IMMUNOLOGY AND PUBLIC HEALTH
Background notes
Introduction
Mammals have well-developed immune systems. As a consequence of living
in densely populated groups humans are particularly liable to transmitted
diseases. To manage these hazards humans have developed public health
measures and immunisation programmes.
A key function of the immune system is to recogni se pathogens, some toxins
and cancer cells as foreign and to create a response to them. The immune
system may also produce allergic responses to harmless foreign materials.
Defence responses include general non-cellular and cellular responses,
including phagocytosis and natural killer cells. Key aspects of the specific
cellular immune response include immune surveillance and clonal selection
theory. Emphasis should be placed on the role of cytokines, antigenpresenting cells and memory cells in the function of T - and B-lymphocytes.
Emphasis is placed on the control of infectious disease by public health
measures. Control of transmission of infectious diseases depends on an
understanding of disease biology and the epidemiology of disease. The
principles of active immunisation and vaccination should be considered ,
using appropriate examples. A study of clinical trials for vaccines should be
used to consider the design of such trials to ensure the elimination of bias,
valid comparisons and minimisation of experimental error by using
randomised, double-blind, placebo-controlled protocols. A study of herd
immunity and public health policy allows aspects of population biology to be
considered. Students should have the opportunity to consider evidence-based
decision making on public health policy issues related to the challenges to
disease control presented by antigenic variation (eg annual influenza
vaccination programme) and pathogens that attack the immune system (eg
HIV and tuberculosis).
Students should already have a clear understanding of the following areas of
content:
 defences against disease (phagocytosis, antibodies, vaccination)
 diseases (viruses, bacteria, fungi, parasit es)
 hygiene (personal, sexual, food, water).
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To introduce this topic, see the suggested activities in Lesson plan 1.
Immune system in health and disease
The human body has the capacity to protect itself against pathogens, some
toxins and cancer cells through the immune system.
(a) Non-specific defences
(i)
Physical and chemical defences
Epithelial cells on the body surface and cavity linings form a physical barrier
and produce secretions that defend against infection .
The body’s first lines of defence against microbes are the barriers offered by
surfaces exposed to the external environment. Very few microorganisms can
penetrate the intact skin, and the various skin glands and tear glands all
secrete antimicrobial chemicals.
The mucus secreted by the epithelial linings of the respiratory and upper
gastrointestinal tracts also contains antimicrobial chemicals, but more
importantly, mucus is sticky. Particles that adhere to it are prevented from
entering the blood. They are either swept by ciliary act ion up into the
pharynx and then swallowed (as occurs in the upper respiratory tract) or
phagocytised by macrophages in the various linings.
Other specialised surface defences are the hairs at the entrance to the nose,
the cough and sneeze reflexes, and the acid secretions of the stomach and
uterus, which kill microbes. Finally, a major defence against infection is the
many relatively innocuous microbes normally found on the skin and other
linings exposed to the external environment. Through a variety of
mechanisms, these microbes suppress the growth of other potentially more
dangerous ones.
Suggested activities – see Lesson plan 2.
(ii)
Inflammatory response
Release of histamine by mast cells causes vasodilation and increased
capillary permeability. The increased blood flow and the secretion of
cytokines result in the accumulation of phagocytes and the delivery of
antimicrobial proteins and clotting elements to the site of infection.
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Inflammation is the body’s local response to infection or injury. Th e
functions of inflammation are to destroy or inactivate foreign invaders and to
set the stage for tissue repair. The steps and cells involved are detailed below:
Mast cells
Mast cells are part of a group of cells called leukocytes (white blood cells)
that are found in almost all tissues and organs. Once activated , mast cells
produce large quantities of histamine. Histamine dilates the surrounding
capillaries and increases their permeability.
Vasodilation and increased capillary permeability
Vasodilation results in increased blood flow to the site of infection
(accounting for the redness and heat associated with inflammation). The
increased blood flow brings an increased number of leukocytes and proteins
to the area.
Increased permeability allows plasma proteins to gain entry from the blood to
the site of infection.
Secretion of cytokines
The leukocytes that arrive at the site of infection secrete cytokines , which act
as chemoattractants (chemotaxins). Chemotaxins stimulate the movement of
phagocytes to the infected area.
