ISBT Science Series (2020) 15, 54–67

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd.

SECTION 2 ISBT Science Series
DOI: 10.1111/voxs.12589

Immunology
Original author: Beryl Armstrong
Reviewer for Second Edition: Veera Sekaran Nadarajan

Introduction • Viruses and the immune response

• Cancer and the immune system
Immunology is the study of the immune system and how the
body protects itself from infection using a variety of meth-
Role of the immune system
ods. Failure of the immune system to function correctly can
result in disease, such as autoimmunity, allergy and cancer. The role of the immune system is to defend the body
Immunological defence is important to confer protection against pathogens and other foreign substances (i.e. foreign
of an organism against invasion by foreign micro- agents) that may be harmful, by identifying and destroying
organisms and to facilitate tissue repair. The body recog- them. Figure 1 shows a simplified version of the location of
nises ‘self’ and targets the foreign ‘non-self’ as potentially the main components of the immune system. Table 1 lists
harmful and to be destroyed. Differentiation between self the main cellular components of the immune system.
and non-self, and the body’s reaction to non-self, forms the The natural barriers of the body i.e. the skin and
basis of the immune response. mucous membranes, guard against the entry of foreign
Allogeneic blood transfusion essentially introduces a agents and serve as the first line of defence, i.e. the inter-
foreign substance into the body. It is therefore crucial face between the body and the environment.
that the blood product to be infused is selected to be as • Intact skin prevents pathogens and other foreign
immunologically compatible as practically possible, i.e. it agents from entering the body.
should match ‘self’ as closely as possible to prevent • Mucous membranes protect vulnerable parts of the
undue immune reaction in the host, to the blood being body that are exposed to air. Examples are the nos-
transfused. An immune reaction can result in reduced trils and eyes, and internally, the gut and lungs. The
clinical efficacy or have an adverse effect on the recipi- mucous secreted by these membranes forms a
ent. Without a clear understanding of immunology, it is
difficult to interpret the clinical rationale and conse-
quences of blood transfusion as well as to interpret
immunohaematological tests in the laboratory.

Learning objectives
By the end of this section, the student should be able to
define and describe the following:
• Role of the immune system
• Innate immunity
• Cells of the immune system
• Inflammation
• Phagocytosis and antigen presentation
• Complement
• Adaptive immunity
• Antigens and antibodies
• Nature of immunogenicity
• Primary and secondary response
• Active and passive immunity
• Characteristics of immunoglobulins
• Immune paralysis and immune tolerance
• Autoimmunity
• Immunodeficiency Fig. 1 Sketch of immune system components.

54
 Immunology 55

Table 1 Cells of the immune system

B lymphocytes Lymphocytes (B cells) responsible for the production of antibodies

Dendritic cells The antigen-presenting cells of the immune system
Granulocytes These are polymorphonuclear cells with a multilobed nucleus whose main function is phagocytosis
Lymphocytes White cells responsible for immune defense by cell-mediated immunity and the production of antibodies
Macrophages Large white cells whose main function is phagocytosis
Monocytes Large white cells whose main function is phagocytosis
Natural-killer (NK) cells A type of lymphocyte that play an important role in the destruction of virally infected cells
T lymphocytes Lymphocytes (T cells) responsible for identifying foreign antigens and initiating the adaptive immune response
Neutrophils White blood cells that mediate innate immunity
Eosinophils White blood cells that help promote inflammation

Table 2 Comparison between innate and adaptive immunity

Innate immunity Adaptive immunity

The response is inborn The response is learned
The response time is the same every time and is usually rapid There is a delay between first exposure and peak of response
The response actions are the same regardless of the The type of response depends on the nature of the immunogens encountered
nature of immunogens encountered
There is no immunologic memory following repeated Immunologic memory follows first exposure, so when the same
exposure to an immunogen and response actions are repeated as before immunogen is encountered again, it is recognised, and response is
faster and better as a result

protective barrier, slowing down and hindering the epithelial barriers to various effector cells and chemicals.
entry of foreign agents into the body. Although rapidly mobilised, the innate immune response
When foreign agents breach the skin or penetrate mucous tends to be generalized. External defence is maintained by
membranes, other defence mechanisms in the body are acti- means of intact skin, by mucous, which traps and elimi-
vated. These include cellular and non-cellular components nates micro-organisms, and by body secretions such as sal-
of the immune system which then start to protect the body iva and perspiration, which have disinfectant properties.
from potential damage by the invading agent(s). The Effector cells and chemical mediators recognise foreign
immune system is broadly classified into two subsystems: agents that enter the body, thereby initiating an immune
innate and adaptive. The innate immune system is evolu- response against them. Pathogens contain structures that
tionarily primitive (i.e. it was developed very early in evolu- exhibit specific motifs (identifying markers) that are not
tionary history and has not changed very much since) but present in mammals. These molecular motifs or patterns
plays an important role as the first line of defence and is are present in many classes of pathogen and are termed
activated early in the immune response. Innate immune pathogen-associated molecular patterns (PAMP). Exam-
response is broad-based and non-specific. Adaptive immu- ples of PAMP include lipopolysaccharides (LPS), mannans
nity is evolutionarily recent (i.e. has developed relatively and teichoic acids that are present on bacterial cell walls.
recently in evolutionary history) and is confined to verte- The innate immune system responds to the presence of
brates. Its response is slower but more flexible, specifically PAMP through a group of proteins termed pathogen-
targeting foreign agents and conferring memory, so that re- recognition receptors (PRR). PRR are expressed on many
exposure to the same agents in future is met with a more of the cells mediating the innate immune response as well
rapid, effective and specifically charged response. Table 2 as within secreted and locally produced molecules that
provides a summary comparing innate and adaptive immu- are involved in inflammatory processes. Cells mediating
nity. Despite differing functions, the two arms work in har- innate immunity include dendritic cells, monocytes,
mony (synergistically) to mount an effective response to macrophages, granulocytes and natural-killer (NK) cells.
infection and tissue injury. An important group of PRR are the Toll-like receptors
(TLR) that are expressed on the innate immune cells and
on the cells of various tissues including epithelial cells,
Innate immunity
endothelial cells and fibroblasts. TLR play an important
Innate immunity includes various components of natural role in the initiation of the innate immune response by
(inborn) host defence that range from non-specific detecting pathogens. Various classes of TLR bind to

