig. ):
The complement pathway. The activation of C3 is central to complement activation.
• The alternative pathway is triggered directly by
binding of C3 to bacterial cell wall components,
such as lipopolysaccharide of Gram-negative
bacteria and teichoic acid of Gram-positive bacteria.
• The classical pathway is initiated when two or more
IgM or IgG antibody molecules bind to antigen,
forming immune complexes. The associated
conformational change exposes binding sites on the
antibodies for C1. C1 is a multiheaded molecule
which can bind up to six antibody molecules. Once
two or more ‘heads’ of a C1 molecule are bound to
antibody, the classical cascade is triggered.
• The lectin pathway is activated by the direct binding
of mannose-binding lectin to microbial cell surface
carbohydrates. This mimics the binding of C1 to
immune complexes and directly stimulates the
Activation of complement by any of these pathways
results in activation of C3. This, in turn, activates the
final common pathway, in which the complement proteins
C5–C9 assemble to form the membrane attack
complex. This can puncture target cell walls, leading to
osmotic cell lysis. This step is particularly important
in the defence against encapsulated bacteria, such as
Neisseria spp. and Haemophilus influenzae. Complement
fragments generated by activation of the cascade can
also act as opsonins, rendering microorganisms more
susceptible to phagocytosis by macrophages and neutrophils. In addition, they are chemotactic
agents, promoting leucocyte trafficking to sites of inflammation.
Some fragments act as anaphylotoxins, binding
to complement receptors on mast cells and triggering
release of histamine, which increases vascular permeability.
The products of complement activation also help
to target immune complexes to antigen-presenting cells,
providing a link between the innate and the acquired
immune systems. Finally, activated complement products
dissolve the immune complexes that triggered the
cascade, minimising bystander damage to surrounding
Mast cells and basophils
Mast cells and basophils are bone marrow-derived cells
which play a central role in allergic disorders. Mast cells
reside predominantly in tissues exposed to the external
environment, such as the skin and gut, while basophils
are located in the circulation and are recruited into
tissues in response to inflammation. Both contain large
cytoplasmic granules which contain preformed vasoactive
substances such as histamine (see Fig. .
Type I (immediate) hypersensitivity response. A After an encounter with allergen, B cells produce IgE antibody against the allergen.
B Specific IgE antibodies bind to circulating mast cells via high-affinity IgE cell surface receptors. C On re-encounter with allergen, the allergen binds to
the IgE antibody-coated mast cells. This triggers mast cell activation with release of vasoactive mediators
Mast cells and basophils express IgE receptors on
their cell surface (see Fig.). On encounter with specific
The structure of an immunoglobulin (antibody) molecule.
antigen, the cell is triggered to release preformed
mediators and synthesise additional mediators, including
leukotrienes, prostaglandins and cytokines. These
trigger an inflammatory cascade which increases local
blood flow and vascular permeability, stimulates smooth
muscle contraction, and increases secretion at mucosal
Natural killer cells
Natural killer (NK) cells are large granular lymphocytes
which play a major role in defence against tumours
and viruses. They exhibit features of both the adaptive
and innate immune systems: they are morphologically
similar to lymphocytes and recognise similar ligands,
but they are not antigen-specific and cannot generate
NK cells express a variety of cell surface receptors.
Some recognise stress signals, while others recognise the
absence of human leucocyte antigen (HLA) molecules
on cell surfaces (down-regulation of HLA molecules by
viruses and tumour cells is an important mechanism
by which they evade T lymphocytes). NK cells can also
be activated by binding of antigen–antibody complexes
to surface receptors. This physically links the NK cell
to its target in a manner analogous to opsonisation, and
is known as antibody-dependent cellular cytotoxicity
Activated NK cells can kill their targets in various
ways. Pore-forming proteins, such as perforin, induce
direct cell lysis, while granzymes are proteolytic enzymes
which stimulate apoptosis. In addition, NK cells produce
a variety of cytokines, such as tumour necrosis factor
(TNF)-α and interferon-γ (IFN-γ), which have direct antiviral
and antitumour effects.