Phagocytosis
Phagocytes arrive and begin to rid the area of bacteria. The phagocyte engulfs
the bacterium in a process known as endocytosis. The bacterium is contained
within an intracellular vesicle. The vesicle fuses with a lysosome and
powerful enzymes digest the bacterium. The end products are then used by
the cell or released by exocytosis.
Complement
Complement proteins are activated in response to infection. Activation of the
first protein results in activation of a second prote in and so on in a cascade.
The complement system consists of at least 30 distinct proteins and is
extremely complex. Activation of the complement system amplifies the
immune response – complement proteins can help to kill the microbe,
stimulate vasodilation, increase permeability and aid phagocytosis.
Tissue repair
The final stage of inflammation is tissue repai r. Platelets form a plug to seal
off the site of injury and clotting elements trigger the coagulation cascade,
which strengthens the platelet plug. Finally, remodelling takes place as the
healing process winds down. The final repair may be imperfect – this results
in a scar.
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Suggested activities – see Lesson plan 3.
(iii) Non-specific cellular responses
A variety of specialised white blood cells provide protection against
pathogens. Phagocytes recognise surface antigen molecules on pathogens and
destroy them by phagocytosis. Natural killer (NK) cells induce the pathogen
to produce self-destructive DNA enzymes in apoptosis. Phagocytes and NK
cells release cytokines, which stimulate the specific immune response.
On rare occasions pathogens break through the host’s physical and chemical
defence mechanisms. The pathogen can then invade host tissues and begin to
colonise and infect the host. It is at this point the immune system must
become mobilised.
The starting point for immunity (whether it is specific, non -specific, humoral
or cell-mediated) is contact of a pathogen with a phagocyte. The primary
function of a phagocyte is to engulf and destroy pat hogens and digest their
remains.
Phagocytes
Phagocytes are found in the blood and in the tissues and they are motile. The
phagoctyte recognises antigens on the surface of the pathogen, to which it
then adheres. The membrane of the phagocyte engulfs the pathogen and
pinches off to form an intracellular vesicle. This vesicle then fuses with a
lysosome (a granular inclusion containing bactericidal substances such as
lysozyme, hydrogen peroxide, proteases, phosphatases, nucleases and
lipases). The toxic substances inside the lysosome are capable of killing and
digesting the engulfed pathogen. Following digestion of the pathogen, the
phagocyte releases a number of inflammatory mediators, some of which
include cytokines. This results in a positive feedback loop, the cytokines
recruiting more phagocytes to the area.
Natural killer cells
NK cells bind to virus-infected and cancer cells without specific recognition
and kill them directly. They participate in antibody-dependent cellular
cytotoxicity.
NK cells constitute a distinct class of lymphocytes. Their major targets are
virus-infected cells and cancer cells. They attack and kill these cells directly.
NK cells are not specific – they are able to attack cells without any
recognition of the specific pathogen involved. NK cells recognise ‘normal’
cells through their expression of Major Histocompatibility Complex (MHC)
class 1 proteins. They recognise foreign cells by the absence of these
proteins. The exact nature of NK cells and their method of action is unknown.
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However, it is known that they kill cells by releasing small cytoplasmic
granules of proteins called perforin and granzyme that cause the target cell to
die by apoptosis (programmed cell death). The perforin is released in close
proximity to the target cell and forms pores in the cell membrane, allowing
granzymes to enter the cell. The granzymes stimulate the cell to produce
enzymes that degrade the DNA of the cell, inducing apoptosis.
As well as their role in non-specific immunity, phagocytes and NK cells also
help to initiate the specific immune response. Following their action against
the pathogen they secrete interleukins – cytokines that serve to stimulate the
specific immune response through the activation of T cells.
Suggested activities – see Lesson plan 4.
(b) Specific cellular defences
(i)
Immune surveillance
A range of types of white blood cell constantly circulate , monitoring the
tissues. If tissues become damaged or invaded, a variety of cells release
cytokines, which recruit specific white blood cells to the site of infection or
tissue damage.
