Immune System (IDK)
Immune System (IDK)
Immune System (IDK)
(IDK)
Introduction
The problems that the mammalian immune system solves are not restricted to higher animals;
they are faced by all forms of life and are ignored by none. The pressure that natural selection
exerts is inexhaustible and unending. Emerging infectious diseases have as much potential to
shape future human history as the epidemics and pandemics of the past. Managing this threat
depends on understanding how to maximize the potential of our sophisticated immune system in
the service of human health.
It is a fundamental property of immunity that no part of our body is cut off from its surveillance.
For this reason, although the immune system may seem a less substantial thing than an organ
such as the heart or the liver, in aggregate, immunity consumes enormous resources, producing
the large number of cells that it depends on for successful functioning. After early childhood,
most immune cells are produced from the bone marrow. Some of these then undergo very
significant secondary education before they are released to patrol the body. Many important
immune cell types have been identified. In a routine blood test, five different kinds of white
blood cell will be counted (Table 1). An immunologist or a haematologist may subdivide these
populations further, on the basis of the proteins that are expressed in their cell membranes.
Among these proteins are receptors by which cells interact with each other and the environment.
Receptors bind ligands which may be receptors on other cells, or soluble molecules such
as cytokines. Cells express hundreds of different types of receptor on their surface. Many carry
out fundamental functions, such as transporting glucose into the cell. The receptors associated
with the immune system are generally concerned with interrogating the environment for
evidence of danger, infection or abnormal cell death. In the course of an immune response, cells
follow a programme, such that the overall outcome maximizes the likelihood of surviving and
eliminating infection or cancer.
Table 1.
White blood cells analysed by routine blood tests. Neutrophils and macrophages respond
quickly to local inrection; lymphocytes co-ordinate the adaptive response
Receptors are also present inside the cell where they play an important role, acting to detect
evidence of infection. Organisms such as viruses can spend most of their life hidden in the
complicated cytoplasm of the cell, making them difficult to recognize from the outside.
Receptors within the cytoplasm can bind to virus-derived signature molecules, such as different
types of nucleic acid and signal that infection is present. Cells use a sophisticated system for
sampling the proteins they are making, to check that none have come from viruses. If cells detect
such telltale signs they respond, by producing cytokines that serve as alarm signals for
surrounding tissues, and by committing rapid and effective suicide that leaves a cell remnant that
can initiate adaptive immunity directed at the inciting infection.
Tackling infections is the job of different types of white blood cell. Early in an immune response,
the most important of these are the innate immune system cells neutrophils and macrophages,
which are the first at the scene of an environmental breach, such as an insect bite. Both of these
cell types are effective killers in their own right. They secrete highly destructive substances
including enzymes that digest proteins and reactive chemicals such as bleach that kill. Then they
engulf and digest what they have damaged, a process called phagocytosis. Infections that are not
destroyed by this attack attract the attention of lymphocytes. These cells embody the functions
of adaptation and memory, allowing the immune system to make increasingly specific responses
and to remember individual types of infection, so that reinfection is met with a faster and more
effective counterattack.
All of these different responses rely on the selective expression of specific families of genes.
Studies of the immune system have been at the forefront of characterizing how different gene
programmes function. Immune cells read the environment through their receptors and then
modify how they use the genes encoded by their DNA. Some groups of genes are switched on,
and others are switched off. This gives the different cell types a great deal of flexibility in how
they handle an infection. Sometimes these gene programmes change the cytokines that cells
secrete, sometimes they change the pattern of receptors on the surface and sometimes they
change how resistant the cell is to infection. Information in the environment can label a specific
location, keeping immune cells from moving away. Other signals affect the whole body, such as
the cytokines that stimulate changes in the regulation of body temperature that lead to fever. The
adaptations that we make in response to infection are measured over many time scales. They may
occur rapidly in minutes and resolve just as fast; they may continue for days until a viral
infection is cleared or they may be long-lasting and change the local anatomy of a tissue such as
the autoimmune disease rheumatoid arthritis. The immune system is, then, a highly connected
web of many different types of response deployed to maintain the status quo of a pathogen-free
internal environment.
