Professional Documents
Culture Documents
J. Stewart
KEY POINTS
The cells of the immune system are divided into high-afnity receptors for the antigen are stimulated
lymphoid and myeloid lineages. The former include to divide. The expanded clones of antigen-specic cells
T lymphocytes and their subsets identied by CD are said to have resulted from clonal selection.
markers, B lymphocytes and natural killer (NK) cells. Lymphocytes are activated by antigen and the
The myeloid lineage includes the neutrophils, appropriate combination of cytokines, signalling
eosinophils and basophils as well as the monocyte/ molecules secreted by other lymphocytes and by
macrophage series and platelets. macrophages.
Innate immunity depends on physical, physiological Humoral acquired immunity leads to antigen-antibody
and chemical barriers to infection, on the response to complexes that neutralize key aspects of microbial
injury and on detection of pathogen-associated activity either directly or through the activation
molecular patterns (PAMPs) by pattern recognition of complement, opsonization and directed
receptors (PRRs). Phagocytic cells and the enzyme cytotoxicity.
cascade known as complement are key effectors Cell-mediated immunity generates cytotoxic
responding to PAMPs and components of acute T lymphocytes (CD8+), which directly kill cells
inammation. containing intracellular pathogens, and helper T cells
Acquired immunity depends on specic recognition of (CD4+), which secrete lymphokines that stimulate other
antigens either directly by antibodies on the surface of effector aspects of immunity.
B cells or through presentation of processed antigens Inherited and acquired defects in the immune system
in the context of MHC molecules by host cells to lead to immunodeciencies that make individuals more
T cells. In contrast to innate immunity, on susceptible to certain infections.
re-exposure the responses are faster, more Damage due to immune reactions may reect attempts
vigorous and more specic. to eliminate micro-organisms or self antigen-directed
Acquired immune responses are driven by the (autoimmune) reactions.
availability of antigen. As they mature, only cells with
The environment contains a vast number of poten- against infectious agents, and most potential patho-
tially infectious organisms viruses, bacteria, fungi, gens are checked before they establish an overt infec-
protozoa and worms. Any of these can cause damage tion. If these defences are breached, the acquired
if they multiply unchecked, and many could kill the immune system is called into play. Acquired immunity
host. However, the majority of infections in the produces a specic response to each infectious
normal individual are of limited duration and leave agent, and the effector mechanisms generated nor-
little permanent damage. This fortunate outcome is mally eradicate the offending material. Furthermore,
due largely to the immune system. the adaptive immune system remembers the particular
The immune system is split into two functional infectious agent and can prevent it causing disease
divisions. Innate immunity is the rst line of defence later. T1
9-1
9-2
9-3
Table 9.3 Examples of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) in innate immunity
pattern recognition receptors (PRRs) on host cells of resistance to disease caused by the micro-organism.
and circulating molecules (Table 9.3). One group of For example, although man is highly susceptible to
PRRs that are still being characterized are the Toll- the common cold, the infection is overcome within a
like receptors. Mammalian Toll-like receptors are few days. In some diseases, it may be difcult to initi-
expressed on different cell types that are components ate the infection, but once established the disease can
of the innate defences, including macrophages, den- progress rapidly, implying a lack of resistance. For
dritic cells, neutrophils, mucosal epithelial cells and example, rabies occurs in both human beings and
endothelial cells. Recognition of microbial compo- dogs but is not readily established as the virus does
nents by these receptors leads to a variety of out- not ordinarily penetrate healthy skin. Once infected,
comes, including cytokine release, inammation and however, both species are unable to overcome the
cell activation. disease. Marked variations in resistance to infection
Innate defences act as the initial response to micro- have been noted between different strains of mice, and
bial challenge and can eliminate the micro-organism it is possible to breed, by selection, rabbits of low,
from the host. However, many microbes have evolved intermediate and high resistance to experimental
strategies to overcome innate defences, and in this tuberculosis.
situation the more potent and specialized acquired
immune response is required to eliminate the patho-
Individual differences and inuence of age
gen. The innate immune system plays a critical role in
the generation of an efcient and effective acquired The role of heredity in determining resistance to infec-
immune response. Cytokines produced by the innate tion is well illustrated by studies on tuberculosis in
immune system signal that infectious agents are twins. If one homozygous twin develops tuberculosis,
present and inuence the type of acquired immune the other twin has a three in one chance of developing
response that develops. the disease, compared with a one in three chance
if the twins are heterozygous. Sometimes genetically
controlled abnormalities are an advantage to the indi-
vidual in resisting infection as, for example, in a
DETERMINANTS OF INNATE IMMUNITY
hereditary abnormality of the red blood cells (sick-
ling). These red blood cells cannot be parasitized by
Species and strains
Plasmodium falciparum, thus conferring a degree of
Marked differences exist in the susceptibility of differ- resistance to malaria in affected individuals.
ent species to infective agents. The rat is strikingly Infectious diseases are often more severe in early
resistant to diphtheria, whereas the guinea-pig and childhood and in young animals; this higher suscepti-
man are highly susceptible. The rabbit is particularly bility of the young appears to be associated with
susceptible to myxomatosis, and human beings to immaturity of the immunological mechanisms affect-
syphilis, leprosy and meningococcal meningitis. Sus- ing the ability of the lymphoid system to deal with and
T1 ceptibility to an infection does not always imply a lack react to foreign antigens. This is also the time when
9-4
infectious agents are encountered for the rst time In conditions where the skin is damaged, such as
(primary exposure), and a memory-acquired immune in patients with burns and after traumatic injury
response cannot be called upon to aid elimination. In or surgery, infection can be a serious problem. The
certain viral infections (e.g. polio and chickenpox), skin is a resistant barrier because of its outer horny
the clinical illness is more severe in adults than in layer consisting mainly of keratin, which is indigest-
children. This may be due to a more active immune ible by most micro-organisms, and thus shields the
response producing greater tissue damage. In the living cells of the epidermis from micro-organisms
elderly, besides a general waning of the activities and their toxins. The relatively dry condition of
of the immune system, physical abnormalities (e.g. the skin and the high concentration of salt in
prostatic enlargement leading to stasis of urine) or drying sweat are inhibitory or lethal to many
long-term exposure to environmental factors (e.g. microorganisms.
smoking) are common causes of increased susceptibil- The sebaceous secretions and sweat of the skin
ity to infection. contain bactericidal and fungicidal fatty acids, which
constitute an effective protective mechanism against
many potential pathogens. The protective ability of
Hormonal inuences and sex these secretions varies at different stages of life, and
There is decreased resistance to infection in those with some fungal ringworm infections of children disap-
diseases such as diabetes mellitus, hypothyroidism pear at puberty with the marked increase of sebaceous
and adrenal dysfunction. The reasons for this decrease secretions.
have not yet been claried but may be related to The sticky mucus covering the respiratory tract acts
enzyme or hormone activities. It is known that gluco- as a trapping mechanism for inhaled particles. The
corticoids are anti-inammatory agents, decreasing action of cilia sweeps the secretions, containing the
the ability of phagocytes to ingest material. They foreign material, towards the oropharynx so that they
also have benecial effects by interfering in some way are swallowed; in the stomach the acidic secretions
with the toxic effects of bacterial products such as destroy most of the micro-organisms present. Nasal
endotoxins. secretions and saliva contain mucopolysaccharides
There are no marked differences in susceptibility to capable of blocking some viruses.
infections between the sexes. Although the overall The washing action of tears and ushing of urine
incidence and death rate from infectious disease are are effective in stopping invasion by micro-organisms.
greater in males than in females, both infectious hepa- The commensal micro-organisms that make up the
titis and whooping cough have a higher morbidity and natural bacterial ora covering epithelial surfaces are
mortality in females. protective in a number of ways:
Their very presence uses up a niche that cannot be
Nutritional factors used by a pathogen.