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different molecular structures on viruses, bacteria, fungi them for ingestion. Important opsonic phagocytic recep-
and other pathogens, leading to phagocytosis and the tors include Fc receptors (FcR) and complement receptors
killing of the pathogen as well as release of pro-inflam- (CR), both of which are described in detail later in this
matory cytokines (signalling molecules that promote section. FcR bind to IgG bound particles while CR bind to
inflammation) and anti-microbial substances that assist in complement molecules deposited on cells and particles
the destruction of the pathogen. following complement activation. Phagocytic cells are
also important for processing ingested extracellular pro-
teins into peptides that then become attached to MHC-I
Inflammation
class molecules, to be taken to and presented to T cells
Inflammation is an early defence process designed to for destruction. T cells are part of the adaptive immune
protect the body from potentially harmful foreign agents process.
and to facilitate the eventual process of tissue repair. Its
primary function is to rapidly destroy or isolate the
Complement
underlying source of danger, remove damaged tissue, and
then restore tissue integrity. The first step in the inflam- Complement (C) consists of a group of more than 20
matory process is the recognition of the offending patho- soluble proteins that play a pivotal (i.e. key, vital) role in
gen or agent. In the case of pathogens, this is achieved the immune response. These proteins are present in the
by detection of PAMP through the various PRR such as plasma in an inactive form until stimulated. It usually takes
the TLR. This leads to the upregulation (activation) of one immunoglobulin M (IgM) antibody molecule or two
certain transcription factors e.g. Nuclear Factor kappa B immunoglobulin G (IgG) antibody molecules in juxtaposi-
(NF-jB) leading to an increased production of proinflam- tion (close together) on a target cell, to initiate the comple-
matory cytokines such as interleukin-1-b (IL-1b), IL-6 ment response. Each complement protein then acts in
and tumour necrosis factor-a (TNF-a). Chemokines further sequential fashion, one activating the next like a cascade.
recruit (i.e. enlist or engage) inflammatory cells such as The result is that complement either becomes attached to
neutrophils and monocytes to the site of damage. The the target cell membrane, making it more susceptible to
gathering together of this immune reaction is helped by phagocytosis, or continues in a chain reaction to its end,
changes in the local vascular system as indicated in the which results in the lysis (breaking) of the cell membrane.
list that follows. The consequences of inflammation and The consequence of cell lysis is loss of cell contents, and
its major signs and symptoms include: cell death. Complement activity is therefore a very impor-
• Increased blood flow (feeling of heat) tant immunological process to address threats to the host.
• Pain The complement cascade is a complicated sequence
• Swelling that in simple terms consists of nine major protein com-
• Increased blood supply to nearby capillaries (red- ponents, C1 to C9. When a component is activated, it is
ness) written with a line on top. The sequence of activation is
• Loss of function in the inflamed area, particularly if C1, C4, C2, C3, C5, C6, C7, C8, C9. The activation stage
a joint is affected involves C1, C4 and C2. The activation is amplified when
• Attraction of phagocytic cells, with evidence of pus hundreds of molecules of C3 are then activated and
as a result of phagocytic activity. become target cell bound, first as C3b and later as C3d.
The cascade sometimes stops at this point. If it continues
to the point of cell lysis, then the remaining components
Phagocytosis and antigen presentation
from C5 onwards play a role, with the membrane attack
Phagocytosis occurs as a result of recognition of particles unit consisting of C7, C8 and C9. The complement cas-
and microbes and their subsequent ingestion by cells cade is discussed in more detail in Section 3: Antigen-an-
which eliminate them. These ‘professional’ phagocytic tibody reactions, from the perspective of its involvement
cells include monocytes, macrophages, neutrophils, den- in antigen–antibody reactions in the laboratory.
dritic cells and eosinophils. They recognise pathogens or The major actions of complement are:
particles (i.e. foreign agents) and engulf them through a • Participation in acute inflammatory processes.
variety of receptors that can be divided into opsonic and • Assisting in opsonisation that helps the process of
non-opsonic. Non-opsonic receptors can directly recog- phagocytosis.
nise molecular motifs, or distinct molecular patterns, on • Modification of cell membranes that results in lysis.
the surface of the phagocytic target such as microbial lec- Complement may become activated in one of three
tins. Opsonic receptors meanwhile detect host-derived ways, each of which causes the activation of C3, splitting
opsonins that attach to the foreign particles and target it into a large fragment (C3b) that attaches to the

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67
 Immunology 57

where only a limited number of foreign molecules or for-

eign molecular patterns are recognised by its cellular and
chemical mediators, adaptive immunity has the capacity
to recognise an infinite number of peptide or carbohy-
drate molecules. This is achieved through the generation
of highly diverse T cell receptors (TCR) and B cell recep-
tors (BCR) that can recognise and bind to foreign mole-
cules. As will be seen in the section on autoimmunity
below, the immune system may sometimes fail to recog-
nise ‘self’, resulting in the host’s own cells being treated
as foreign.