Challenges
An effective immune system must be able to interpret changes in the world around it and respond
appropriately. To do this, it has to solve a number of specific problems.
Discrimination
Immune systems have an uneasy relationship with the environment. Most of the time an
encounter with something new is harmless, but the small fraction of times that it is not can be
very dangerous indeed. An effective immune system must be able to discriminate such
differences, distinguishing self from non-self and distinguishing harmless non-self from
dangerous non-self. For much of the 20th Century, research in immunology was focused on
understanding how it achieved the former. It was spurred by an important early observation: that
it was possible for animals to develop specific immune reactions against chemicals such as dyes,
which had never existed in Nature. The ability to learn how to recognize these previously
unknown structures implied that the immune system had solved the problem of how to classify
and recall the shapes of individual molecules. Unravelling the biological machinery that achieves
this was a signature achievement of 20th Century immunology.
This remarkable flexibility underlines the fact that the immune system interrogates the
fundamental building blocks of the environment. A process of recognition at a near molecular
scale allows the immune system to exploit the fact that all organisms are defined by proteins
encoded in their genes. A measles virus is made of different proteins from those of a rabies
virus. An Escherichia coli bacterium has a different structure from that of a spirochaete. By
classifying the environment in terms of the proteins it contains, and by continuously sampling
these proteins, the immune system executes a very active form of monitoring that it links to a
stringent verification process and which must incorporate an ability to learn. As part of a defence
against a potentially dangerous environment, each individual develops their own unique immune
system, which acknowledges only itself. Everything that is not recognized might be a threat.
Flexibility
The immune system's ability to adapt flexibly to strange environmental changes is critical in
fighting infections and cancer. Because our bodies have a remarkable capacity for renewal, and
almost every cell is a factory working day and night to turn over worn out molecules, breaking
them down into building blocks that are reused to make replacements, infection or cancer can
arise at any time. Every time a cell divides, there is a small chance that it may develop a random
unpredictable mutation that will transform it into a cancer. Infections reproduce much more
rapidly than their hosts and can change their appearance to allow them to evade recognition. An
effective immune system must cope with this unpredictability.
We can picture this as an ongoing evolution of the environment and it presents a special
challenge for an immune system. In contrast with most organs, such as the heart, which does the
same job throughout life, the immune system needs to adapt to an environment that is always
changing. This problem is solved by investing in strategies that exploit the power of random
change itself. Using randomness in this way creates waste, but preserves responsiveness. Even
identical twins, which share the same genes, have immune systems that become increasingly
different from each other from birth to old age, as each twin independently makes hundreds of
thousands of unique random responses to the environment.
Managing infection
For a microbial infection to develop, the pathogen must get close enough to interact with
individual cells. The skin and mucous membranes make this close approach difficult. Physical
barriers provide innate protection, such as the tough overlapping cells of the skin and chemical
barriers, and enzymes, such as lysozyme in snot and tears and the acid in the stomach, also kill
many bacteria. These outward-facing surfaces actually encourage the presence of non-pathogenic
microbes. By welcoming and supporting a co-operating microbial population, little opportunity
is left for more dangerous relatives to move in. The healthy immune system lives happily with
this symbiotic microbial farm, but still reacts when there is a dangerous infection. As our
understanding of the ecology of this ‘microbiome’ grows, it may offer new therapies that can
support the exclusion of disease causing organisms.
When pathogens do penetrate these defences and seek to live within our bodies and within our
cells, they pose many threats, from quiet coexistence to wholesale cell destruction and death.
There is wide diversity in pathogens’ methods of attachment and entry. For every individual
pathogen, this process is tailored to species, to specific cell types and to defined cell-surface
receptors. Each infection uses a different door into the cell. Blocking off these routes of entry can
stop an infection before it starts. By producing antibodies, the immune system can neutralize an
infection before the key to the cell turns in that particular doorway. But this must be carried out
one key at a time.
