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172 Part 3 Inflammation and immune disease
In our everyday lives we are constantly coming into contact with potentially harmful foreign
agents, including pathogens (disease-causing micro-organisms: bacteria and viruses). A
variety of mechanisms play vital roles in defending our bodies from the threat of invasion.
Defence is provided by physical barriers to penetration, the most obvious of which is the
skin; other examples include nasal hair and eyelashes. Chemical barriers are also in place,
for example acid in the stomach and the antibacterial enzyme, lysozyme, found in tears. In
addition, a number of reflex responses serve to expel foreign agents which have managed
to overcome these initial obstacles and have entered the body; these include sneezing,
coughing, lacrimation, and vomiting.
When a pathogen does manage to gain access, or when injury occurs, or when mutated
(cancerous) cells develop, normal function can be restored by the actions of the immune
system. The complex processes which are set in train involve a whole host of cells and
mediators, and collectively give rise to the inflammatory response. Cellular and chemical
components act in concert to neutralize or destroy ‘non-self’ agents. The correct
functioning of the immune system is crucial to life. Where it is compromised, the individual
succumbs to infections which can be life-threatening. Such a situation can be inherent (i.e.
the individual is born with it), or acquired, for instance through HIV infection or use of
immunosuppressant drugs.
In order to act effectively, the body obviously needs a way of recognizing what is and isn’t
‘self’. On occasion this system goes awry, and the body turns the powers of the immune
system on itself, destroying its own proteins. This is the basis of autoimmune disorders
such as rheumatoid arthritis, which is covered in Chapter 9. In other cases, normally
innocuous substances such as pollens can provoke an immune response in susceptible
individuals; this can lead to local pathologies affecting the skin (eczema), nose and throat
(hay fever), or lungs (asthma).
Such conditions are treated with drugs that target the overactive immune response
(anti-inflammatory and immunosuppressant drugs), or a specific aspect of it
(immunomodulatory drugs). In order to understand the ways in which such drugs have
their effects, an appreciation of the basis of the immune system is first necessary.
P3.1 Cells of the immune system
The blood-borne cellular components of the immune system are the white blood cells
(leucocytes). These serve as the mobile units of the internal defence system, being rapidly
transported in the bloodstream to where they are needed. During the immune response,
these cells are able to leave the blood vessels through gaps which develop between the
endothelial cells (see below), and migrate into the affected tissue where they carry out their
specific roles. There are five types of leucocyte.
1. Neutrophils engulf, kill, and enzymatically digest micro-organisms (phagocytosis).
These are the first circulating cells to arrive at the site of infection or damage.
2. Eosinophils play a similar role to neutrophils, but in addition contain granules packed
with toxic substances. These are released to kill invading parasites. Eosinophils play a
central role in allergic responses.
3. Basophils are similar to mast cells (see below), synthesizing and storing histamine, a
powerful mediator of the immune response. They are the least numerous of the leucocytes.
P3.2 The immune system 173
4. Monocytes follow neutrophils and basophils to the site of infection/injury. Once in the
area, they differentiate into macrophages capable of destroying tissue debris and
micro-organisms by phagocytosis.
5. Lymphocytes. These belong to two main classes—B- and T-cells—and are central to
the responses of the adaptive immune system (see below). Natural killer cells are
specialized lymphocytes.
Neutrophils, basophils, and eosinophils are collectively termed polymorphonuclear
granulocytes,1 reflecting the unusual multi-lobed appearance of the nucleus and the
mediator-containing granules in the cytoplasm. In contrast, monocytes and lymphocytes
are described as mononuclear agranulocytes, as they have a more conventionally shaped
round nucleus,and an absence of granules.
These five white blood cell types are the body’s mobile defence system. They are aided in
their roles by non-circulating mast cells, which are similar to basophils. When activated, mast
cells release histamine and other preformed substances contained in granules, triggering the
inflammatory response. Mast cells are strategically located at sites where infiltration by
pathogens is more likely (e.g. the lungs and skin). As such, they may be the first cells to come
into contact with a pathogen; they often therefore kick-start the immune process.
P3.2 The immune system
The immune system confers protection through two major components, whose actions
are separate but interrelated.
1. The innate immune system, the first line of defence, is responsible for immediate and
non-specific responses to foreign invaders, or to substances released due to cellular/
tissue damage. We are born with these mechanisms in place, and previous exposure
to the triggering agent is not required.