T lymphocytes: cell-mediated immunity

Thymus dependent lymphocytes, also known as T lym-
phocytes or T cells, are responsible for cellular defence
- lymphocytes circulate throughout the body as small
lymphocytes. T lymphocytes recognise foreign molecules
that are presented by HLA Class-I and Class-II express-
ing cells. All nucleated cells as well as platelets,
express HLA Class-I molecules. HLA Class-II molecules
are restricted to professional (specialised) antigen-pre-
senting cells such as macrophages and dendritic cells.
Professional antigen-presenting cells are those cells that
specialise in presenting an immunogen (i.e. antigen) to
a T cell. When encountering an antigen, these cells can
attach, process and present the antigen molecule on its
cell surface, bound to the HLA molecule. T lymphocytes
Fig. 2 Sequential activation of complement – classical pathway. interact with the antigen complex via its TCR. This
results in the activation of the T lymphocyte and
pathogen causing the activation, and a small fragment release of various cytokines that facilitate cell-mediated
(C3a) that is released into the plasma and promotes immunity and humoral immunity. For more information
inflammation: on HLA, see Section 6: Blood Group Systems.
• Classical pathway (1): initiated as a result of some The results of this contact are:
antigen-antibody reactions and the activation of the • T lymphocytes with a specific reactivity site are pro-
C1-complex. Fig. 2 shows the sequential activation duced, which can then react directly with the partic-
of complement via the classical pathway. ular foreign immunogen that was presented to them
• Alternative pathway (2): triggered by the presence of by the antigen-presenting cell in the first place.
polysaccharides and lipopolysaccharides found on These activated T cells also release lymphokines,
the surfaces of micro-organisms and tumour cells. which instruct uncommitted lymphocytes (develop-
An antigen-antibody reaction is not required as acti- ing lymphocytes that are not yet committed to a
vated C3 (specifically C3b) binds directly to the sur- specific function) on the nature of these immuno-
face of the pathogen, thus by-passing the activation gens, so that they too can react with the immuno-
Stage 1 shown in Fig. 2. gens and destroy the cells on which they are
• Lectin pathway (3): triggered by the binding of man- situated. This greatly amplifies the intensity of the
nan-binding lectin (found in the plasma) to mannan immune response.
residues on the pathogen. This results in the cleaving • Circulating memory cells are produced. These are
of C3 and the production of C3b and C3a. responsible for the anamnestic or ‘memory’
response, which occurs on subsequent contact with
the same immunogen. This facility allows for the
Adaptive immunity recognition and rapid elimination of micro-organ-
The adaptive immune response is brought about or medi- isms containing immunogens that were encountered
ated by T and B lymphocytes. Unlike innate immunity before.

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58

It is cell-mediated immunity that causes delayed hyper- Antigens and antibodies

sensitivity reactions. This is an inflammatory reaction that
Antigens
occurs a few days after exposure to an immunogen. Such
Although the use of the term antigen is always correct when
a response is caused by T lymphocytes and macrophages
discussing laboratory testing, when an antibody is first stim-
and not by antibodies. One of the unfortunate conse-
ulated to be produced, the foreign substance that elicits the
quences of delayed-type hypersensitivity is the rejection
immune response is correctly called an immunogen. Because
of a graft such as a transplanted organ.
of the common usage of the term’s ‘antigen’ and ‘immuno-
gen’, they are viewed as synonyms, and are often used inter-
B lymphocytes: humoral immunity
changeably. Although antigens can stimulate the production
The humoral immune response occurs when antibodies
of antibodies, they must be immunogenic to do so.
are produced. This is initiated when soluble immunogens
Most antigens are of biologic origin. These are usually
entering the lymphatic system (usually via lymph nodes),
proteins, but they may also be polysaccharides, lipids or
are taken up by antigen-presenting cells such as macro-
nucleic acids. The actual antigenic determinant (or epi-
phages and dendritic cells. The antigens are processed
tope) is usually small, with a molecular mass of at least
and presented in complex with HLA Class-II molecules to
10 000 Daltons (Da). This determinant is often coupled to
T lymphocytes that contain CD4 receptors. These are
a carrier such as a red blood cell (which has on its surface
known as ‘helper cells’. The activated helper cells then
many different antigenic determinants or epitopes).
secrete cytokines such as IL-4 that stimulate B lympho-
Haptens are substances with a molecular mass of less
cytes. The B cells become differentiated into plasmacytes
than 10 000 Da, which when coupled with larger carrier
(plasma cells), and memory B cells. The plasmacytes ini-
proteins become immunogenic (capable of provoking
tially produce IgM antibodies. Interaction with other
antibody response) but are not immunogenic on their
receptors present on the B lymphocyte such as CD40 with
own. Despite their small size, haptens are however, cap-
the T cell receptor induces immunoglobulin switching
able of reacting with antibodies.
and production of IgG antibodies. The strength of the
When considering blood transfusion, one should note
response is regulated by T helper and T suppressor lym-
the following. To avoid life-threatening reactions, com-
phocytes (T lymphocytes that carry CD8 receptors). Helper
patibility tests between recipient, and the products
cells boost the immune response; suppressor cells stop or
intended for infusion, are performed prior to giving a
regulate the production of antibody. Plasmacytes usually
blood transfusion. Nevertheless, a blood transfusion inevi-
continue to secrete antibodies for several weeks after acti-
tably involves the introduction of foreign matter into the
vation. Memory B cells remain in the body for many
recipient, as no two individuals are alike. Antigens are
years, retaining a high affinity for the antigen that stimu-
expressed on red cells and within soluble factors in
lated their activation.
plasma. These antigens can induce the formation of new
‘Naturally occurring’ antibodies found in the ABO
antibodies in the recipient or provoke an antigen-anti-
blood group system are formed as a result of humoral
body reaction if the corresponding antibody to antigen
immune response to environmental A and B antigens,
introduced during transfusion is already present in the
that are similar in immunogenic nature to human red cell
recipient. Conversely, antibodies present in the transfused
antigens. For example, A and B antigens may be present
plasma can react with corresponding host antigens.
on ingested particles, or in medical vaccinations or on
bacteria. Newborns do not have their own ABO alloanti-
Definition of immunogen. An immunogen is a foreign
bodies; it takes time and exposure to the environment,
substance, that when it enters the body of an immunocom-
before they develop.
petent vertebrate animal that lacks that substance, is cap-
able of provoking the formation of antibodies that will
A note on CD terminology
react specifically with it. The term antigen is sometimes
The cluster of differentiation (abbreviated to CD) is a pro-
used as a synonym for immunogen and although antigens
tocol for the identification of cell surface molecules that
can react with specific antibodies, they may not necessarily
provide targets for the phenotyping of cells. CD molecules
be able to provoke an antibody response. Immunogens and
often act as receptors for various other molecules, and
antigens are widespread in the environment; such as in the
some play a role in cell signaling. Some examples are
surrounding air, in foods and in vaccines. They are also
CD8 found on cytotoxic T cells and NK cells, and CD4
found on micro-organisms and on blood and other cells.
found on T helper cells. In order to distinguish these cells,
they may be referred to as CD8 cells and CD4 cells. To
Definition of antigen. An antigen (Ag) is a substance
date more than 370 unique CD clusters and sub clusters
that when introduced into the circulation of a subject
have been identified.