A pathogen that has penetrated the defences of the skin and mucous membranes and established
itself within or between cells, or a cell that has turned into a cancer, can only be eliminated by
killing. This is a dangerous business, and when the immune system is battling with an infection,
it may put the life of the host at risk. Sometimes when it is not infection, but an adverse reaction
to a drug or a treatment for cancer which activates the immune system, this leads to critical
illness. There is a delicate balance between what is successful and what is sustainable when
invoking a full-blown immune reaction.
Moreover, some infections cannot be killed off reliably by the immune system. Viruses that
evade immunity, by hiding within cells, lead to repeated bouts of illness as limited as cold sores
or as destructive as AIDS. Cancers that escape from immune control can continue to grow, may
metastasize and then kill in different ways.
In meeting all of these kinds of assault, there is a middle path that an immune response must
keep to, between too much destruction and not enough. In this zone, it is quite ruthless in
sacrificing itself to terminate an infection. When common cold viruses have hijacked cells in the
throat to replicate, these virus factories are not rehabilitated, but destroyed by killer cells. Where
a bacterium has penetrated the skin and established a viable colony, suicidal white blood cells fill
the area with bleach that they make themselves, killing indiscriminately and leaving behind a
wasteland of debris that needs to be engulfed, digested and processed by the immune system.
Memory
One of the most significant features of the immune response is its ability to retain a memory of
previous infections. This both protects individuals from reinfection and limits the spread of
infection in a community. Immune memory can be very long-lasting; when adults were studied,
their memory for the measles infection was decaying so slowly, it would have taken over
3000 years to decrease by half. This goes well beyond life-long protection. These robust durable
changes are the reason that, when we vaccinate, the protection this produces delivers long-term
benefits.
Within an individual, immune memory must be distributed throughout the body. Circulating
antibodies travel in the blood, reaching everywhere the circulation does; memory also develops
outside the bloodstream within tissues. Killer cells can remain on guard where the immune
defences broke down in the past, alert but not activated, ready to attack rapidly if reinfection
occurs.
Finally, some infections have such a profound impact on a species that the imprint of individual
pathogens can be perceived in the tree of evolution. If an infection is lethal, only individuals who
have genes that encode effective resistance will survive to produce the next generation. Modern
methods of analysing inheritance have demonstrated how the co-evolution of host and infection
has shaped the make-up of the immune system and the receptors it uses for recognizing and
fighting pathogens.
All immune systems address and solve these challenges. How mammals achieve this complex
task is the story of an integrated system of biological processes, often using strategies that
surprised their discoverers, whose elegance and power continue to provide new insights for
students of immunology young and old.
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Discrimination
Adaptive immunity
The immune system uses many different receptors to interrogate the environment. These are
usually proteins and are found in the blood, in tissue fluids or bound to the cell surface. The
antibody receptor, also called an immunoglobulin (Ig), was the first antigen-specific receptor to
be characterized and is commonly drawn as a Y-shaped cartoon. It is formed by the combination
of two identical heavy and two identical light chains. Such an Ig comprises three globular
domains connected by more flexible linkers; the two binding domains, coded for by variable
regions, have identical specificity for antigen (Figure 1). The globular Ig structure is a widely
adapted template that is used by many molecules both inside and outside the immune system.
The structure is known as the Ig domain (or fold) and proteins that contain such a domain are
members of the ‘immunoglobulin superramily’.