2. The adaptive (or acquired) immune system, the second line of defence, is customized
to act against specific pathogens to which the individual has been exposed. It is
responsible for ‘immunological memory’, where subsequent exposure to a given
invader elicits a more efficient response; this is exploited in the practice of vaccination
(see Section P3.2.3).
P3.2.1 The innate immune system
The pathways triggered by the innate immune system lead to inflammation. The ultimate
aim of the inflammatory response is to remove invaders and/or cellular and tissue debris,
and to prepare the damaged area for subsequent repair and healing. The inflammatory
response is crucial to survival.
The major blood-borne cellular mediators of the innate immune response are the
phagocytic neutrophils. These cells are attracted into the affected area by signals from
1 These cells are so named because of the propensity of their granules to staining by various dyes; eosinophils are
readily stained by the red dye eosin, basophils by a basic blue dye, and neutrophils show no preference (i.e. are
neutral).
174 Part 3 Inflammation and immune disease
damaged cells, or by substances associated with, or released from, the pathogen.
Neutrophils express receptors that recognize parts of the foreign agent (e.g. bacterial
peptides) or components of damaged tissue. Activation of these receptors triggers the
release of local signalling molecules (cytokines and chemokines; see Section P3.3),
which further the immune response. Resident non-circulating mast cells and dendritic
cells aid in this work by phagocytosing foreign material. Mast cells are activated by
interaction with the pathogenic material, and respond by releasing the contents of
granules packed with preformed cytokines (see Section P3.3) and histamine, and by
engulfing the pathogen.
The concerted actions of the cellular components and substances either released or
synthesized locally, bring about the changes seen during the inflammatory response:
• vasodilatation, delivering more immune cells and plasma proteins to the area
• increased vascular permeability, allowing components of blood, including leucocytes
and plasma proteins, to escape into the inflamed tissue.
These changes to the affected area are also responsible for the well-known characteristics
of inflammation (see Figure P3.1). The localized vasodilatation is responsible for the
redness and feeling of warmth. The increased permeability of blood vessels leads to
leakage of fluid into the area, causing swelling. Pain arises from the distension of the tissue
as a result of the swelling, and also because of the sensitization of afferent pain fibres by
chemical mediators of inflammation (particularly prostaglandins, see below).
Pathogen invasion/
Tissue damage
Mast cells release histamine and
other inammatory mediators
Local vasodilatation
↑ Blood
Warmth Redness Swelling Pain
Figure P3.1 Steps in the development of inflammation.
The release from mast cells of histamine and other inflammatory mediators plays a central role in the
initiation of the inflammatory response, giving rise to many of the well-known manifestations (red
boxes).
supply to
area
Complement cascade activated
↑ Phagocytosis
Destruction of pathogen
Tissue healing
↑ Vascular permeability
Local accumulation of
uid, plasma proteins,
and leucocytes
P3.2 The immune system 175
Complement
Amongst the plasma proteins delivered to the area are those that comprise the complement
cascade (so named because it ‘complements’ other actions of the immune system). The
complement proteins are proteolytic enzymes, each one inactive until cleaved by the
preceding enzyme in the cascade, in a manner analogous to the cascade of coagulation
factors described in Chapter 4. Activation can be initiated in one of two ways.
1. The alternate complement pathway is activated as part of the innate immune response
through non-specific interaction with the foreign invader.
2. The classical complement pathway is activated specifically by binding to antibody–
antigen complexes (see later) as part of the adaptive immune system.
The peptides generated through the cascade have numerous roles which augment the
immune response. Several of them act together to form membrane attack complexes that
embed into the surface membranes of micro-organisms, creating holes and causing lysis.
Other roles for the activated complement proteins include:
• acting as opsonins—attaching to the surface of the micro-organism to facilitate
ingestion by phagocytes
• stimulating mast cells to secrete further mediators
• acting as a chemo-attractant, to draw leucocytes to the area
• activating leucocytes.
Together these actions reinforce the inflammatory response. The activated complement
components are short-lived, restricting their activity to that area where their effects
arerequired, within the immediate vicinity of the initiating trigger (the micro-organism
itself).
Natural killer cells are specialized lymphocytes, and also take part in the innate immune
response. Their role is to kill virus-infected cells and cancer cells by directly lysing them on
first exposure. In so doing they provide immediate and non-specific defence whilst the
slower-acting adaptive response is gearing up.