Leukocytes (white blood cells) are the most numerous cells of the immune
system. They are produced in the bone marrow and use the blood to transport
themselves around the body – they are constantly on the lookout for
microbes, pathogens, antigens etc. Leukocytes can leave the circulatory
system and enter the tissues, where they function.
If the tissues become damaged or invaded, leukocytes are capable of secreting
over 100 different protein messengers known collectively as cytokines.
Cytokines regulate host cell growth and function in both specific and non specific defences. Secretion of cytokines can trigger a number of responses.
Some cytokines are chemokines (chemoattractants). Once secreted these
chemokines attract phagocytes (non-specific) and T cells (specific) to the site
of injury. This stimulates an inflammatory response as well as an immune
response.
Suggested activities – see Lesson plans 5 and 6.
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(ii)
Clonal selection theory
The body has a vast array of lymphocytes, each with a single type of
membrane receptor specific for one antigen. When a receptor is activated by
the binding of an antigen, the lymphocyte repeatedly divides , resulting in a
clonal population of lymphocytes.
Clonal selection theory states that each antigen-reactive B cell or T cell has
only a single type of antigen-specific receptor on its surface. When
stimulated by interaction with a specific antigen, each cell is capable of
dividing, making a copy of itself. The anti gen-driven B and T cells continue
to divide, resulting in multiple copies (or clones). Because of the infinite
variety of antigens available, a large number of antigen -reactive cells are
available in the body and each cell is capable of expanding into an a ntigenreactive clone. However, antigen-reactive cells must avoid interactions and
subsequent immune reactions with self-antigens in the host.
Suggested activities – see Lesson plan 7.
(iii) T and B lymphocytes
Lymphocytes respond specifically to antigens on foreign cells, cells infected
by pathogens and toxins released by pathogens.
Lymphocytes are the essential cells in specific immune defences.
Lymphocytes must recognise the specific foreign matter to be attacked. Any
foreign molecule that can trigger a specific immune response against itself or
the cell bearing it is termed an antigen.
T lymphocytes
One group of T lymphocytes destroy infected cells by inducing apoptosis.
Another group of T lymphocytes secrete cytokines that activate B lymphocytes
and phagocytes.
T lymphocytes mature in the thymus. T cells consist of two major subsets :
cytotoxic T cells and helper T cells.
Cytotoxic T cells are attack cells. They travel to the location of their target,
bind to them via antigens on the target and, following activation, they
directly kill the target via secreted chemicals. Responses mediated by
cytotoxic T cells are directed against the body’s own cells , where these have
become cancerous or infected. There are several mechanisms of target cell
killing by activated cytotoxic T cells. One of the most important is by
apoptosis. Apoptosis is programmed cell death – the infected cell is
instructed to kill itself. Within the infected cell, endogenous enzymes are
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activated that break down the cell nucleus and its DNA, as well as other cell
organelles. Importantly, the cell membrane is not destroyed, so when the cell
dies its contents are not dispersed. Instead the cell sends out chemical
messengers that attract neighbouring phagocytic cells to engulf and d igest the
dying cell.
Helper T cells facilitate the activation of both B cells and cytotoxic T cells.
Helper T cells must combine with an antigen and become activated. Once
activated they secrete cytokines that act on B cells and cytotoxic T cells that
have also bound to antigens. B cells and cytotoxic T cells cannot function
properly unless they are stimulated by cytokines produced by helper T cells .
B lymphocytes
Each B lymphocyte clone produces a specific antibody molecule that will
recognise a specific antigen surface molecule on a pathogen or a toxin.
Antigen–antibody complexes may inactivate a pathogen or toxin or render it
more susceptible to phagocytosis. In other cases the antigen–antibody
complex stimulates a response that results in cell lysis.
B cells mature in the bone marrow. All new generations of B cells are derived
from and are identical to their parent cells – hence they are all clones. On
activation, B cells differentiate into plasma cells, which secrete antibodies.
The antibodies combine with a specific antigen and guide an attack that
eliminates the antigens or the cells bearing them. The antibodies bind to the
antigen on the surface of the cell, but they do not directly kill the cell .
Instead, they link the target cell to the actual ki lling mechanism.