Antibody structure
Antibody cartoons are often drawn in a Y-shape, as on the left. This picture represents an IgG
molecule, made from two identical heavy (red and blue) and two identical light (yellow and
green) chains. The top of the Y (called the Fab region) contains two variable regions that each
bind the same antigen. The bottom of the Y is the constant (Fc) region, which interacts with cell
receptors, complement, etc. On the right is a crystal structure of an IgG2 antibody. The heavy
chains (red and yellow) and light chains (blue and green) are identical. This antibody is ∼10 nm
from bottom to top. (From
TimVickers. https://commons.wikimedia.org/wiki/File:Antibody_IgG2.png)
Antibodies are soluble and do two things. At one end, they bind firmly to a target (antigen),
whereas at the other, they signal to immune cells. Antibodies are divided into a number of
different families, called isotypes (Table 2) and their production is a carefully regulated process
involving cell–cell interactions that control which antibodies are made. Antibody research in the
first half of the 20th Century focused on antibodies that could be purified from serum. Once
the amino acids that made up the different chains were defined, attention turned to
understanding how antibodies were produced by individual cells. It was discovered that, for most
antibodies, their generation depended on co-operation between at least two types of cell: a cell
that processed and presented targets (antigens) from the environment [antigen-presenting cell
(APC)] and a lymphocyte that recognized the target antigen on the APC. This lymphocyte (now
called a T-cell or T-lymphocyte) directed either the production of antibodies or killed the cell
presenting the antigen (Figure 2).
Table 2.
The rive main types or antibody isotype which have dirrerent roles in the immune response
Figure 2
The adaptive immune response to inrection
Infection, detected by APCs, triggers specific T-cells that co-ordinate killing and antibody
production which stop the infection.
One early idea to explain how T-cells determined what to respond to was that the immune
system only presented antigens from infections, but this was wrong. To the surprise of many
immunologists, studies in the 1980s which defined the receptor molecules on the surface of cells
that controlled this targeting process revealed that essentially all cells presented antigens. A
healthy immune system surveys these antigens constantly, but this does not provoke a response.
This challenges the impression that the immune system spends most of its time doing nothing.
Quite the opposite: it is constantly reviewing the environment, checking whether anything is
amiss. The immune system has a carefully developed sense of self which it generates through a
process of education.
The lymphocyte's antigen receptors recognize a family of cell-surface molecules on APCs that
are collectively known as major histocompatibility (MHC) determinants. In humans, these are
also called human leucocyte antigens (HLAs). These molecules are a combination of material
derived from the environment (the antigen), bound in the flexible jaws of the MHC molecule
which hold it in place. The rest of the MHC molecule acts as a scaffold orientating the MHC–
antigen complexes at a cell's surface where they can be scanned by a lymphocyte (Figure 3). In
this way, cells display a constantly changing picture of the proteins that they are making as
antigens loaded into their MHC molecules, and these antigens come from inside and around
cells. This sampling strategy is effective because disguise is very difficult at the molecular level.
A bacterial cell makes many proteins that do not resemble those made by an animal cell; a cell
making a virus inside does not look like a normal cell.
Figure 3
Antigen processing I
A protein molecule (on the left) is digested by the cell and a fragment from it (shown in green) is
loaded into an MHC molecule that is then displayed on the surface of the cell (on the right),
oriented so that it can be scanned by T-cells. The MHC molecule is ∼7 nm tall above the cell
membrane. Not to scale. Jawahar Swaminathan and MSD staff at the European Bioinformatics
Institute https://commons.wikimedia.org/w/index.php?curid=6292018
The commonest type of antigens presented by MHC molecules are peptides, short stretches of
amino acids (eight to 30) which are processed from proteins. The source of this material may be
the internal or external environment of the cell that presents it. Two types of MHC molecule,
class I and class II, are involved in this process. All cells, except for red blood cells, present a
selection of antigens from the proteins that they are making bound by MHC I. Each cell wears a
collection of MHC–antigens on its surface that act as bar codes, identifying that cell to the
immune system. Some immune cells called APCs are specialized to present antigen, and load
antigens into MHC I and MHC II. They are continuously hoovering up proteins from the
environment, using enzymes to digest them to produce short peptides, and loading them into the
jaws of the MHC within the cell, before these molecules are displayed on the surface. In APCs,
these two parallel processing pathways provide a real-time survey of whatever the environment
contains (Figure 4).
Figure 4
Antigen processing II
Internally produced and externally captured proteins are loaded on to MHC molecules inside
APCs. Internally produced proteins are presented by MHC class I molecules, which are found on
all the cells in the body. Externally acquired proteins are presented by MHC class II molecules
on specialized APCs. Once loaded, molecules are exported to the cell surface.