P3.2.2 Adaptive immune response
The adaptive (or acquired) immune response is a tailored attack on a particular invading
pathogen to which the body has already been exposed. The main cellular participants are
the two types of lymphocytes:
• B-lymphocytes (B-cells) are responsible for secreting antibodies directed against foreign
invaders such as bacteria and the toxins they produce (antibody-mediated immunity).
• T-lymphocytes (T-cells) are responsible for directly interacting with and killing virus-
infected cells and cancer cells (cell-mediated immunity).
A simplified scheme showing the roles played by B- and T-cells in the adaptive immune
response is shown in Figure P3.2.
In order to specifically and effectively defend against invasion, both B-cells and T-cells must
be able to identify foreign agents. They do so through recognition of antigens—unique
176 Part 3 Inflammation and immune disease
1
Stem
cell
B-cell
Plasma
cell
+
IL-4
Th2
cell
Antibodies
2
Helper
T-cell
Helper
T-cell
34
–+
APC
Th1
cell
IFNγ
+
IL-2
Killer
T-cell
Killer
T-cell
Direct killing
of infected
cells
APC
Natural
killer cells
Figure P3.2 Simplified diagram of the roles of B- and T-cells in adaptive immunity.
1. B-cells and T-cells are derived from common precursor stem cells. 2. Antigen-presenting cells (APCs) ingest
and process antigen and present it to naive T-cells, which are thereby activated. Depending on the nature of the
signals received, activated T-cells proliferate and differentiate into either T-helper 1 (Th1) or T-helper 2 (Th2) cells.
3. Th1 cells are involved in cell-mediated immunity, secreting interleukin-2 (IL-2) to stimulate killer T-cells that are
able to kill virus-infected cells. Th1 cells also secrete interferon gamma (IFN-), which activates natural killer (NK)
cells and macrophages. IFN- stimulates the proliferation of Th1 cells, whilst inhibiting proliferation of Th2 cells.
4. Th2 cells cooperate in the activation of B-cells through secretion of a number of cytokines, importantly IL-4.
The activated B-cells proliferate to produce antibody-synthesizing plasma cells.
Macrophages
molecules such as fragments from the outer coats or membranes of bacteria or viruses.
This recognition event triggers the immune response.
B-lymphocytes
B-cells have specific surface receptors which bind a particular type of antigen. When
activated, most B-cells differentiate into plasma cells which secrete antibodies
P3.2 The immune system 177
(immunoglobulins) directed against that specific antigen. A few activated B-cells become
dormant memory cells. (Many antigens require T-helper cell involvement to elicit B-cell
activation; see later.)
Antibodies are Y-shaped molecules with identical antigen binding sites or fragments
(termed Fab) at the two tips, and a non-variable constant region (Fc) at the base. There are
five major classes of immunoglobulin: IgA, IgD, IgE, IgG and IgM. They show differences in
the Fc region which result in different biological roles.
Antibodies have a number of strategies for combating pathogens. For instance, they can
combine with toxins to stop them interacting with cells (neutralization), or can cross-link
antigen molecules to form clumps (agglutination). The most important function of antibodies,
however, is to enhance the activity of the innate immune system.
• The interaction between antibody and antigen exposes a binding site for complement
on the Fc region of the antibody molecule. The complement cascade is thereby
activated (through the classical pathway) in the immediate vicinity of the pathogen.
• When antibodies are bound to microbial antigens, the exposed Fc region binds
receptors on phagocytes (neutrophils and macrophages) and encourages
phagocytosis.
• The antibody–antigen interaction also stimulates the action of natural killer cells to
release toxins that destroy antibody-coated target cells.
T-lymphocytes
T-cells mediate defence against viral infections, and like B-cells they express receptors on
their surface which bind specific antigens. Unlike B-cells, however, they directly interact
with their targets (cell-mediated immunity). There are three main classes of T-cells with
distinct roles, and they can be identified by key surface proteins, termed cluster of
differentiation (CD) proteins:
1. Cytotoxic (killer) T-cells destroy host cells containing viruses, as well as cancer cells and
transplanted cells, by unleashing chemicals that lyse the target cells. They express CD8
proteins, and are known as CD8+ T-cells.