They compete for nutrients.
The adverse effects of poor nutrition on susceptibility They produce byproducts that can inhibit the
to certain infectious agents are not now seriously growth of other organisms.
questioned. Experimental evidence in animals has
shown repeatedly that inadequate diet may be corre- It is important not to disturb the relationship between
lated with increased susceptibility to a variety of bac- the host and its indigenous ora.
terial diseases, associated with decreased phagocytic Commensal organisms from the gut or bacteria
activity and leucopenia. In the case of viruses, which normally present on the skin can cause problems if
are intracellular parasites, malnutrition may have an they gain access to an area that they do not normally
effect on virus production, but the usual outcome is populate. An example of this is urinary tract infec-
enhanced disease as a result of impaired immune tion resulting from the introduction of Escherichia
responses, especially the cytotoxic responses. coli, a gut commensal, by means of a urinary cathe-
ter. Some commensal organisms possessing low
virulence (see p. ) that are provided with the 2
circumstances by which to cause infections may
MECHANISMS OF INNATE IMMUNITY
be referred to as opportunistic pathogens. Infections
with these opportunists are quite widespread, often
Mechanical barriers and surface secretions
appearing as a result of medical or surgical treatment
The intact skin and mucous membranes of the body that breaches the innate defences or reduces the
afford a high degree of protection against pathogens. hosts ability to respond. T1
9-5
9-6
CLASSICAL ALTERNATIVE
C4 C3
C4a C3a
C1q
C1r + I.C. C4b C3b
C1s Activator
surface
C2 B
D
C2b Ba
C3
C3
convertase C4b2a C3bBb
C3a
C3b
Amplification
loop
C3 C4b2a3b C3bBb3b
convertase
C5
C5a
C5b
C6
C7
C5b67
C8
C9
Membrane attack
C5b6789 complex
Fig. 9.2 Complement activation: classical and alternative pathways. Enzymatic reactions are indicated by thick arrows. I.C., immune complex.
of C1 to its ligand: immune complexes containing IgG C4 to produce C4a and a reactive C4b (Fig. 9.2). C4a
or IgM and certain micro-organisms and their prod- is released and some of the C4b becomes attached to
ucts. This causes a conformational change in the C1 a surface. C2 binds to the surface-bound C4b, becomes
complex that leads to the auto-activation of C1r. The a substrate for the activated C1 complex, and is split
enzyme C1r then converts C1s into an active serine into C2a and C2b. The C2b is released, leaving C4b2a
esterase that acts on the thioester-containing molecule the classical pathway C3 convertase. This active T1
9-7
enzyme then generates C3a and the unstable C3b convertase will lead to more C3b deposition. Immune
from C3. A small amount of the C3b generated binds complexes composed of certain immunoglobulins
to the activating surface and acts as a focus for further (e.g. IgA and IgE) also function as protected sites
complement activation. Activation of the classical for C3b and activate complement by the alternative
pathway is regulated by C1 inhibitor and by a number pathway. Poor activation surfaces are made more sus-
of molecules that limit the production of the C3 ceptible to deposition by the presence of antibody that
convertase. generates C3b by the classical pathway.
The so-called lectin pathway is initiated by mannose-
binding lectin (a secreted PRR) attaching to the
Membrane attack complex
surface of a micro-organism. This leads to the produc-
tion of C4b2a and the generation of C3b on the acti- The next step after the formation of C3b is the cleav-
vating surface. age of C5 (Fig. 9.3). The C5 convertases are gener-
ated from C4b2a of the classical pathway and C3bBb
of the alternative pathway by the addition of another
Alternative pathway
C3b molecule. These membrane-bound trimolecular
Intrinsically, C3 undergoes a low level of hydrolysis complexes selectively bind C5 and cleave it to give
of an internal thioester bond to generate C3b. This uid-phase C5a and membrane-bound C5b. The for-
molecule complexes, in the presence of Mg2+ ions, with mation of the rest of the membrane attack complex
factor B, which is then acted on by factor D to produce is non-enzymatic. C6 binds to C5b, and this joint
C3bBb. This is a C3 convertase, which is capable of complex is released from the C5 convertase. The for-
splitting more C3 to C3b, some of which will become mation of C5b67 generates a hydrophobic complex
membrane bound. that inserts into the lipid bilayer in the vicinity of the
The initial binding of C3b generated by either the initial activation site. Usually this is on the same cell
classical or the alternative pathway leads to an ampli- surface as the initial trigger, but occasionally other
cation loop that results in the binding of many more cells may be involved. Therefore bystander lysis
C3b molecules to the same surface. Factor B binds to can take place, giving rise to damage to surrounding
the surface-bound C3b to form C3bB, the substrate tissue. There are a number of proteins present in body
for factor D a serine esterase which is present in uids to limit this potentially dangerous process by
very low concentrations in an already active form. binding to uid-phase C5b67. C8 and C9 bind to the
The cleavage of factor B results in the formation of membrane-inserted complex in sequence, resulting in
the C3 convertase, C3bBb, which dissociates rapidly the formation of a lytic polymeric complex containing
unless it is stabilized by the binding of properdin (P), up to 20 C9 monomers. A small amount of lysis can
forming the complex C3bBbP. This convertase can occur when C8 binds to C5b67, but it is the poly-
cleave many more C3 molecules, some of which merized C9 that causes the most damage.
become surface bound. This amplication loop is a
positive feedback system that will cycle until all the
Functions
C3 is used up unless it is regulated carefully.
The activation of complement by either pathway gives
rise to C3b and the generation of a number of factors
Regulation
that can aid in the elimination of foreign material.
The nature of the surface to which the C3b is bound The complete insertion of the membrane attack
regulates the outcome. Self cell membranes contain complex into a cell will lead to membrane damage
a number of regulatory molecules that promote the and lysis, probably by osmotic swelling. Some thin-
binding of factor H rather than factor B to C3b. This walled pathogens, such as trypanosomes and malaria
results in the inhibition of the activation process. On parasites, are killed by complement-mediated lysis.
non-self structures the C3b is protected, as regulatory Some Gram-negative bacteria can be killed by com-
proteins are not present, and factor B has a higher plement in conjunction with lysozyme. However,
afnity for C3b than factor H at these sites. complement-mediated lysis is of limited impor tance
Thus the surface of many micro-organisms can sta- as a bactericidal mechanism compared with phago-
bilize the C3bBb by protecting it from factor H. In cyte destruction of bacteria. Inherited deciencies of
addition, another molecule, properdin, stabilizes the the terminal components are associated with infection
complex. The deposition of a few molecules of C3b by gonococci and meningococci, which can survive
on to these surfaces is followed by the formation inside neutrophils and for which complement-
T1 of the relatively stable C3bBbP complex. This C3 mediated killing is important.