All MHC molecules work in the same basic way, as a scaffold to present antigen, but as a species
we have in our heritage a repository of many different MHC molecules (1122 common and well-
documented different alleles as of 2013). This diversity at the level of the population of all
humans, is narrowed down in the individual, who inherits about nine MHC molecules at random
from their parents. Your own MHC molecules define your tissue type which is the major barrier
to successful organ transplantation, and the reason we keep records of the tissue type of potential
donors. The chance of meeting a stranger who shares the same MHC molecules as you is tiny,
which is why, among a panel of 20 million potential donors, 2–5% of individuals will not find an
exact match. Even an individual with the commonest set of HLA genes found in the U.K., who
needed a transplant, would only find a few hundred potential donors among this panel. This is
also why your best chance of finding a compatible donor is searching among your close relatives,
with whom you share genes.
Of course, the complexity of this system did not arise to frustrate transplant surgeons. The
immune system uses it, because each of these many different MHC molecules presents a unique
selection of antigens processed from the same underlying proteins. For example, the antigens
that are presented from the liver of one person will be different from the antigens presented from
the liver of an unrelated person. In this way, the representation of self established by an
individual's MHC, presenting its self-proteins to its own lymphocytes, is a very private system of
identification that is difficult to copy, allowing the immune system to discriminate between
foreign tissue transplants, invading infections and cancerous cells.
The sensor that interacts with the MHC–antigen complex is called the T-cell receptor (TCR or
TcR). This receptor is part of a complicated structure called the TCR complex (it is formed by
the combination of six different protein chains in four pairs). Two TCR chains (α and β) make up
the sensor that examines MHC molecules (Figure 5), and the other chains are used for signalling
the results of that examination into the T-cell. They are often omitted from cartoons that show
the TCR at the cell surface. The signals that the TCR generates within the T-cell depend on
the arrinity of the interaction of the α and β sensor chains with the MHC–antigen. In essence,
each TCR measures the affinity of this interaction and provides a read-out to the T-cell which
determines the subsequent response of that cell. An activated TCR sends signals across the
cytoplasm of the cell to the nucleus where it initiates programmes that change the pattern of
genes that are being expressed and therefore some of the proteins made by the cell.
Innate immunity
Discrimination is also a key aspect of the innate immune system. This is an area of research that
has grown explosively since studies at the close of the 20th Century identified families of
receptors that sampled the environment for the presence of molecules associated with pathogens
(called pathogen-associated molecular patterns; PAMPs). One of the first pathways of this kind
to be worked out in detail exploited the discovery that a receptor cloned from insects, and
implicated in their sensitivity to infection, was related to the gene for a similar protein that could
be found in mammalian cells. This molecule, called Toll-like receptor 4 (TLR4) is a key
mediator of the effects of sepsis in patients critically sick with infections. When it binds to
bacteria, TLR4 triggers the release of cytokines that stimulate the whole immune system
producing fever and, in the seriously ill, shock. TLR4 signalling can trigger the activation and
recruitment of neutrophils and macrophages that can kill or limit the spread of infection at an
early stage, allowing time for the adaptive immune response to develop.
Receptors that recognize PAMPs are found both outside and inside cells. As a group, these
innate immune system receptors survey the environment for everything from viruses to fungal
infections. The scope of this sensing network is an indication of the importance that an early
reaction to infection plays in the survival of its victim. Innate immune responses slow infections
down, giving the rest of the immune system time to catch up. Disorders of the innate immune
response cause ‘autoinrlammatory’ diseases, often manifesting as spontaneous bouts of illness
and fever.