2. Helper T-cells are not directly involved in the destruction of invaders, but modulate the
behaviour of other immune cells through the secretion of cytokines. Importantly, helper
T-cells are crucial for the activation of B-cells in response to most antigens
(T-dependent antigens). There are two distinct types of helper T-cell responsible for
different patterns of immune response through the secretion of different types of
signalling molecules, or cytokines (see later). The pathway of differentiation followed by
naive T-cells into either T-helper 1 (Th1) or T-helper 2 (Th2) cells is dependent on signals
received during activation, and these in turn will be tailored to meet the particular threat
at hand. Th1 cells are largely involved in cell-mediated responses (activation of
cytotoxic T-cells), whereas Th2 cells cooperate in the proliferation of B-cells, and in the
generation of antibodies and memory cells (see below). Both Th1 and Th2 cells express
CD4 proteins, and are therefore known collectively as CD4+ T-cells.
3. Regulatory T-cells suppress both the innate and adaptive immune responses to prevent
them escalating out of control. They express both CD4 and CD25 proteins, and are
known as CD4+ CD25+ T-cells.
178 Part 3 Inflammation and immune disease
As with B-cell activation, a small subset of the T-cells that have been activated by
exposure to a particular antigen remain in a dormant state. In this way the immune system
is primed in readiness for a subsequent encounter with that same antigen.
Antigen-presenting cells
In order for T-lymphocytes to recognize them, antigens must be processed and presented
by antigen-presenting cells. These are most commonly dendritic cells or macrophages
which engulf the micro-organism, breaking down the outer coat or membrane, and
presenting a fragment of it on their surface; other cell types can also act in this capacity
including some B-cells. Dendritic cells and macrophages are especially abundant in
locations where pathogens can enter the body (e.g. the skin, where they are known as
Langerhans cells, lungs, and digestive tract).
In order to prevent the immune system from attacking host cells, it must be able to recognize
self-antigens. This is the role of major histocompatibility complex (MHC) molecules
which are expressed on virtually all cells. Cells infected with a pathogen are recognized
by T-cells through a combination of MHC molecules and antigen presented on the cell
surface. The nature of MHC molecules varies from one person to the next. This variability
underlies transplant rejection; the transplanted cells express MHC molecules different from
those of the new host, whose immune system therefore attacks what it seesas foreign
tissue. In autoimmune diseases such as rheumatoid arthritis (Chapter 9), the ability to
recognize self breaks down and antibodies are generated against normal hosttissue.
P3.2.3 Immunological memory
As mentioned earlier, a small subset of activated T- and B-cells remains in the body in
readiness for subsequent exposure to the same antigen. If this occurs, the memory cells
are activated to meet the challenge with a faster and stronger response than when the
antigen was first encountered. This is the basis of vaccination; a weakened strain of a
pathogen is introduced in order to prepare an immunological memory to combat a
subsequent fully fledged attack.
P3.3 Inflammatory mediators
The immune responses are coordinated by a large number of short-lived chemical mediators
which act as local hormones to direct and control events. These molecules are mainly
produced by the immune cells themselves, and have effects on either the cell from which
they are released (an autocrine signal), or cells in the immediate vicinity (a paracrine signal).
P3.3.1 Histamine
Histamine is released from activated mast cells during inflammation and causes the local
vascular changes noted earlier (vasodilatation and increased permeability; see Figure P3.1).
P3.3.2 Eicosanoids
Also central to the inflammatory response are a group of compounds called eicosanoids.
These molecules are derived from arachidonic acid, a constituent of the plasma membrane.
Their lipid characteristics preclude them from being preformed and stored in cells; instead
P3.3 Inflammatory mediators 179
Phospholipids
they are generated as required (Figure P3.3). The principal eicosanoids are prostaglandins
and thromboxanes (collectively called prostanoids) and leukotrienes. The first step in
leukotriene production from arachidonic acid is catalysed by 5-lipoxygenase. This enzyme
is mainly found in the lungs, platelets, mast cells, and white blood cells. The leukotrienes
generated are of two types.
1. LTB4, produced mainly by neutrophils, has the most important role in inflammation. It
attracts neutrophils and macrophages to the affected area, and stimulates lymphocytes
to proliferate and release cytokines.
2. Cysteinyl leukotrienes LTC4, LTD4, and LTE4 are produced by leucocytes, including
eosinophils, and have a central role in the pathogenesis of asthma, eliciting
bronchoconstriction and increased mucus secretion (see Chapter 11).