9-8
C5
C8
C5a
C7
C6
C5b C9
C3b C6 C5b
C8 C8
Phagocytic cells have receptors for certain comple- The essential features of these cells are that they:
ment components that facilitate the adherence of
are actively phagocytic
complement-coated particles. Therefore, complement
contain digestive enzymes to degrade ingested
is an opsonin, and in certain circumstances this attach-
material
ment may lead to phagocytosis.
are an important link between the innate and
Two of the molecules released during the comple-
acquired immune mechanisms.
ment cascade, C3a and C5a, have potent biological
activities. These molecules, known as anaphylatoxins, Part of their role in regard to acquired immunity
trigger mast cells and basophils to release mediators is that they can process and present antigens, and
of inammation (see below). They also stimulate neu- produce molecules that stimulate lymphocyte differ-
trophils to produce reactive oxygen intermediates, entiation into effector cells.
whereas C5a on its own is a chemo-attractant and acts The role of the phagocyte in innate immunity is to
directly on vascular endothelium to cause vasodilata- engulf particles (phagocytosis) or soluble material
tion and increased vascular permeability. (pinocytosis), and digest them intracellularly within
specialized vacuoles. The macrophages present in the
walls of capillaries and vascular sinuses in spleen,
Cells liver, lungs and bone marrow serve an important role
in clearing the bloodstream of foreign particulate
Phagocytes material such as bacteria. So efcient is this process
Micro-organisms entering the tissue uids or blood- that the repeated nding, generally by sensitive broth
stream are rapidly engulfed by neutrophils and mono- culture, of a few bacteria or yeasts in the bloodstream
nuclear phagocytes. In the blood the latter are known usually indicates that there is a continuing release of
as monocytes, whereas in the tissues they differentiate micro-organisms from an active focus such as an
into macrophages. In connective tissue they are known abscess or the heart valve vegetations found in bacte-
as histiocytes, in kidney as mesangial cells, in liver as rial endocarditis.
Kupffer cells, in bone as osteoclasts, in brain as micro- The ability of macrophages to ingest and destroy
glia, and in the spleen, lymph node and thymus as the micro-organisms can be impaired or enhanced by
sinus-lining macrophages. depression or stimulation of the phagocyte system. T1
9-9
Chemotaxis Binding
For phagocytic cells to be effective, they must be
attracted to the site of infection. Once they have
passed through the capillary walls they move through
the tissues in response to a concentration gradient of
molecules produced at the site of damage. These Ingestion
chemotactic factors include:
products of injured tissue
factors from the blood (C5a)
substances produced by neutrophils and mast cells
(leukotrienes and histamine)
bacterial products (formyl-methionine peptides). Phagolysosome
Neutrophils respond rst and move faster than
monocytes. Digestion
9-10
Within phagocytes there are several oxygen- the immune system. Natural killing is present without
independent mechanisms that can destroy ingested previous exposure to the infectious agent and shows
material. Some of these enzymes can damage mem- all the characteristics of an innate defence mechanism.
branes. For example, lysozyme and elastase attack NK cells have also been implicated in host defence
peptidoglycan of the bacterial cell wall, and then against cancers by a mechanism similar to that used
hydrolases are responsible for the complete digestion to combat virus infection. Natural killing is enhanced
of the killed organism. The cationic proteins of lyso- by interferons that appear to stimulate the production
somes bind to and damage bacterial cell walls and of NK cells and also increase the rate at which they
enveloped viruses, such as herpes simplex virus. The kill the target cells.
iron-binding protein lactoferrin has antimicrobial
properties. It complexes with iron, rendering it una-
vailable to bacteria that require iron for growth. The Eosinophils
high acidity within phagolysosomes (pH 3.54.0) may Eosinophils are granulocytes with a characteristic
have bactericidal effects, probably resulting from bi-lobed nucleus and cytoplasmic granules. They are
lactic acid production in glycolysis. In addition, many present in the blood of normal individuals at very low
lysosomal enzymes, such as acid hydrolases, have acid levels (<1%), but their numbers increase in patients
pH optima. There are signicant differences between with parasitic infections and allergies. They are not
macrophages and neutrophils in the killing of micro- efcient phagocytic cells, although their granules
organisms. Although macrophage lysosomes contain contain molecules that are toxic to parasites. Large
a variety of enzymes, including lysozyme, they lack parasites such as helminths cannot be internalized by
cationic proteins and lactoferrin. Tissue macrophages phagocytes and therefore must be killed extracellu-
do not have myeloperoxidase but probably use cata- larly. Eosinophil granules contain an array of enzymes
lase to generate the hydrogen peroxide system. Normal and toxic molecules active against parasitic worms.
macrophages are less efcient killers of certain patho- The release of these molecules must be controlled so
gens, such as fungi, than neutrophils. The microbi- that tissue damage is avoided. The eosinophils have
cidal activity of macrophages can, however, be greatly specic receptors, including Fc and complement
improved after contact with products of lymphocytes, receptors, that bind the labelled target (i.e. antibody
known as lymphokines. or complement-coated parasites). The granule con-
Once killed, most micro-organisms are digested and tents are then released into the space between the cell
solubilized by lysosomal enzymes. The degradation and the parasite, thus targeting the toxic molecules
products are then released to the exterior. onto the parasite membrane.
9-11
Leukotrienes Neutrophils, mast cells, basophils Vasodilatation, increased vascular permeability, contraction of
smooth muscle, induction of cell adherence and chemotaxis
Complement components Plasma Cause mast cells to release inammatory mediators; C5a is a
(e.g. C3a, C5a) chemotactic factor
a
In rodents, 5-hydroxytryptamine (serotonin) is present in mast cells and basophils.
cellular events that occur during an inammatory The same molecules, vasoactive amines, prostag-
reaction are: landins and kinins, increase vascular permeability,
allowing plasma and plasma proteins to traverse
vasodilatation
the endothelial lining. The plasma proteins include
increased vascular permeability
immunoglobulins and molecules of the clotting and
cellular inltration.
complement cascades. This leaking of uid causes
These changes are brought about mainly by chemical swelling (oedema), which in turn leads to increased
mediators (Table 9.4), which are widely distributed in tissue tension and pain. Some of the molecules them-
a sequestered or inactive form throughout the body selves, for example prostaglandins and histamine,
and are released or activated locally at the site of stimulate the pain responses directly. The inamma-
inammation. After release they tend to be inacti- tory exudate has several important functions. Bacteria
vated rapidly, to ensure control of the inammatory often produce tissue-damaging toxins that are diluted
process. by the exudate. The presence of clotting factors results
There is increased blood supply to the affected area in the deposition of brin, creating a physical obstruc-
owing to the action of vasoactive amines, such as tion to the spread of bacteria. The exudate is drained
histamine and 5-hydroxytryptamine, and other medi- continuously by the lymphatic vessels, and antigens,
ators stored within mast cells. These molecules are such as bacteria and their toxins, are carried to the
released: draining lymph node where immune responses can be
generated.
as a consequence of the production of the
The production of chemotactic factors, including
anaphylatoxins (C3a and C5a) that trigger specic
C5a, histamine, leukotrienes and molecules specic
receptors on mast cells
for certain cell types, attracts phagocytic cells to the
following interaction of antigen with IgE on the
site. The increased vascular permeability allows easier
surface of mast cells
access for neutrophils and monocytes, and the vasodil-
by direct physical damage to the cells.
atation means that more cells are in the vicinity. The
Other mediators, such as bradykinins and pro- neutrophils arrive rst and begin to destroy or remove
staglandins, are produced locally or released by plate- the offending agent. Most are successful but a few die,
lets. The vasodilatation causes increased blood supply releasing their tissue-damaging contents to increase
to the area, giving rise to redness and heat. The result the inammatory process. Mononuclear phagocytes
is an increased supply of the molecules and cells that arrive on the scene to nish off the removal of the
T1 can combat the agent responsible for the initial trigger. residual debris and stimulate tissue repair.