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 Immunology 59

lacking that antigen, can stimulate the production of a

specific antibody.
In blood banking, the term antigen is used as the point
of reference because the blood group systems are defined
by antigens on red blood cells.

Antibodies
When an immunogen enters the body, an immune
response may occur. This means that the immunogen is
recognised as foreign by the host lymphocytes, which
then start to manufacture specific antibodies. This process
occurs in the lymph nodes, liver and spleen, which
together form the reticuloendothelial system. Antibodies
are usually released into the plasma. However, certain
antibodies do not appear to circulate but are fixed to
body tissues or cells and are termed ‘sessile’.
An important characteristic of antibodies is that they
are specific. An antibody will only bind to an antigen
identical to, or very similar to, the antigen that initially
stimulated its production. As each plasma cell can pro- Fig. 3 Lock and key principle of antigen-antibody reaction.
duce antibody with only one specificity and the body is
faced with a vast number of different pathogens bearing
differing antigens, the immune system is required to gen- molecule that stimulates the adaptive immune response
erate large numbers of plasma cells, each producing anti- while the antigen is the molecule that binds to the anti-
bodies of differing specificities. body or T cell receptor. Some very small molecules can
bind to antibodies, but they cannot initiate an immune
Definition of antibody. An antibody (Ab) is a specifi- response by themselves. Such small molecules are called
cally reactive immunoglobulin produced in response to haptens. For example, drugs such as penicillin are usually
immunogenic stimulus, the objective of the antibody haptens or incomplete antigens. They require a carrier,
being to react with and destroy the immunogen that stim- such as a protein, before they can induce an immune
ulated its production. response.
The specificity of an antibody is determined by the The strength and quality of the immune response
shape of the variable region of the light chains (see depends on many variables. Factors that may play a role
Fig. 7) i.e. an antibody will bind to an antigen that has a include:
complementary structure to the antibody’s variable • Age and physiological state of the individual (host)
region. being immunised.
The antigen–antibody recognition may be compared • Capacity of the individual to respond (individuals
with a lock and key, the concept of which is depicted in vary greatly from one another).
Fig. 3. Antigen and antibody must match each other for a • Chemical nature and molecular size of the immuno-
reaction to take place. Figuratively speaking, the key gen.
needs to fit the lock for the recognition to occur. The • Volume and frequency of each inoculum (dose of
‘match’ may also be likened to the way in which one immunogen administered, and timing).
jigsaw puzzle piece fits the next. • Route of administration (e.g. subcutaneous, intravas-
cular).
Nature of immunogenicity • Presence or absence of adjuvants.
Adjuvants are inert substances injected together with
For a substance to be immunogenic, and stimulate a immunogen when deliberately provoking an antibody
response, it must appear to be foreign to the host and be response, as in immunisation programmes. They amplify
of adequate size (more than 10 000 Da). It can be of pro- antibody response and their action is largely threefold:
tein origin e.g. Rh, or a carbohydrate or sugar e.g. ABO. • There is a better response to a smaller dose of
Even lipids and nucleic acids can be immunogenic. All immunogen.
immunogens are antigens but not all antigens are • There is a more sustained or longer lasting response.
immunogens. By definition, the immunogen is the • There is greater production of antibody.