Prostanoids are generated via a cyclo-oxygenase-catalysed pathway (Figure P3.3).
They comprise a group of five biologically active, but short-lived, compounds, of which
two, PGE2 and PGI2 (also known as prostacyclin), are central to the inflammatory
response. These are synthesized and released from tissues, such as vascular
endothelium, and from immune cells including macrophages, neutrophils, and mast
cells; they act locally, in concert with other mediators, to promote inflammation. The
effects of the principal eicosanoids are outlined in Table P3.1; not all are concerned with
inflammation.
Phospholipase-A
2
Arachidonic acid
12-Lipoxygenase 15-Lipoxygenase Cyclo-oxygenase 5-Lipoxygenase
12-HETE
Lipoxins
A and B
LTA
4
LTC
LTD
PGI
TXA
2
PGF
2
2α
PGD
PGE
2
2
LTB
4
LTE
Figure P3.3 Eicosanoid synthesis.
The eicosanoids are derived from arachidonic acid liberated from phospholipids in cell membranes by the action of
phospholipase A2. This is converted into leukotrienes via 5-lipoxygenase-catalysed pathways, or into prostanoids through the
action of cyclo-oxygenase enzymes. Two further enzymes, 12-lipoxygenase and 15-lipoxygenase, are involved in the synthesis
of the chemotaxin, 12-hydroxyeicosatetraenoic acid (HETE), and the anti-inflammatory lipoxins. PG, prostaglandin; TX,
thromboxane; LT, leukotriene.
4
4
4
180 Part 3 Inflammation and immune disease
Table P3.1 Effects of the principal eicosanoids
Eicosanoid Effect
Prostaglandin I2
(prostacyclin)
Thromboxane A
Prostaglandin F2
Prostaglandin D
Prostaglandin E
Leukotriene B
Cysteinyl leukotrienes
(LTC4, LTD4 and LTE4)
2
2
2
4
Vascular
smooth
muscle
Dilatation
Constriction
Dilatation
Dilatation
Vascular
permeability
Platelet
aggregation
Respiratory
smooth
muscle
Constriction
Constriction
Pain Other
Uterine contraction
Gastric acid;
Gastric mucus
Movement of white
blood cells (chemotaxis)
Respiratory mucus
P3.3.3 Cytokines and chemokines
Numerous protein or peptide mediators released by immune cells orchestrate the immune
response; these are collectively termed cytokines. The production of cytokines and
expression of their corresponding receptors are upregulated during inflammation. The
mode of action of these mediators is complex, often involving reciprocal interactions
between different cytokines to bring about the final response. The roles of a number of key
cytokines are listed in Table P3.2.
Chemokines are a subset of cytokines with chemoattractant properties. They help to
coordinate the immune response by controlling the migration of leucocytes to the
affectedarea.
Table P3.2 Some examples of important cytokines
Cytokine Main sources Function/effect
Granulocyte macrophage colonystimulating factor (GM-CSF)
Interleukin 1 (IL-1) Macrophages,
Interleukin 2 (IL-2) T-cells Stimulates growth and differentiation of T- and B-cells and natural
Interleukin 4 (IL-4) Th2 cells, mast cells,
Interferon (IFN-)
Tumour necrosis factor (TNF-)
Macrophages, mast cells,
T-cells, natural killer cells
monocytes, B-cells,
dendritic cells
macrophages
Th1 cells and natural killer
cells
Macrophages Kills tumour cells
Stimulates bone marrow stem cells to produce leucocytes, leading
to an increase in numbers of circulating cells
Inflammation, fever, pain
Maturation and proliferation of B-cells
Modulates stimulation of leucocytes
killer cells
Stimulates proliferation of T- and B-cells and immunoglobulin synthesis
Important in allergic reactions
Proliferation of Th1 cells, inhibition of Th2 cells
Activation of natural killer cells and macrophages
Stimulates cytokine expression by macrophages
Key regulator of inflammation
Th1, T-helper 1 cells; Th2, T-helper 2 cells
P3.3 Inflammatory mediators 181
The picture presented here of the immune system and the responses evoked by
pathogens is obviously highly simplified. Numerous additional cells as well as mediators
are involved in the complex processes, and doubtless many more are yet to be
discovered. However, it is hoped that the scheme presented is sufficiently detailed to
enable you to appreciate the actions of the therapeutic agents used to tackle inflammatory
disorders; the most common conditions are covered in the following chapters.