9-12
When the swelling is severe there may be loss of Actively acquired immunity is long lasting, although
function to the affected area. If the offending agent it may be circumvented by antigenic change in the
is quickly removed, the tissue will soon be repaired. infecting micro-organism. Passively acquired immu-
The inammatory process continues until the nity provides only temporary protection. Passive
conditions responsible for its initiation have been immunity may be transferred to the fetus by the
resolved. In most circumstances this occurs fairly passage of maternal antibodies across the placenta.
rapidly, with an acute inammatory reaction lasting
for a matter of hours or days. If, however, the causa-
tive agent is not easily removed or is reintroduced TISSUES INVOLVED IN IMMUNE REACTIONS
continuously, chronic inammation will ensue with
the possibility of tissue destruction and complete loss For the generation of an immune response, antigen
of function. must interact with and activate a number of different
cells. In addition, these cells must interact with one
another. The cells involved in immune responses are
ACQUIRED IMMUNITY organized into tissues and organs in order that these
complex cellular interactions can occur most effec-
Micro-organisms that overcome or circumvent the tively. These structures are collectively referred to as
innate non-specic defence mechanisms or are admin- the lymphoid system, which comprises lymphocytes,
istered deliberately (i.e. active immunization) come up epithelial and stromal cells arranged into discrete
against the hosts second line of defence: acquired capsulated organs or accumulations of diffuse lym-
immunity. To give expression to this acquired form phoid tissue. Lymphoid organs contain lymphocytes
of immunity it is necessary that the antigens of the at various stages of development and are classied
invading microorganism come into contact with cells into primary and secondary lymphoid organs.
of the immune system (macrophages and lymphocytes) The primary lymphoid organs are the major sites
and thereby initiate an immune response specic for of lymphopoiesis. Here, lymphoid progenitor cells
the foreign material. The cells that respond are pre- develop into mature lymphocytes by a process of
committed, because of their surface receptors, to proliferation and differentiation. In mammals, T lym-
respond to a particular epitope on the antigen. This phocytes develop in the thymus, and B lymphocytes
response takes two forms, humoral and cell mediated, in the bone marrow and fetal liver. It is within the
which usually develop in parallel. The part played by primary lymphoid organs that the lymphocytes
each depends on a number of factors, including the acquire their repertoire of specic antigen receptors in
nature of the antigen, the route of entry and the indi- order to cope with the antigenic challenges that the
vidual who is infected. individual receives during its life. It is also within these
Humoral immunity depends on the appearance in tissues that self-reactive lymphocytes are eliminated
the blood of antibodies produced by plasma cells. to protect against autoimmune disease.
The term cell-mediated immunity was originally The secondary lymphoid organs create the environ-
coined to describe localized reactions to organisms ment in which lymphocytes can interact with one
mediated by T lymphocytes and phagocytes rather another and with antigen, and then disseminate the
than by antibody. It is now used to describe any effector cells and molecules generated. Secondary
response in which antibody plays a subordinate role. lymphoid organs include lymph nodes, spleen and
Cell-mediated immunity depends mainly on the devel- mucosa-associated lymphoid tissue (e.g. tonsils and
opment of T cells that are specically responsive to Peyers patches of the gut). These organs have a char-
the inducing agent, and is generally active against acteristic structure that relates to the function they
intracellular organisms. carry out, with areas composed of mainly B cells or
Specic immunity may be acquired in two main T cells.
ways:
1. induced by overt clinical infection or inapparent
DEVELOPMENT OF THE IMMUNE SYSTEM
clinical infection
2. deliberate articial immunization.
In man, lymphoid tissue appears rst in the thymus at
This is active acquired immunity, and contrasts with about 8 weeks of gestation. Peyers patches are distin-
passive acquired immunity, which is the transfer of guishable by the fth month, and immunoglobulin-
preformed antibodies to a non-immune individual by secreting cells appear in the spleen and lymph nodes at
means of blood, serum components or lymphoid cells. about 20 weeks. From this time onwards, IgM and T1
9-13
16 Thoracic
15 duct
Internal Splenic
14 jugular vein vein
13 Birth
12
IgG Splenic
11 artery
Efferent
10 lymphatics
Antibody level (mg/ml)
9
8
Spleen
7
6 Capillaries
5
4
Tissue spaces
3 IgA
2 MALT
1 IgM
Lymph
node Afferent
Adult
0 2 4 6 80 2 4 6 8 10 12 level lymphatics
Time (months)
Fig. 9.6 Lymphocyte recirculation. MALT, mucosa-associated lymphoid
Maternal IgG tissue.
Infant IgG
IgM mature there before proceeding via the circulation
IgA to the secondary lymphoid organs. T cell precursors
leave the bone marrow and mature in the thymus
Fig. 9.5 Immunoglobulin levels in the fetus and neonate. Adult levels before migrating to the secondary lymphoid organs.
of the major isotypes are shown as normal ranges with mean serum
Once in the secondary lymphoid tissues, the lym-
levels.
phocytes do not remain there but move from one
lymphoid organ to another through the blood and
IgD are synthesized by the fetus (Fig. 9.5). At birth the lymphatics (Fig. 9.6). One of the main advantages of
infant has a blood concentration of IgG comparable this lymphocyte recirculation is that during the course
to that of the maternal circulation, having received of a natural infection the continual trafcking of lym-
IgG but not IgM via the placenta. The rate of synthesis phocytes enables many different lymphocytes to have
of IgM in the infant increases rapidly within the rst access to the antigen.
few days of life but does not reach adult levels until Only a very small number of the lymphocytes will
about a year. Serum IgG does not reach adult levels recognize a particular antigen. Pathogens can enter
until after the second year, and IgA takes even longer. the body by many routes, but must be carried from
There is an actual drop in the level of IgG from birth the site of infection to the secondary lymphoid tissues
due to the decay of maternal antibody, with the lowest where they are localized and concentrated on the
levels of total IgG at around 3 months of age. This dendritic processes of macrophages or on the surface
corresponds to an age of marked susceptibility to a of antigen-presenting cells. If the infection is in the
number of infections. Cell-mediated immunity can be tissues, antigen is carried in the lymphatics to the
stimulated at birth, but these reactions may not be as draining lymph node. Under normal conditions there
powerful as in the adult. is a continuous active ow of lymphocytes through
lymph nodes, but when antigen and antigen-reactive
cells enter there is a temporary shut-down of the exit.
LYMPHOCYTE TRAFFICKING Thus, antigen-specic cells are preferentially retained
in the node draining the source of the antigen. This is
Lymphocytes differentiate and mature in the primary partly responsible for the swollen glands (lymph
lymphoid organs and then enter the blood lymphocyte nodes) that can sometimes be found during an infec-
T1 pool. B cells are produced in the bone marrow and tion. Microbes present on mucosal surfaces are taken
9-14
up by specialized cells known as M cells, and are then there is no reason why some could not recognize self
delivered to the mucosa-associated lymphoid tissues molecules. An obviously important attribute of the
such as the tonsils and Peyers patches. Blood-borne immune system is that it is able to discriminate
antigens are trapped in the spleen. The passage of between self and non-self . During development,
lymphocytes through an area where antigen has been any lymphocyte with a receptor that binds strongly to
localized facilitates the induction of an immune self molecules is eliminated.
response. Lymphocytes with appropriate receptors
bind to the antigen and become activated. Once acti-
vated, the lymphocytes mature into effector cells. In
CELLULAR ACTIVATION
the case of B lymphocytes they become plasma cells
and secrete antibody. T lymphocytes leave the second-
When an individual is exposed to foreign material,
ary lymphoid tissue and return to the site of infection
selected lymphocytes respond. B lymphocytes pro-
to destroy the infectious agent.
liferate and differentiate into antibody-producing
There is evidence for non-random migration of
plasma cells and memory cells. T lymphocytes are
lympho cytes to particular lymphoid compartments.
stimulated to become effector cells that can directly
For example, lymphocytes that home to the gut are
eliminate the foreign material or produce molecules
selectively transported across endothelial cells of
that help other cells to destroy the pathogen. The
venules in the intestine. It appears that lymphocytes
type (immunity or tolerance) and magnitude of the
have specic molecules on their surface that pre-
response, if generated, depends on a number of
ferentially interact with endothelial cells in different
factors, including the nature, dose and route of entry
anatomical sites. A lymphocyte that was initially stim-
of the antigen, and the individuals genetic make-up
ulated by antigen in a Peyers patch will migrate to
and previous exposure to the antigen.
the draining lymph node, respond, and memory cells
The rst stage in the production of effector cells
will be produced. It is important that these memory
and molecules is activation of the resting cells. This
cells migrate back to the area where the same patho-
involves various cellular interactions with maturation
gen might be encountered again. Therefore, they are
of the response, leading to a co-ordinated, efcient
found preferentially in the mucosa-associated lym-
production of effector T cells, immunoglobulin and
phoid tissue.
memory cells.