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60

Primary and secondary response

Primary response
When the individual is first exposed to an immunogen,
then immunogen presenting cells such as macrophages
and dendritic cells process and present it in such a way
that it can be recognised by T helper cells. Activation of
the T helper cells facilitates and induces the development
of clonal B lymphocytes that can produce antibodies
specific to that immunogen. If the immunogen is encoun-
tered by the host for the first time, the antibody may
become detectable in the plasma between five and 180
days afterwards. The antibody level rises gradually,
Fig. 4 Graph showing immunoglobulin response.
remains fairly stable for a while and then gradually
declines. The class of antibody produced first is usually
IgM. The antibody undergoes switching to IgG at a later Natural active immunity. When an individual contracts
phase. An important step in the primary immune response measles or mumps or some other infectious disease, the
is the generation of a clone of memory B cells that retain body responds by producing antibodies against the infec-
the capacity to recognise the antigen on re-exposure, tious agent and overcoming it. The individual usually
after which they clonally proliferate. These memory B recovers and does not suffer the same infection again.
cells are long-lived and the ability to recognise the same This is because if the same infectious agent enters the
antigen may be retained for many years. Circulating body in the future, it is recognised by the memory cells
memory B cells facilitate an immediate and brisk IgG and eliminated. Similarly, in blood transfusion, organ
immune response if the individual is exposed again to the transplantation and during pregnancy, foreign antigens
same antigen. This is called the secondary response. are introduced into the circulation of the host, and this
may provoke antibody development.
Secondary response
When a second or subsequent exposure to the same anti- Artificial active immunity. Lifelong immunity may be
gen occurs, the antibody response is usually much more provoked artificially by medical immunisation, such as
rapid. Higher levels of antibody are produced, and the hepatitis B vaccination. In this case, controlled doses of
response is much more sustained. This is because retained attenuated organisms (organisms that have been rendered
memory B cells in the body can recognise the antigen harmless), or non-infectious laboratory-created immuno-
that was encountered during primary response and react gens, are administered, so that the individual does not
more efficiently and effectively. Secondary response is become ill yet mounts an antibody response and becomes
therefore also referred to as the recall or anamnestic immune and protected against the infection in the future.
response. The antibodies produced in the secondary
response are usually IgG. Passive immunity
Figure 4 is a graph showing the time lag, log (increase Passive immunity does not involve the immune system of
in strength), plateau and decline phases of primary (IgM) the individual concerned. Immunity is conferred by intro-
and secondary (IgG) immunoglobulin response to duction of antibodies (immunoglobulins) into the individ-
immunogenic stimulation. ual from some other source. Because the immune
response of the host is not involved, there will be no
memory or recall regarding the infectious agent and
Active and passive immunity
therefore no immunity beyond the lifespan of the intro-
Active immunity duced immunoglobulin. The immunity may be regarded
Active immunity is known as such because the host is as natural or artificial, based on the method by which the
actively involved in antibody production as a result of antibodies are introduced.
coming into contact with an immunogen. Because the
immune response is initiated in the host, the immunity Natural passive immunity. Placental transfer of mater-
that results is long lasting. The immunity may be nal antibodies to the fetus (mainly IgG), or transfer of
regarded as natural or artificial, based on the method by maternal antibodies to the newborn during breastfeeding
which the immunogen is introduced into the host. (mainly IgA), ensures that the infant will have protection

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 Immunology 61

against those infections to which its mother is immune. antigen. IgM is therefore referred to as a pentavalent
The protection afforded by the mother is limited to the antibody or a cyclic pentamer. When IgM red cell anti-
lifespan of the transferred antibodies, and the infant is bodies are mixed with a suspension of red cells bearing
just as susceptible as any other non-immune individual the corresponding antigens, each IgM molecule is large
when the maternal antibodies reach the end of their lifes- enough to simultaneously bind to red cell antigen sites
pan. In addition to antibodies, complement is transferred on adjacent red cells. Figure 5 is a diagrammatic repre-
from mother to child and this assists in providing further sentation of IgM. This activity results in a latticework of
protection. haemagglutination and is readily visible as a clumping
reaction in the laboratory. An important result of some
Artificial passive immunity. Administration of specific IgM activity is the activation of complement. However,
immunoglobulins to non-immune individuals at the time IgM antibodies cannot cross the placenta from mother to
of exposure to infectious agents may prevent illness in fetus, so they play no role in causing haemolytic disease
the short term. Concentrated immunoglobulins are of the fetus and newborn. Figure 6 is a diagrammatic rep-
obtained by fractionation of specially selected donations resentation of haemagglutination, depicting the antigenic
of plasma. For example, plasma from blood donations determinants on the red cells as dots.
with a high level of hepatitis B antibodies may be frac-
tionated to extract the hepatitis B immunoglobulin. This Immunoglobulin G (IgG)
concentrate, if given to a susceptible, non-immune indi- About 80% of circulating antibodies are IgG, and this
vidual, would help prevent infection with hepatitis B on immunoglobulin is small enough (160 000 Da) to infil-
that occasion. The state of immunity is only effective for trate the tissues of the body. IgG molecules are equally
as long as the immunoglobulin from the donated plasma distributed in both intra- and extracellular space.
remains in the circulation of the individual receiving the Although each IgG molecule has two antigen-combining
concentrate.

Limitations of the immune system

Some viruses persist even after antibody production has
occurred as they are of a nature where they cannot be
totally cleared by the antibodies of the host. In such
cases, the host becomes a carrier, and can infect others.
Such viruses, an example of which is the human immun-
odeficiency virus (HIV), may eventually destroy the host.
Other viral diseases, such as influenza, may infect the
same individual many times. This is because there are
many different forms of viruses that cause influenza, and
these are immunologically distinct. Each time a new
influenza virus invades the host, it is seen as being
encountered for the first time and therefore a primary
immune response is initiated.
Fig. 5 IgM molecule.

Characteristics of immunoglobulins
In humans, five distinct classes of immunoglobulins or
antibodies are found. These are IgM, IgG, IgA, IgD and
IgE.

Immunoglobulin M (IgM)
IgM is usually the first immunoglobulin produced in the
primary response. IgM constitutes 5–10% of circulating
antibodies. It is a large molecule (900 000 Da) and is
mainly confined to the bloodstream. The molecule con-
sists of five monomers joined in a cyclic manner, and
although there are theoretically 10 antigen-combining
sites, only five sites are readily available to combine with Fig. 6 Diagrammatic representation of haemagglutination.