Antibodies can act as opsonins – they can link a phagocyte to an antigen,
which then triggers phagocytosis. In other cases, antibodies can activate the
classical complement pathway. This results in the production of chemicals
that make the cell membrane ‘leaky’, causing cell lysis.
Antibody-mediated responses are the major defence against bacteria, viruses
and other microbes in the extracellular fluid, and against toxic molecules .
Suggested activities – see Lesson plans 8 and 9.
Recognition of self and non-self
T lymphocytes have specific surface proteins that allow them to distinguish
between the surface molecules of the body’s own cells and cells with foreign
molecules on their surface. Failure in regulation of the immune system leads
to an immune response to self cells (autoimmune disease). Allergy is a
hypersensitive response to an antigen that is normally harmless.
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While T cells are maturing, their antigen receptors are tested for potential
self-reactivity. For the most part, T lymphocytes bearing receptors for
molecules already present in the body are either rendered non -functional or
are destroyed by apoptosis – thus the body normally has no mature
lymphocytes that react against self components. The immune system exhibits
self-tolerance. Failure of self-tolerance can lead to autoimmune disease.
Major histocompatibility complex (MHC) are molecules that mark body cells
as ‘self’. T lymphocytes have specific receptors that can recognise MHC and
therefore recognise cells that belong to the body. Sometimes the body loses
tolerance for self, this then leads to autoimmune disease.
Autoimmune disease is caused by an inappropriate immune attack triggered
by the body’s own proteins acting as antigens. The immune attack, mediated
by auto-antibodies and self-reactive T cells, is directed specifically against
the body’s own cells that contain these proteins.
Allergy refers to diseases in which immune responses to environmental
antigens cause inflammation and damage to the body itself. Antigens that
cause allergies are called allergens. Most allergens are relatively or
completely harmless: it is the immune response to them that causes damage.
Allergy is a result of the immune system going wrong.
Suggested activities – see Lesson plan 10.
Antigen-presenting cells
When pathogens infect tissue, some phagocytes capture the pathogen and
display fragments of its antigens on their surface. These antigen -presenting
cells activate the production of clones of T lymphocytes, which move to the
site of infection under the direction of cytokines. B lymphocytes activated by
antigen-presenting cells and T lymphocytes produce clone s of B lymphocytes
that secrete antibodies into the lymph and blood , from where they make their
way to the infected area.
After a microbe or other non-cellular antigen has been phagocytosed by a
macrophage it is partially broken down into smaller fragments . These
fragments bind to MHC class II proteins, which are then transported to and
displayed on the plasma membrane. The antigen fragments are presented to T
lymphocytes (antigen presentation). The antigenic binding of the antigen
presenting cell (APC) to the T lymphocyte causes the T lymphocyte to
proliferate and differentiate into a clone of activated helper T cells . These
secrete cytokines, which recruit more lymphocytes to the area of infection.
The arriving lymphocytes secrete more cytokines which stimulate B
lymphocytes to produce large quantities B lymphocyte clones, which produce
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antibodies that are then secreted into the lymph and blood, making their way
to the infected area.
Memory cells (immunological memory)
Some T and B lymphocytes produced in response to antigens by clonal
selection survive long term as memory cells. A secondary exposure to the
same antigen rapidly gives rise to a new clone of lymphocytes, producing a
rapid and greater immunological response.
Once a lymphocyte is activated to divide and differentiate it forms two clones
of cells. One clone contains a large number of effector cells – short-lived
cells that combat the antigen. The other clone consists of memory cells, long lived cells bearing receptors specific for the same antigen. This antigen driven cloning of lymphocytes is called clonal selection (see earlier). The
primary immune response (the first time the body is exposed to an antigen)
takes 10–17 days from initial exposure until selected lymphocytes generate
the maximum effector cell response. During this time the effected individual
may become ill. On re-exposure to the same antigen some time later , it takes
only 2–7 days to produce a response of greater magnitude and which lasts for
a prolonged period of time – this is the secondary immune response. Memory
cells are poised to proliferate and differentiate rapidly when they meet the
same antigen. The antibodies produced during the secondary immune
response have a greater affinity for the antigen compared to those produced in
the primary immune response.
Suggested activities – see Lesson plan 11.
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