Cross-linking of the B cell antigen receptor, surface
immunoglobulin, is the initial trigger for activation.
CLONAL SELECTION
When this happens, a number of biochemical changes
are instigated. These changes probably act through
During their development in the primary lymphoid
protein kinases that cause the synthesis of RNA and
tissues both T and B lymphocytes acquire specic cell
ultimately immunoglobulin production. In some cases
surface receptors that commit them to a single anti-
this is all that is required to stimulate antibody pro-
genic specicity. For T cells this receptor remains the
duction. However, for the majority of antigens this
same for its life, but the surface immunoglobulin on
initial cross-linking is not enough, and molecules
B cells can be modied as a result of somatic muta-
produced by T cells are also required.
tions. In the B cell this is mirrored in the modication
of the antibody produced by the cell on exposure to
its specic antigen. The lymphocytes are activated
Thymus-independent antigens
when they bind specic antigen and then proliferate,
differentiate and mature into effector cells. A number of antigens will stimulate specic immu-
The lymphocytes reactive to any particular antigen noglobulin production directly. These T-independent
are only a small proportion of the total pool. There- antigens are of two types: mitogens and certain large
fore, antigen binds to the small number of cells that molecules.
can recognize it and selects them to proliferate and Mitogens are substances that cause cells, particu-
mature so that sufcient cells are formed to mount an larly lymphocytes, to undergo cell division (i.e. prolif-
adequate immune response. A cell that responds to an eration). Certain glycoproteins, called lectins, have
antigenic trigger and proliferates will give rise to cells mitogenic activity. These molecules have specicity
with a genetically identical makeup (i.e. clones). This for sugars; they bind to the cell surface and activate
phenomenon is therefore known as clonal selection. all responsive cells. The response to the mitogens
Lymphocyte receptors, generated in the primary is therefore polyclonal, as lymphocytes of many
lymphoid tissues, are created in a random fashion, so different specicities are activated. However, at low T1
9-15
concentrations these mitogens do not cause poly- Antigen processing and presentation
clonal activation but can lead to the stimulation of
specic B cells. Lipopolysaccharide is an example of The development of an antibody response to a T-
a B cell mitogen. dependent antigen requires that the antigen becomes
Some large molecules with regularly repeating associated with MHC class II molecules (i.e. proc-
epitopes, for instance polymers of D-amino acids and essed) and expressed on the cell surface (i.e. presented)
simple sugars such as pneumococcal polysaccharide in a form that helper T cells can recognize.
and dextran, can interact directly with the B cell All cells express MHC class I molecules, but class
surface immunoglobulin. They may also be held on II molecules are conned to cells of the immune
the surface of specialized macrophages in secondary system the antigen-presenting cells. These cells
lymphoid tissues, and the B cells interact with them present antigen to MHC class II-restricted T cells (the
there. The multiple repeats of the epitope interact with CD4-positive [CD4+] population) and therefore play
a large number of surface immunoglobulin molecules; a key role in the induction and development of
the signal that is generated is sufcient to stimulate immune responses. Within lymph nodes, different
antibody production. antigen-presenting cells are found in each of the main
The immune response generated to these antigens areas (Table 9.5).
tends to be similar on each exposure, that is, IgM is There are a large number of antigen-presenting cells
the main antibody and the response shows little in the body, most of which constitutively express
memory. This suggests that class switch and memory MHC class II molecules. Other cells, such as T lym-
production require additional factors (products of phocytes and endothelium, can be induced to express
T lymphocytes). MHC class II molecules by suitable stimuli such as
lymphokines. The relative importance of each type
depends on whether a primary or secondary response
is being stimulated and on the location. The most
Thymusdependent antigens studied antigen-presenting cells are the macrophages
Many antigens do not stimulate antibody production and dendritic cells. However, it is now apparent that
without the help of T lymphocytes. These antigens in certain situations B cells may be important antigen-
rst bind to the B cell, which must then be exposed to presenting cells. The relative importance of B cells
T cell-derived lymphokines (helper factors) before becomes greatest during secondary responses, espe-
antibody can be produced. For the second activation cially when the antigen concentration is low. Here the
signal (i.e. help) to be targeted effectively at the B B cells can specically engulf antigen via their surface
cell, the T and B cells must be in direct contact. For immunoglobulin. In a primary response, specic B
this to happen, the B and T cell epitopes must be cells are at a low frequency and their receptors are of
linked physically. However, T cells only recognize low afnity; in this situation macrophages and den-
antigen that has been processed and presented in dritic cells are probably most important.
association with products of the major histocompat- The key feature of all antigen-presenting cells is
ibility complex (MHC), so it is impossible for native that they can ingest antigen, degrade it and present it,
antigen to form a bridge between surface immu- in the context of MHC class II molecules, to T cells.
noglobulin and the T cell receptor. The B cell binds The antigen is taken into the antigen-presenting
to its epitope on free antigen, but there is no site on cells and enters the endocytic pathway. Before it is
this molecule to which the T cell can bind, because it destroyed completely, peptide fragments are taken to
requires antigen associated with MHC products. The a structure called the compartment for peptide loading.
answer to this problem can be seen when the require- MHC class II molecules are synthesized within the
ments for antigen presentation in T cell recognition endoplasmic reticulum and are also transported to
T1 are considered. the compartment for peptide loading, where they
9-16
associate with the processed antigen. The MHC class products to control the antibody class, afnity and
II molecule with the bound peptide is then transported memory. The rst cells to be activated are CD4+ T
to the cell surface. cells that recognize the antigen in association with
MHC class II molecules (see above). These cells
T cell activation respond to the signal of the antigen fragmentMHC
complex, and produce a variety of lymphokines that
The activation of resting CD4+ T cells requires two
act on B cells.
signals. The rst is antigen in association with MHC
As far as B cell development is concerned, the
class II molecules, and the second is the co-stimulatory
antigen-stimulated cells develop under the inuence
signal. The generation of the rst of these signals
of IL-4 (previously known as B cell stimulation
has just been discussed (i.e. antigen presentation).
factor), which is produced by closely adherent T
The second signal is delivered by the same antigen-
cells. IL-5 and IL-6 then bring the cells to a state
presenting cell that gave the rst signal. The co-
of full activation with terminal differentiation into
stimulatory signal is mediated by the interaction of a
an immunoglobulin-producing plasma cell. All this
molecule on the antigen-presenting cell engaging with
happens within a germinal centre of a lymph node
its receptor on the T cell. The best characterized
secondary follicle that has evolved to facilitate the
pairing is B7 on the antigen-presenting cell and CD28
necessary cellular and molecular interactions.
on the T cell.
Therefore, for both B and T cell activation, two
When both of these signals are generated, biochem-
stimuli are required:
ical changes occur within the T cell, leading to RNA
and protein synthesis. The responsive cells progress 1. The recognition of antigen makes sure that only
through the cell cycle from the G0 to the G1 phase. those cells that will be effective against the
The cells start to express IL-2 receptors and produce foreign material are recruited.
IL-2, a T cell growth factor that causes the expansion 2. The provision of the co-stimulatory signal has
of the responsive T cell population. IL-2 was origi- evolved to control the process and aid
nally thought to be the only T cell growth factor, but discrimination of self and non-self .
it is now known that IL-4 and IL-1 can support T cell
growth, although they are not as potent. After about
2 days, IL-2 synthesis stops, whereas IL-2 receptors HUMORAL IMMUNITY
remain for up to a week if the cell is not reactivated.