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62

sites, it acts as a monomer or monovalent antibody that

coats or sensitises a single antigen on a single cell. Sensi-
tisation is not a visible reaction, even with the use of a
microscope, and requires the addition of other agents in
order to be detected in the laboratory. The in vivo coating
of cells by IgG antibodies is a catalyst or trigger for the
activation of neutrophils and macrophages. IgG is found
in various subtypes: IgG1, IgG2, IgG3 and IgG4. All IgG
subtypes except IgG2 cross the placenta and may there-
fore be implicated in haemolytic disease of the fetus and
newborn, and all subtypes except IgG4 can activate com-
plement. Each subtype has a highly specific role to play
in the immune response.
Figure 7 is a diagrammatic representation of IgG. It
illustrates the two fragment antigen binding (Fab) por-
tions, which are responsible for the attachment to antigen
Fig. 8 Diagrammatic representation of red cell sensitization by IgG anti-
at the time of reaction, and the fragment crystallizable bodies.
portion that initiates the involvement of complement and
to which antihuman globulin is specifically directed the total immunoglobulin produced each day. It is a weak
(Fig. 8). The role of complement and of antihuman globu- opsonin and is a poor activator of complement.
lin in antigen-antibody reactions in vitro is described in
detail in Section 3: Antigen-antibody reactions. Immunoglobulin D (IgD)
IgM and IgG are of primary importance in the field of IgD is present in only minute amounts in the bloodstream
blood transfusion. A brief account of the other three and it is usually fixed to the plasma membranes of imma-
types of immunoglobulins follows: ture B lymphocytes. where it plays a role in the activation
of B cells.
Immunoglobulin A (IgA)
IgA is found mainly in mucosal secretions and in the sal- Immunoglobulin E (IgE)
iva, although it is also present in the bloodstream, partic- IgE plays a major role in allergy, allergic reactions and
ularly after immunisation. It is secreted into the intestines conditions such as asthma and anaphylaxis. It is present
in large amounts and accounts for approximately 15% of in trace amounts, even in severely allergic individuals,
comprising approximately 0.05% of the immunoglobulins
present.

General terminology of immunoglobulins

• Immunoglobulins are commonly referred to as anti-
bodies.
• Alloantibodies (sometimes called isoantibodies) or
isoagglutinins are terms used to describe antibodies
against antigens found in members of the same spe-
cies (e.g. antibodies against the red cells of humans
who are group A are found in the plasma of humans
who are group B).
• Heteroagglutinins or heterophile antibodies are
directed against different interspecies-specific anti-
gens (e.g. Forssman antigen).
• Autoantibodies or autoagglutinins describe antibod-
ies that are directed towards antigens within the
same individual (e.g.
• antibodies found in the plasma of an individual and
that react specifically with that individual’s own
cells). Table 3 outlines the general properties of IgM
Fig. 7 IgG molecule. and IgG antibodies.

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67
 Immunology 63

Table 3 General properties of IgM and IgG

Property IgM IgG

Immune response Primary Secondary

Time lapse for response Prolonged: 5–180 Rapid: 2–3 days
to antigen days
Pattern of response Antibody level rises, Antibody level
reaches a plateau increases, reaches a
and may then plateau and then
decline declines very slowly
over time
Total percentage in 5–10% 80%
bloodstream
Shape of antibody Cyclic pentamer Monomer
molecule
Antigen-combining Five (theoretically One (theoretically two)
sites 10)
Length of molecule in 300 A 120 
A
Angstrom units
Type of reaction Haemagglutination Sensitization is the
against red cells with is the typical typical result of
the corresponding result of a reaction, and is not
antigen, in saline reaction, and is usually observable
observable
Mass (measured in 900 000 Da 160 000 Da
Daltons)
Sedimentation 19S 7S
coefficient: (measured
in Svedberg units)
Complement fixation Yes Yes
Optimum reaction 2°C to 24°C 37°C
temperature
Ability to cross the No Yes
placenta
Neutralized by Yes No
dithiothreitol (DTT) or
2-mercaptoethanol (2-
ME):
Half-life: 5 days 18–23 days

chimera is an individual whose cells originate from more

Immune paralysis and immune tolerance
than one zygote. The one zygote develops into the indi-
The immune system of the host may fail to respond when vidual, whereas the other implants in the host. Although
large amounts of immunogens are presented to it. This may the implant contains different antigens, they are tolerated
be caused by the immune system being overwhelmed with by the host as ‘self’. This is a rare occurrence but aptly
immunogens, and therefore failing to act (becoming tran- describes immune tolerance.
siently or temporarily paralysed), or by the immune system Immune tolerance is also used to describe the fact that
becoming ‘confused’ by the simultaneous presence of sev- an individual does not usually produce antibodies against
eral different immunogens. The result is immune paralysis; his/ her own antigens. A breakdown in this immune tol-
there is no response, and antibodies are not developed. erance - or recognition of self - results in the production
On the other hand, immune tolerance can occur when of autoantibodies.
the host ‘tolerates’ a foreign immunogen such as a group Expected antibodies may also be absent in hypogam-
O chimera with tolerance for A antigen, lacking the maglobulinaemia (lack of immunoglobulin), after
expected anti-A antibody in the serum/plasma. A genetic transplantation, and in old age.