The adaptive immune system
Anatomy of the adaptive immune system.
A Macroanatomy B Anatomy of a lymph node.
If the innate immune system fails to provide effective
protection against an invading pathogen, the adaptive
immune system (Fig. ) is mobilised. This has three
• It has exquisite specificity and is able to
discriminate between very small differences in
• It is highly adaptive and can respond to an
unlimited number of molecules.
• It possesses immunological memory, such that
subsequent encounters with a particular antigen
produce a more effective immune response than the
There are two major arms of the adaptive immune
response: humoral immunity involves antibodies produced
by B lymphocytes; cellular immunity is mediated
by T lymphocytes, which release cytokines and kill
immune targets. These interact closely with each other
and with the innate immune system, to maximise the
effectiveness of the response.
• Primary lymphoid organs. The primary lymphoid
organs are involved in lymphocyte development.
They include the bone marrow, where both T and B
lymphocytes are derived from haematopoietic stem
cells (p. 993) and where B lymphocytes also mature,
and the thymus, where T lymphocytes mature.
• Secondary lymphoid organs. After maturation,
lymphocytes migrate to the secondary lymphoid
organs. These include the spleen, lymph nodes and
mucosa-associated lymphoid tissue. These organs
trap and concentrate foreign substances, and are
the major sites of interaction between naïve
lymphocytes and microorganisms.
The thymus is a bilobed structure organised into cortical
and medullary areas. The cortex is densely populated
with immature T cells, which migrate to the medulla to
undergo selection and maturation. The thymus is most
active in the fetal and neonatal period, and involutes
after puberty. Failure of thymic development is associated
with profound T-cell immune deficiency (p. 80), but
surgical removal of the thymus in childhood (usually in
the context of major cardiac surgery) is not associated
with significant immune dysfunction.
The spleen is the largest of the secondary lymphoid
organs. It is highly effective at filtering blood and is an
important site of phagocytosis of senescent erythrocytes,
bacteria, immune complexes and other debris. It is also
a major site of antibody synthesis. It is particularly
important for defence against encapsulated bacteria,
and asplenic individuals are at risk of overwhelming
Lymph nodes and mucosa-associated lymphoid tissue
Lymph nodes are positioned to maximise exposure to
lymph draining from sites of external contact. Their
structure is highly organised, as shown in Figure 4.4B.
More diffuse unencapsulated lymphoid cells and follicles
are also present on mucosal surfaces: for example,
in Peyer’s patches in the small intestine.
Absorption, transport and storage of lipids. Pathways of lipid transport are shown; in addition, cholesterol ester transfer protein
exchanges triglyceride and cholesterol ester between VLDL/chylomicrons and HDL/LDL, and free fatty acids released from peripheral lipolysis can be taken
up in the liver. (ABCA1/ABCG1 = ATP-binding cassette A1/G1; Apo = apolipoprotein; BA = bile acids; C = cholesterol; CE = cholesterol ester; FFA = free
fatty acids; HDL = mature high-density lipoprotein; HL = hepatic lipase; HMGCoAR = hydroxy-methyl-glutaryl-coenzyme A reductase; IDL = intermediatedensity
lipoprotein; iHDL = immature high-density lipoprotein; LCAT = lecithin cholesterol acyl transferase; LDL = low-density lipoprotein; LDLR =
low-density lipoprotein receptor (Apo B100 receptor); LPL = lipoprotein lipase; SRB1 = scavenger receptor B1; TG = triglyceride; VLDL = very low-density
Lymphoid tissues are physically connected by a network
of lymphatics, which has three major functions: it provides
access to lymph nodes, returns interstitial fluid to
the venous system, and transports fat from the small
intestine to the blood stream (see Fig. ). The
lymphatics begin as blind-ending capillaries, which
come together to form lymphatic ducts. These enter and
then leave regional lymph nodes as afferent and efferent
ducts respectively. They eventually coalesce and drain
into the thoracic duct and thence into the left subclavian
vein. Lymphatics may be either deep or superficial, and,
in general, follow the distribution of major blood vessels.