The discrimination of appropriate targets that require an immune response from those that do not
is the key to immunity. Unleashing the immune system is a risky business. If the reaction is too
strong, it can kill its host. If it is not strong enough, the infection may do the same. To carry out
this difficult balancing act, the immune system comes with many checks that operate as the
response to a pathogen progresses. One of the first mechanisms is a process of double-checking,
before even starting to respond, called ‘co-stimulation’. The need for co-stimulation was
deduced once it was understood that the immune system could generate antigen-specific
receptors at random and throughout life. By continuously making new and unique T-cells and B-
cells, there is a constant risk of producing an autoreactive antigen-specific cell that targets self-
antigens. To explain how receptors that recognize self-antigens could be turned off rather than
on, if they bound a self-antigen, it was suggested that full activation of immunity required two
signals, one from the antigen-specific receptor and a second from a hypothetical co-stimulatory
pathway. This insight, developed ahead of the description of the receptor pathways by which it
operated, was very fruitful in explaining how antigen-specific signalling could have two
apparently opposite effects, one shutting down the cell, the other spurring full activation. By
adding a checking mechanism to the activation process, the immune system increases its
discriminatory power, reducing the risk of errors. As these mechanisms became elucidated down
to the level of individual signalling pathways, it was possible to uncover how this strategy has
been applied to a number of different types of immune cell interaction. Another important check
is provided by antigen-specific T-cells that shut down responses. These are called T regulatory
cells. This population is devoted to negative feedback, limiting dangerous responses to
autoantigens.
In summary, immune discrimination is distributed across many cell types. It depends on
recognizing the molecular signatures of the diverse world of pathogens. To initiate a rapid first
response, it employs many receptors that have become ‘educated’ through the process of
evolution, to bind with high specificity to molecular structures associated with infection, and
then signal to destructive cells like neutrophils and macrophages to attack (innate immunity). A
second sophisticated system, which recognizes and ignores ‘self’, attacks antigens that it does
not know (adaptive immunity). By using a highly variable family of MHC molecules that are
essentially unique for each individual, every immune system sees the world of pathogens
differently, making it difficult for infection to develop an effective disguise. By constant
surveillance, the immune system provides a safe space to carry out normal functions of life. And,
as a bonus, the immune system can carry on learning, so that long-lived animals that are exposed
to new rapidly dividing infections, have recourse to real-time evolution of immune memory that
can defeat infection.
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Selective killing
The most desirable immune response is one that stops an infection in its tracks, before it has
established a foothold in the body. Phagocytosis of bacteria in the tissues and antibody-mediated
blockade of virus entry into cells work this way. But if, once an infection was established within
a cell, the immune system did no more, or if a cell that had turned into a cancer was ignored,
viruses and cancers would be unstoppable. To deal with these eventualities, cells of the immune
system control powerful lethal weapons. This ability is so striking that the cells that specialize in
execution are known as cytotoxic killer cells.
Killers discriminate by using recognition receptors. Cytotoxic T-cells use the TCR and the CD8
co-receptor which together interact with MHC I. In this way, they can interrogate any nucleated
cell in the body. When cytotoxic T-cells recognize an infected target cell, they kill it rapidly and
move on to the next cell.
Natural killer cells, part of the innate response, use a different approach to selecting their
targets. These cells patrol the body asking themselves whether the tissues that they survey
express MHC I molecules. If the cells that are being examined do, then they move on, but if not,
they will become activated and kill. This provides an alternative method of surveillance, which
does not depend on specific antigen, and frustrates a strategy that some pathogens employ, of
inhibiting the surface expression of MHC I. By insisting that nucleated cells report on their
protein production, the window of opportunity that viruses have to squeeze through to be
successful is narrowed further.
Cell killing is a specialized function that occurs in a series of steps. First the cytotoxic cells make
close contact with the target and mobilizes intracellular granules to this area of contact. Then
these granules fuse with the cell membrane of the cytotoxic cell and release a number of
proteins. One, called perrorin, forms a pore in the cell membrane of the target. This pore allows
the entry of other proteins called granzymes that trigger rapid cell death. A second pathway, that
probably plays a minor role in cytotoxicity, is that involving a receptor on the cytotoxic cells
called FasL binding to its partner on the target cell called Fas. This interaction triggers a suicide
signal within the target cell.