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64

environmental toxins such as mercury and some

Autoimmunity
pesticides. Some infections can cause immunodefi-
An autoantibody is an antibody that the body directs ciency e.g. infection with HIV impairs the individ-
against its own healthy cells. When this situation results ual’s immune response to infection by micro-
in illness, the individual is said to have an autoimmune organisms.
disease. Examples of such diseases are:
• Systemic lupus erythematosus (SLE) results in Viruses and the immune response
inflammation and tissue damage and can affect
many parts of the body. The signs and symptoms of The role of cytotoxic cells
SLE occur intermittently as episodes or ‘flares’ of ill- After a virus has infected a host it enters the target cells
ness alternating with periods of absence of disease. of the host where it can survive and replicate. Different
SLE does not target specific parts of the body but is viruses will target different cells, e.g. poliomyelitis
widespread. viruses target nerve cells and the hepatitis viruses target
• Immune thrombocytopenic purpura (ITP) targets only liver cells. When they are inside the targeted cells, the
platelets, causing thrombocytopenia. cells of the host’s immune system are unable to detect
• Autoimmune haemolytic anaemia (AIHA) is the the virus directly and employ an indirect method to
result of the body producing antibodies against its determine its presence in the cell. Molecules of the
own red cells. major histocompatibility complex (MHC) display frag-
The reason why the body starts producing autoanti- ments of the proteins made by the virus on the surface
bodies is not clearly understood, but results from a of the cell. Circulating cytotoxic T cells have specialised
loss of immunological tolerance, which is the ability proteins on their surface (called T cell receptors) which
of the immune system to ignore ‘self’ and to react enable them to recognise these viral protein fragments.
only with ‘non-self’. It may be that some individuals Following this recognition, cytotoxic factors are released
are genetically prone to do so, or it may be that the by the T cell which kill the infected cell and thus also
condition is triggered by the presence of harmful sub- the infecting virus.
stances such as viruses or toxic contaminants in the Some viruses are able to prevent the MHC molecules
environment. from displaying the viral proteins on the surface of the
infected cell, but this reduction in the number of MHC
molecules on the surface of the cell is recognised by
Immunodeficiency
another of the cells of the immune system – the NK cells.
Immunodeficiency describes a condition in which the host If an NK cell identifies a cell displaying fewer than
is unable to react effectively with and overcome harmful expected MHC molecules, it releases cytotoxic factors that
agents, such as viruses, bacteria or abnormal (tumour) kill the virally infected cell.
cells. The immune system malfunctions and the individual The cytotoxic factors are stored within granules in the
is said to be immunocompromised. This state is either cytotoxic T cells and NK cells until their release is trig-
inherited, in which case the individual is born with the gered by contact with an infected cell. The cytotoxic fac-
problem, or it is acquired as the result of some trigger. tors include those that make holes in the membrane of
Triggers are known to include viruses, immunosuppres- the infected cell and those that initiate a process called
sant drugs, malnutrition and stress. Immunodeficiency apoptosis or programmed cell death. In both examples
leads to the individual becoming vulnerable to oppor- the end result is the death of the infected cell and the
tunistic infections; those that do not normally cause dis- death of the virus.
ease in healthy individuals. Examples of why an
individual would be immunocompromised include the The role of interferons
following: Cells which are invaded by viruses are able to produce
• Inherited primary immunodeficiency is a rare state small protein molecules called interferons. These
in which the individual is unable to produce anti- interferons directly interfere with the virus’s ability to
bodies as a result of a genetic disorder/ abnormality. replicate and alert nearby cells of the presence of the
• Acquired secondary immunodeficiency may be virus. This alerting signal causes the nearby cells to
caused by a variety of factors such as drugs e.g. increase the number of MHC molecules on their
chemotherapy, as the drugs administered (in this surfaces where they are recognised by circulating T
case to control cancer) adversely affect the cells of cells. In this way the process of eliminating foreign
the immune system, malnutrition, aging and agents is accomplished.

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67
 Immunology 65

The role of antibodies escape detection by NK cells and replicate relatively

Viruses can be bound by antibodies in an infected host unhindered.
before they are able to enter the target cells. This binding
reaction neutralizes the virus and prevents it from enter-
Cancer and the Immune System
ing the target cells, activated circulating phagocytes that
promote phagocytosis and can activate the complement Introduction
system, resulting in increased phagocytosis or cell lysis Cancer cells differ from normal host cells in several ways:
(of the invading virus). • Normal cells divide and grow as part of the individ-
ual’s normal growth during childhood, or if there is
Human Immunodeficiency Virus and the immune a need to repair damaged tissue due to injury. Can-
response cer cells divide and grow when no further growth is
The human immunodeficiency virus (HIV) is a retrovirus required. The signals that halt cell replication of nor-
that is the cause of acquired immunodeficiency syndrome mal cells are ignored and the tumour increases in
(AIDS) in humans. It differs from most other viral infec- size.
tions in that the virus specifically targets some of the • Normal cells respect boundaries and do not encroach
cells of the immune system, thus inhibiting the immune on neighbouring cells or organs. Cancer cells have
response. no such respect and often invade adjacent tissue.
HIV infects T cells which carry the CD4 molecule, the This is one reason why it is sometimes difficult to
‘helper’ cells of the immune system which play an impor- remove a tumour surgically.
tant role in mobilizing the NK (natural killer) cells when • Normal cells (other than blood cells) remain in the
an infection occurs. Infection of the CD4 cells results in a positions in which they were created. For example,
decline in the number of CD4 T cells and a reduction in kidney cells do not wander off to the brain. Cancer
the level of cell-mediated immunity. The host becomes cells, by contrast, may break free from their original
progressively more susceptible to infection and to cancer. positions and float in the bloodstream to other parts
of the body. The cancer cells metastasize to create
The role of the innate immune response. Cells of the tumours in other organs.
immune system, such as macrophages, and NK cells are • Normal cells have a finite lifespan, after which they
the first line of defence against viruses, including HIV. die and are replaced by new cells. This is because
However, macrophages are one of the target cells for HIV the structure found at the end of each chromosome,
and the infected cells lose their ability to kill the invading called the telomere, becomes shorter each time a cell
viruses and present the viral antigens to the T cells in the divides, and when it becomes too short the cell dies.
usual way. This failure plays a significant role in the Cancer cells are able to restore their telomeres so
overall failure of the immune system to deal effectively that they do not shorten with each cell division, with
with HIV. the result that the cell does not die and is ‘immor-
NK cells can destroy cells that have reduced tal’.
expression of MHC molecules on their surface and in • Normal cells can become cancerous when mutations
this way, play an important part in the defence against result in the cell continuing to grow and divide
HIV. when further growth is not required; essentially their
growth is out of control. In addition, these mutations
The role of antibodies. >Antibodies against HIV are may give cancer cells the ability to invade tissues
produced after a significant delay following infection that are both nearby and also those located in dis-
(this delay in the appearance of antibodies is often tant parts of the body.
referred to as the ‘window period’). Antibodies may only • The mutations that give rise to cancer cells may be
be present at a low level during the acute phase of the inherited but are more often caused by carcinogens
infection. Neutralising antibodies that target proteins in the environment. Some individuals have a genetic
involved in the viral entry into the host’s cells play an predisposition to cancer, in that some mutations
important role in the control of HIV infection, and in already exist, making it more likely that the cells
some infected hosts delay the reduction in the number of will become cancerous. Because several mutations
CD4 lymphocytes. However, by infecting and replicating are usually required for cancer to develop, if some
within CD4 T cells, HIV is able to effectively disable one are inherited, it is more likely that cancer will occur.
of the major components of the adaptive immune The need for several mutations to take place, and the
response. Within the CD4 cells, HIV is able to fact that mutations take place over time, is one

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67
66

explanation for the fact that cancer is more common Key points
in older individuals.
• The role of the immune system is to defend the body
Types of cancer against pathogens and other foreign substances.
Broadly, cancers are named for the type of cells in which • The major components of the immune system are
the cancer first arose. the bone marrow and thymus.