Therefore, there is a built-in limitation on T cell Synthesis of antibody
growth and clonal expansion. When stimulated, T
On exposure to antigen, antibody production follows
cells secrete IL-2, which interacts with IL-2 receptors
a characteristic pattern (Fig. 9.7). There is a lag phase
to mediate growth. This can be in an autocrine
during which antibody cannot be detected. This is the
fashion if the same cell that released the IL-2 is stimu-
time taken for the interactions described above to take
lated. If the responding cell is in the vicinity of the
place and for antibody to reach a level that can be
producer, the stimulation is in a paracrine manner.
measured. There is then an exponential rise in the
IL-2 is not present at detectable levels in the blood;
antibody level or titre. This log phase is followed by
therefore no endocrine activity is involved (i.e. action
at a distant site). The end-result is the production of
a large number of activated CD4+ T lymphocytes.
The other main type of T lymphocyte is the CD8+
T cell. Antigen recognition by these cells is restricted Plateau
by MHC class I molecules. Again, these cells require Log Decline
two signals to be activated: (1) antigen fragment in
association with MHC class I and (2) the co-stimulatory
Antibody titre
B cell activation
Time
Mitogens and T-independent antigens have an inher-
Antigen
ent ability to drive B cells into division and differentia-
tion. T-dependent responses rely on T cells and their Fig. 9.7 Pattern of antibody production following antigen exposure.
T1
9-17
9-18
9-19
9-20
Table 9.6 Examples of some cytokines that are of importance in the immune system
IFN- T lymphocytes (TH1 and Tc) Leucocytes and tissue cells Macrophage activation
NK cells Induction of MHC class I and II
Antibody class switch
Antiviral effect
GM-CSF T lymphocytes Immature and committed progenitor Stimulates growth and differentiation of
Macrophages cells in bone marrow myelomonocytic cells
Endothelial cells Macrophage activation
Fibroblasts
Many of the molecules detailed above act synergistically to produce their biological effects.
GM-CSF, granulocytemacrophage colony-stimulating factor; IL, interleukin; IFN, interferon; MHC, major histocompatibility complex; NK, natural
killer; TNF, tumour necrosis factor.
characteristics; they are heterogeneous and have dif- CD4+ T cells secrete the lymphokines that activate
ferent activation requirements. macrophages. Therefore, the presentation of antigen
-Interferon is a powerful macrophage-activating by an antigen-presenting cell leads to the production
molecule that increases the uptake of antigens by of lymphokines by TH1 cells specic for the antigen
an enhanced expression of Fc and complement recep- involved. The lymphokines produced then activate
tors; the activities of intracellular enzymes involved any responsive macrophage in the vicinity of the
in killing are also raised. As -interferon causes an responding cells. The activation process appears to
increase in MHC class II expression, there will be depend on the presence of a number of lymphokines
an enhanced presentation of antigen to CD4+ T cells. that act synergistically to induce activation. For
This leads to the production of more lymphokines and example, pure IL-2, IL-4 or -interferon is unable to
more effective elimination of the offending material. induce resistance to infection, but if -interferon is T1
9-21
INFLAMMATION
Pyrogens TISSUE REPAIR
Prostaglandins MACROPHAGE Enzymes and
Complement components growth factors
Clotting factors
combined with any of the others then resistance is be able to process the antigen. MHC class I- and class
observed. II-restricted recognition by CD8+ and CD4+ T cells
Macrophages and monocytes themselves are requires antigen processing. The pathways that lead
capable of producing a number of important cytokines. to association of an antigen fragment with a particular
These monokines include: restriction element are not fully understood.
Immune responses are generated in secondary lym-
IL-1
phoid tissues, such as lymph nodes. As a number of
IL-6
cells and molecules must all interact, the architecture
various colony-stimulating factors
of the secondary lymphoid tissue has evolved for the
TNF-.
efcient induction of an immune response. In a sec-
TNF- and IL-1, acting independently and together, ondary immune response the cells involved are at a
have effects on many leucocytes and tissues. TNF- different stage of activation: they are memory cells,
is responsible for the tumoricidal activity of macro- having already been exposed to antigen. Therefore,
phages but is also implicated in the elimination of the growth factor signals may not be so critical,
certain bacteria and parasites. It has a synergistic although antigen in association with MHC class II
effect with -interferon on resistance to a number of molecules is still required. In this situation B cells are
viral infections. important as antigen-presenting cells.
CD8+ T cells, as we have seen, recognize antigen
fragments associated with MHC class I molecules. All
GENERATION OF IMMUNE RESPONSES cells have MHC class I molecules on their surface and
are therefore expected to be capable of presenting
As discussed above, the generation of humoral and antigen fragments to cytotoxic T cells, which are, for
cell-mediated responses requires the recognition of the most part, MHC class I restricted. The antigen
antigen, by the responding cell, as the rst signal and fragments derived from endogenously synthesized
a co-stimulation second signal. TH cells, as has been molecules, for instance from a virus, are produced at
emphasized, recognize antigen fragments only when a site distinct from the endocytic vesicles where exog-
in association with MHC class II molecules. The dis- enous antigens are processed.
tribution of MHC class II molecules is limited, in At or around the site of protein synthesis, endog-
normal situations, to certain cells of the immune enously produced antigen fragments become associ-
system: the antigen-presenting cells. In certain circum- ated with the newly produced MHC class I molecules.
stances non-lymphoid cells can present antigens if The MHC class II molecule picks up internalized
they are induced to express MHC class II molecules. antigen within the compartment for peptide loading
To stimulate a TH cell the antigen must be taken into (CPL), as it moves to the cell surface. In this compart-
the cell and re-expressed on the surface in association ment, antigen fragments cannot bind to the MHC
with MHC class II molecules. As the T cell antigen class I molecules because these molecules have already
receptor recognizes antigen fragments bound to the associated with endogenously produced antigenic
T1 MHC molecules, the antigen-presenting cell must also fragments within the endoplasmic reticulum and
9-22
never go to the CPL. Thus the site where the antigen or not formed, no immune response will be generated
is processed determines whether it will associate with to that antigen. There is what is known as a hole in
MHC class I or class II molecules. This separation of the T cell repertoire.
processing pathways explains why CD4+ and CD8+ T
cells are involved in the destruction of exogenous and
endogenous antigens, respectively. CONTROL OF IMMUNE RESPONSES
If a particular antigen does not become associated
with either MHC class I or class II molecules, no An antigen can induce two types of response: immu-
T-dependent immune response will be directed against nity or tolerance. Tolerance is the acquisition of
that antigen. As MHC class II molecules are involved non-reactivity towards a particular antigen. The gen-
in the initiation of immune responses by presenting eration of immunity or tolerance depends largely on
antigen fragments to TH cells, they can control whether the way in which the immune system rst encounters
or not a response takes place. It has been clearly the antigen. Once the immune system has been stimu-
shown that the level of an immune response to a par- lated, the cells involved proliferate and produce a
ticular antigen is controlled by the MHC class II mol- response that eliminates the offending agent. It is then
ecules. The genes that code for these molecules (MHC important to dampen down the reacting cells; various
class II genes) have therefore been referred to as feedback mechanisms operate to bring this about.
immune response genes.