Humoral immunity B lymphocytes
These specialised cells arise in the bone marrow. Mature
B lymphocytes (also known as B cells) are found in bone
marrow, lymphoid tissue, spleen and, to a lesser extent,
the blood stream. They express a unique immunoglobulin
receptor on their cell surface (the B-cell receptor),
which binds to soluble antigen. Encounters with antigen
usually occur within lymph nodes, where, if provided
with appropriate signals from nearby T lymphocytes,
stimulated antigen-specific B cells respond by proliferating
rapidly in a process known as clonal expansion. This
is accompanied by a highly complex series of genetic rearrangements,
which generates B-cell populations that
express receptors with greater affinity for antigen than
the original. These cells differentiate into either longlived
memory cells, which reside in the lymph nodes, or
plasma cells, which produce antibody.
Immunoglobulins (Ig) are soluble proteins made up of
two heavy and two light chains (Fig. ). The heavy
chain determines the antibody class or isotype, i.e. IgG,
IgA, IgM, IgE or IgD. Subclasses of IgG and IgA also
occur. The antigen is recognised by the antigen-binding
The structure of an immunoglobulin (antibody) molecule.
to the initial antibody response, secondary antibody
responses do not require additional input from T lymphocytes.
This allows the rapid generation of highly
specific responses on pathogen re-exposure.
T lymphocytes (also known as T cells) mediate cellular
immunity and are important for defence against viruses,
fungi and intracellular bacteria. They also play an
important immunoregulatory role, orchestrating and
regulating the responses of other components of the
immune system. T-lymphocyte precursors arise in bone
marrow and are exported to the thymus while still
immature (see Fig. below). Within the thymus, each
cell expresses a T-cell receptor with a unique specificity.
These cells undergo a process of stringent selection to
ensure that autoreactive T cells are deleted. Mature T
lymphocytes leave the thymus and expand to populate
other organs of the immune system. It has been estimated
that an individual possesses 107–109 T-cell clones,
each with a unique T-cell receptor, ensuring at least
partial coverage for any antigen encountered.
T cells respond to protein antigens, but they cannot
recognise these in their native form. Instead, intact
protein must be processed into component peptides
which bind to a structural framework on the cell surface
known as HLA (human leucocyte antigen). This process
is known as antigen processing and presentation, and it
is the peptide/HLA complex which is recognised by
individual T cells. While all nucleated cells have the
capacity to process and present antigens, specialised
antigen-presenting cells include dendritic cells, macrophages
and B lymphocytes. HLA molecules exhibit
extreme polymorphism; as each HLA molecule has the
capacity to present a subtly different peptide repertoire
to T lymphocytes, this ensures enormous diversity in
recognition of antigens within the population.
T lymphocytes can be segregated into two subgroups
on the basis of function and recognition of HLA molecules.
These are designated CD4+ and CD8+ T cells,
according to the ‘cluster of differentiation’ (CD) antigen
expressed on their cell surface. CD8+ T cells recognise
T-lymphocyte function and dysfunction (green boxes).
antigenic peptides in association with HLA class I molecules
(HLA-A, HLA-B, HLA-C). They kill infected cells
directly through the production of pore-forming molecules
such as perforin, or by triggering apoptosis of the
target cell, and are particularly important in defence
against viral infection. CD4+ T cells recognise peptides
presented on HLA class II molecules (HLA-DR, HLA-DP
and HLA-DQ) and have mainly immunoregulatory
functions. They produce cytokines and provide
co-stimulatory signals that support the activation of
CD8+ T lymphocytes and assist the production of mature
antibody by B cells. In addition, their close interaction
with phagocytes determines cytokine production by
both cell types.
CD4+ lymphocytes can be further subdivided into
subsets on the basis of the cytokines they produce:
• Typically, Th1 cells produce IL-2, IFN-γ and TNF-α,
and support the development of delayed type
hypersensitivity responses .
• Th2 cells typically secrete IL-4, IL-5 and IL-10, and
promote allergic responses .
• A further subset of specialised CD4+ lymphocytes
known as regulatory cells are important in immune
regulation of other cells and the prevention of