• Carcinomas start in the epithelial cells that line body • The secondary lymphatic tissue includes the spleen,
cavities. tonsils, lymph vessels, lymph nodes, adenoids and liver.

• Sarcomas start in the mesenchymal cells in bones, • The liver, spleen and lymph nodes are collectively
muscles and other tissues. known as the reticuloendothelial system.

• Leukaemias and lymphomas are blood cancers that • There are two strategies for body defence; innate
affect the white cells. Leukaemia affects the bone and adaptive.
marrow and results in too many white blood cells; • Innate or natural defence does not vary, even fol-
lymphomas affect the lymph nodes and the lympho- lowing multiple exposures to the same foreign sub-
cytes. stance, whereas the adaptive response becomes
stronger with repetitive stimulation.
The role of the immune system • Adaptive immunity is seen only in vertebrates.
As has been described earlier in this Section, the immune • Immune defence is multifaceted – it has many
system works fundamentally on the principle of discrimi- options including phagocytosis, chemical agents,
nating between ‘self’ and ‘non-self’ and mounting an complement and the production of antibodies for
immune response to rid the host of the latter. This enables removing harmful agents.
the host to remove parasites and thus prevent, or at lease • Opsonins are chemicals produced by the body that
limit, infection. Non-self is identified by differences in promote phagocytosis.
biochemistry, such as the recognition of microbial carbo- • Once phagocytes are activated, they release soluble
hydrate residues on invading micro-organisms. This substances called cytokines, which regulate the
recognition triggers the events that lead to the destruction strength of the immune response.
of the pathogen. • Complement consists of a group of soluble proteins
Cancer cells, though, start out as ‘self’ and although that are present in the plasma in an inactive form
they go through many changes that may be recognised until stimulated by an antigen-antibody reaction.
by the immune system, leading to the death of the They then act in a sequential fashion, each activat-
cancerous cell, some of the less immunogenic cancerous ing the next.
cells may escape this detection. By the time a tumour is • Complement either becomes fixed to target cells that
detected, the tumour will have evaded the host’s system are then more easily subjected to phagocytosis, or
of immunosurveillance and is essentially unaffected by continues its chain reaction to its end, which results
the expected immune response. in cell lysis.
The DNA in cancer cells often directs the mutated cell • Lymphocytes are the white cells critical to adaptive
to produce abnormal molecules, called tumour antigens, immunity. T lymphocytes are responsible for cellular
on the cell membrane. These tumour antigens are recog- defence and the production of lymphokines, whereas
nised by the cells of the immune system, mainly the NK B lymphocytes are responsible for the development
cells, as non-self and the cells are destroyed. It seems of antibodies.
likely that this happens regularly even in healthy hosts. • An antigen is capable of specific combination with
However, cancer cells possess complex mechanisms antibody. It is frequently used as a synonym for
that allow them to escape recognition as non-self, and immunogen, although some antigens that react with
the immune responses that would otherwise prevent the antibodies are not capable of eliciting an immune
development of a malignant tumour. response.
Cancer can reduce the immune response by spreading • An immunogen is capable of provoking an immune
to the bone marrow, most often in leukaemia and lym- response when introduced into an immunocompetent
phoma, but also in other types of cancer. vertebrate in which it is foreign.
Cancer treatment can also weaken the immune • To be immunogenic, the substance must appear
response, in part because the number of white cells pro- foreign to the host.
duced by the bone marrow is reduced. Examples of the • A hapten is a substance with a molecular mass of
treatment most likely to have this effect are chemother- less than 10 000 Da, which when coupled with a lar-
apy and radiotherapy. ger carrier protein can become immunogenic.

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67
 Immunology 67

• During primary response, when the host encounters • In certain circumstances the body does not respond to
an immunogen for the first time, IgM antibodies are the presence of foreign immunogens, either because
formed. of immune paralysis or because of immune tolerance.
• After secondary (learned) response, most circulating • An alternative name for an antibody is an immunoglob-
antibodies are IgG. ulin. They fall into five major classes: the two of most
• An adjuvant is a substance combined with an practical importance in blood transfusion practice are
immunogen to make it more immunogenic to the IgM and IgG; the others are IgA, IgD and IgE.
host. Adjuvants are usually inert substances of a • There are many characteristics that differentiate IgM
molecular mass large enough to attract immunologi- and IgG antibodies, such as the ability to cross the
cally competent cells, which then ‘find’ the antigen placenta and activate complement.
on the surface of the adjuvant, and the process of • An autoantibody is an antibody that the body directs
antibody production starts. This tactic is sometimes against its own healthy cells, often resulting in dis-
used to increase the effectiveness of vaccination. ease.
• Active immunity signifies that the immune system • The immune system protects the host against viruses
of the host is activated, so the response will be long through the actions of cytotoxic cells, interferons
lasting. and antibodies.
• Passive immunity is the term used when the immune • Although there are several differences between nor-
system in not activated, and defence is carried out mal cells and cancer cells, normal cells can become
by the antibodies of another – such as maternal anti- cancerous following a series of mutations.
bodies crossing the placenta and protecting the new- • The immune system plays an important role in pro-
born – for only a limited period of time. tecting the host against cancer.

© 2020 The Author. Journal Compilation © 2020 Blackwell Publishing Ltd. ISBT Science Series (2020) 15, 54–67