It should be obvious that if an antigen cannot asso-
Role of antigen
ciate with the MHC class II molecules of an individual
then no immune response will be generated. As the The primary regulator of an immune response is the
MHC molecules are polymorphic, the cells of some antigen itself. This makes sense, as it is important to
individuals will present, and therefore respond to, initiate a response when antigen enters the host and
certain antigen fragments, whereas cells from other once it has been eliminated it is wasteful, and in some
individuals will not. Fortunately, more than one anti- cases dangerous, to continue to produce effector
genic fragment can be generated from each pathogen; mechanisms.
otherwise individuals who did not respond to the
particular sequence would be vulnerable to that
Role of antibody
micro-organism. In addition, individuals have at least
six different MHC class II genes and therefore an Many biological systems are controlled by the product
increased chance that some fragments will bind to at inhibiting the reaction once a certain level has been
least one of their MHC class II molecules. Variations reached. This type of negative feedback is seen with
in the levels and specicity of response occur in indi- antibody, which may act by blocking the epitopes on
viduals who have different MHC class II molecules the antigen so that it can no longer stimulate the cell
and have therefore produced different MHCantigen through its receptor.
complexes on their cells. As antibody levels rise there is competition between
Immune response gene effects can also be control- free antibody and the B cell receptor. Consequently,
led at the level of the T cell receptor. If an individual only those B cells that have a receptor with a high
does not have a T cell with a receptor that recognizes afnity for antigen will be stimulated and therefore
a particular antigenMHC complex, no response will produce high-afnity antibody. For this reason anti-
be generated. The T cell receptor repertoire is gener- body feedback is thought to be an important driving
ated in the thymus, where the genes of the immature force in afnity maturation.
T cells are rearranged to give rise to a functioning
receptor. T cells that cross-react too strongly with self
Regulatory T cells
molecules are deleted, as are cells whose receptors do
not interact with self MHC molecules. Therefore, T TH cells control the generation of effector cells by
cells that interact weakly with MHC molecules are producing helper factors. However, the factors that
selected to mature and leave the thymus. When these stimulate the expansion of B and T cell numbers do
cells later come across an antigenMHC complex, the not work indenitely. Maturation factors are also
presence of antigen strengthens the weak T cell produced that control terminal differentiation into
receptorMHC interaction, leading to a stimulatory effector cells. Under the inuence of these latter lym-
signal being transmitted to the T cell. If, for some phokines, the action of the proliferation factors is
reason, T cells that respond to a particular MHC inhibited mainly by making the effector cell unrespon-
antigen conguration have been deleted, suppressed sive to their effects. T1
9-23
Other T lymphocytes have been described that for the rst time are particularly susceptible to toleri-
provide negative signals to the immune system. zation in the presence of low doses of antigen. The
Certain regulatory T cells limit the development of requirement for two signals in the stimulation of B
antibody-producing cells and effector T cells. The cells and the generation of effector T cells can give rise
activity of these cells can involve both the production to tolerance. Both cell types require stimulation via
of soluble factors and direct cellcell interactions. the antigen receptor and help from a specic T cell.
If the helper factors are not produced, the responding
cells will be functionally deleted. Therefore, the elimi-
TOLERANCE nation of self-reactive T cells in the thymus during T
cell maturation is an important step in maintaining a
Two forms of tolerance can be identied: natural and state of tolerance. Tolerance can also be induced by
acquired tolerance. The non-response to self molecules active suppression. Some T cells are capable of induc-
is due to natural tolerance. If this tolerance breaks ing unresponsiveness by acting directly on B cells or
down and the body responds to self molecules, an other T cells. These regulatory T cells can be antigen-
autoimmune disease will develop. Natural tolerance specic and probably produce signals that actively
appears during fetal development when the immune suppress cells capable of responding to a particular
system is being formed. In experimental animals the antigen.
introduction of foreign material at the time of birth It was originally thought that unresponsiveness
leads to tolerance. Acquired tolerance arises when a to self was controlled by the elimination of all self-
potential immunogen induces a state of unresponsive- reactive cells before they matured. This cannot be
ness to itself. This has consequences for host defences, true, as self-reactive B cells are found in normal adult
as the presence of a tolerogenic epitope on a pathogen animals. It is thought that these B cells are controlled
may compromise the ability of the body to resist by a lack of T cell help, that is, TH cells have been
infection. eliminated.
An antigen can induce different effects on the two
arms of the immune system. During an infection the
host is exposed to a variety of antigenic determinants IMMUNODEFICIENCY
on a micro-organism. These epitopes are present
at differing concentrations and possibly at different The immunologically competent cells of the lymphoid
times during the infection. The epitopes can act as tissues derived from, renewed by and inuenced
either immunogens or tolerogens. Therefore, it is pos- by the activities of the thymus, bone marrow and
sible that the antibody response to a particular antigen other lymphoid tissues can be the subject of disease
may be quite pronounced while the cell-mediated processes. The deciency states seen are either due
response may be lacking, or vice versa. Alternatively, to defects in one of the components of the system
both arms of the immune response may be stimulated itself, or secondary to some other disease process
or tolerized. affecting the normal functioning of some part of the
Generally, high doses of antigen tolerize B cells, lymphoid tissues. Deciency of one or more of the
whereas minute doses given repeatedly tolerize T cells. defence mechanisms can be inherited, developmental
For acquired tolerance to be maintained, the tolero- or acquired. The types of infections and diseases seen
gen must persist or be administered repeatedly. This in patients with immunodeciencies relate to the role
is probably necessary because of the continuous the affected component plays in the normal situation.
production of new T and B cells that must be made An individual whose immune system has been
tolerant. depressed in any of these ways is said to be immuno-
Several mechanisms play a role in the selective lack compromised. The compromised host is prone to
of response to specic antigens. As each lymphocyte infectious diseases that the normal individual would
has a receptor with a single specicity, the elimination easily eradicate or not succumb to in the rst place.
of a specic cell will render the individual tolerant to Some examples of predisposing factors are given in
the epitope it recognizes and leave the rest of the rep- Table 9.7.
ertoire untouched. This mechanism relies on self mol-
ecules interacting with the receptor and causing their Defective innate defence mechanisms
elimination. It is proposed that during lymphocyte
Defects in phagocyte function take two forms:
development the cell goes through a phase in which
contact with antigen leads to death or permanent 1. Where there is a quantitative deciency of
T1 inactivation. Immature B cells encountering antigen neutrophils that may be congenital (e.g. infantile
9-24
Immunosuppression for transplant or Diminished cell-mediated and humoral Lung infections, bacteraemia, fungal infections,
cancer immunity urinary tract infections
Viral immunosuppression (e.g. measles, Impaired function of infected cells Secondary bacterial infections, opportunistic
human immunodeciency virus, pathogens
EpsteinBarr virus)
Tumour of immune cells Replacement of cells of the immune system Bacteraemia, pneumonia, urinary tract infections
Breakdown of tissue barriers (e.g. Breach innate defence mechanisms Bacterial infections, opportunistic pathogens
surgery, burns, catheterization)
Inhalation of particles due to Damage to cilia, destruction of alveolar Chronic respiratory infections, hypersensitivity
employment or smoking macrophages reactions
9-25
and lower respiratory tracts, where IgA is normally These are known as hypersensitivity reactions and
protective. result from an excessive or inappropriate response to
Individuals with T cell defects tend to have more an antigenic stimulus. The mechanisms underlying
severe and persistent infections than those with anti- these deleterious reactions are those that normally
body deciencies. A lack of T lymphocytes is often eradicate foreign material, but for various reasons the
associated with abnormal antibody levels, as TH cells response leads to a disease state. When considering
are involved in the generation and control of humoral each of the four hypersensitivity states it is important
immunity. Patients with T cell defects suffer from to remember this fact and consider the underlying
viral, intracellular bacterial, fungal and protozoan defence mechanism and how it has given rise to the
infections rather than acute bacterial infections. In the observed immunopathology.
DiGeorge syndrome (congenital thymic aplasia) the Various classications of hypersensitivity reactions
person is born with little or no thymus. Individuals have been proposed; probably the most widely
who survive develop recurrent and chronic infections, accepted is that of Coombs and Gell. This recognizes
including pneumonia, diarrhoea and yeast infections, four types of hypersensitivity that are considered
once passive maternal immunity has waned. in turn.
9-26
be a self molecule or a drug or microbial product swellings can occur. In some cases of tuberculosis,
passively adsorbed on to a cell surface. The cell sarcoidosis, leprosy and streptococcal infections, vas-
that is covered with antibody is then destroyed by cular inammatory lesions are seen mainly in the legs.
the immune system. A variety of infectious diseases These are variously referred to as erythema nodosum,
caused by salmonellae and mycobacteria are associ- nodular vasculitis and erythema induratum, and may
ated with haemolytic anaemia. There is evidence, be due to the deposition of immune complexes and
particularly in studies of salmonella infection, that the development of an Arthus reaction.
the haemolysis is due to an immune reaction against In systemic disease the clinical manifestations
bacterial endotoxin that becomes coated on to the depend on where the immune complexes form or
erythrocytes of the patient. lodge skin, joints, kidney and heart being particu-
larly affected.
Drugs such as penicillin and sulphonamides can
Type III: immune complex
cause type III reactions. The most susceptible patients
As discussed above, when a soluble antigen combines develop rashes (urticarial, morbilliform or scarlatini-
with antibody the size and physical form of the form), pyrexia, arthralgia, lymphadenopathy and
immune complex formed depends on the relative perhaps nephritis some 812 days after being given the
proportions of the participating molecules and is drug. It is likely that similar events occur in many
affected by the class of antibody. Monocytes and mac- bacterial and viral infections (see Chs 12 and 10,
rophages are very efcient at binding and removing respectively).
large complexes. These same cell types can also elimi-
nate the smaller complexes made in antibody excess,
Type IV: cell-mediated or delayed
but are relatively inefcient at removing those formed
in antigen excess. Type III hypersensitivity reactions This form of hypersensitivity can be dened as a spe-
appear when there is a defect in the systems involving cically provoked, slowly evolving (2448 h), mixed
phagocytes and complement that remove immune cellular reaction involving lymphocytes and macro-
complexes, or when the system is overloaded and the phages. The reaction is not brought about by circulat-
complexes are deposited in tissues. This latter situa- ing antibody but by sensitized lymphoid cells. This
tion occurs when antigens are never completely elimi- type of response is seen in a number of allergic reac-
nated, as with persistent infection with an organism, tions to bacteria, viruses and fungi, in contact derma-
autoimmunity and repeated contact with environmen- titis and in graft rejection. The classical example of
tal factors. this type of reaction is the tuberculin response that is
The tissue damage that results from the deposition seen following an intradermal injection of a puried
of immune complexes is caused by the activation of protein derivative (see p. ) from tubercle bacilli 3
complement, platelets and phagocytes in essence, an in immune individuals. An indurated inammatory
acute inammatory response. In general, the degree reaction in the skin appears about 24 h later and per-
and site of damage depend on the ratio of antigen to sists for a few weeks. In humans the injection site
antibody. At equivalence or slight excess of either is inltrated with large numbers of mononuclear
component, the complexes precipitate at the site of cells, mainly lymphocytes, with about 1020% macro-
antigen injection or production and a mild, local type phages. Most of these cells are in or around small
III hypersensitivity reaction occurs (e.g. the Arthus blood vessels. The type IV hypersensitivity state arises
reaction). In contrast, the complexes formed in large when an inappropriate or exaggerated cell-mediated
antigen excess become soluble and circulate, causing response occurs.
more serious systemic reactions (e.g. serum sickness), Cell-mediated hypersensitivity reactions are seen
or eventually deposit in organs, such as skin, kidneys in a number of chronic infectious diseases caused by
and joints. The type of disease and its time course myco-bacteria, protozoa and fungi. Because the host
depends on the immune status of the individual. is unable to eliminate the micro-organism, the anti-
The local release of antigens from an infectious gens persist and give rise to a chronic antigenic stimu-
organism can cause a type III reaction. A number of lus. Thus, continual release of lymphokines from
parasitic worms, although undesirable, cause little or sensitized T cells results in the accumulation of
no damage. However, if the worm is killed it can large numbers of activated macrophages that can
become lodged in the lymphatics, and the inamma- become epithelioid cells. These cells can fuse together
tory response initiated by antigenantibody com- to form giant cells. Macrophages express antigen
plexes causes a blockage of lymph ow. This leads fragments on their surface in association with MHC
to the condition of elephantiasis in which enormous class I and II molecules, and are therefore the targets T1
9-27
of TC cells and stimulate more lymphokine produc- specicities, suggesting that immune response gene
tion. This whole process leads to tissue damage with effects may be involved.
the formation of a chronic granuloma and resultant There are a number of examples where potential
cell death. auto-antigenic determinants are present in exogenous
Penicillin sensitization is a common clinical compli- material. These preparations may provide a new
cation following topical application of the antibiotic carrier, a T cell-stimulating determinant that provokes
in ointments or creams. This and other substances autoantibody formation. The encephalitis sometimes
that cause contact sensitivity are not themselves anti- seen after rabies vaccination with the older vaccines is
genic and become so only in combination with pro- thought to result from a response directed against the
teins in the skin. The Langerhans cells of the epidermis brain that is stimulated by heterologous brain tissues
are efcient antigen-presenting cells favouring the present in the vaccine.
development of a T cell response. These cells pick up Micro-organisms are a source of cross-reacting anti
the newly formed antigen in the skin and transport it gens, sharing antigenic determinants with tissue com-
to the draining lymph node where a T cell response is ponents. This may be an important way of inducing
stimulated. Here, the specic T cells are stimulated to autoimmunity. The group A streptococcus, which is
mature, and then return to the site of entry of the closely associated with rheumatic fever, shares an
offending material and release their lymphokines. In antigen with the human heart. Heart lesions are a
a normal situation these would help to eliminate a common nding in rheumatic fever, and anti-heart
pathogen, but in this case the continual or subsequent antibody is found in just over 50% of patients with
exposure to the foreign material leads to an inappro- this condition. Nephritogenic strains of type 12 group
priate response. The reaction site is characterized by A streptococci carry surface antigens similar to those
a mononuclear cell inltrate peaking at 48 h. The found in human glomeruli, and infection with these
clinical symptoms in these contact dermatitis lesions organisms has been associated with the development
include redness, swelling, vesicles, scaling and exuda- of acute nephritis. Some of the immunopathology
tion of uid (i.e. eczema). seen in Chagas disease has been attributed to a cross-
reaction between Trypanosoma cruzi and cardiac
muscle.
AUTOIMMUNITY Autoimmunity can be induced by bypassing T cells.
Self-reactive cells can be stimulated by polyclonal
A fundamental characteristic of the immune system activators that directly activate B cells. A number of
of an animal is that it does not, under normal circum- micro-organisms or their products are potent polyclo-
stances, react against its own body constituents. nal activators; however, the response that is generated
Mechanisms, as we have seen, exist that allow the tends to be IgM and to wane when the pathogen is
immune system to tolerate self and destroy non-self. eliminated. Bacterial endotoxin, the lipopolysaccha-
Occasionally these mechanisms break down and ride of Gram-negative bacteria, provides a non-
autoantibodies are produced. specic inductive signal to B cells, bypassing the need
Genetic factors appear to play a role in the develop- for T cell help. A variety of antibodies are present in
ment of autoimmune diseases and there is a strong infectious mononucleosis, including autoantibodies,
association between several autoimmune diseases as a result of the polyclonal activation of B cells by
and particular HLA (human leucocyte group A) EpsteinBarr virus.
RECOMMENDED READING
T1
9-28
During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend
to these matters and return this form with your proof.