All cells are able to commit suicide and this type of cell death is called apoptosis; it is very
important in development and in the immune system. In the thymus, where, as explained above,
most of the lymphocytes that audition for a role as useful effector cells die, it is through the
process of apoptosis that this occurs. Apoptosis also frustrates some viral infections and protects
individual cells from becoming cancerous. Cancers only develop if they have mutations that
block the activation of apoptosis, and viruses produce proteins to stop apoptosis switching on. In
this way, the transformed or infected cell can survive signals that would otherwise lead to it
killing itself.
The final common pathway of apoptosis is a proteolytic cascade which digests the contents of
the cell and fragments its genetic material; the cell shrivels up and exposes signals at its surface
that tell neighbouring phagocytes to eat it. The enzymes that carry out this process come from a
family called caspases (cysteine proteases that cleave proteins after aspartic acid residues).
There are several different ways to initiate this process, but they share a common final pathway.
One feature of ‘normal’ apoptosis, such as occurs in the thymus, is that it does little to stimulate
inflammation. This means that cells can die without initiating an effector immune response. In
contrast, in an aggressive infection, where cells death occurs alongside signals that stimulate
innate immune activation, accompanying adaptive responses will also occur. Successful immune
responses reach an appropriate match between the threat and the response, producing enough
killing to manage infection, but not so much that the host is compromised. If this is not achieved,
the outcome may be disastrous in the short-term, because an infection is not controlled, or
because the immune response is so aggressive that the body collapses. Or dangerous in the long-
term because a chronic infection becomes established or because the immune system over-reacts
and develops specific responses that attack healthy tissue.
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Managing inrection
Developing precisely targeted adaptive immunity is a core capacity of the immune response, but
there are many other important and interlocking effector functions which are essential to
successfully overcoming colonization by a pathogen, or adapting to live with long-term
infection. As our understanding of them continues to grow, we learn how to exploit these
mechanisms to treat disease. But we can also look back at the beginning of immunology and see
how many of the themes were established early in the history of the science.
In 1882, a Russian refugee called Elie Metchnikoff carried out an experiment on starfish larvae.
He put small thorns into them and when he returned the next morning to study the result
microscopically, he discovered that the thorns were surrounded by cells. This experiment
changed the course of his research, alerting him to the importance of cellular function in immune
responses. These cells, which were phagocytes, could ‘eat’ infections to protect the host. In
subsequent decades, following this discovery, there was a fierce debate weighing up the relative
importance of such cells. We now understand that they are a crucial element that functions
alongside antibodies and complement activation fighting infection. Phagocytes are part of the
first wave of response to many kinds of infection. Two types of cell, called neutrophils and
monocytes, are produced and stored in reservoirs in the bone marrow. Early soluble signals,
released into the blood in response to infection, stimulate increased cell production in the bone
marrow and the release of phagocytes into the circulation, where they can be detected as a sign
of infection by blood tests measuring white cell numbers. This early mobilization can slow down
the spread of pathogens, trapping them locally and hindering their growth.
Macrophages and neutrophils also produce toxic chemicals that kill, and enzymes that disrupt
tissue. For the individual cells, this is a suicidal strategy: they are sacrificed to end infection.
This destruction can result in the formation of an abscess; a collection of dead immune cells and
dead bacteria. Such a focus of infection can be relatively benign, if it is localized to peripheral
soft tissues and heals quickly. The same kind of response in a more vulnerable tissue, such as the
kidney or the eye, can cause irreversible damage. It may eliminate the infection, but destroy the
function of the organ that has been affected. Healing that is delayed or incomplete, because the
infection cannot be cleared, can produce chronic damage and long-term disability. Antibiotic
therapy is some help, but chronic infection of this kind continues to be a cause of illness and
disability worldwide.
Eating infections is not without risk for the phagocyte. Following engulfment, the target is
surrounded in a structure (a phagosome) that fuses with a second organelle called
a lysosome, which provides enzymes to digest the bacteria. These enzymes are activated by
lowering the pH of the environment. Certain infections, such as tuberculosis (caused
by Mycobacterium tuberculosis) and Legionnaire's disease (cause by Legionella pneumophila)
resist this process, inhibit the fusion of the phagosome with the lysosome, and use this route as a
way to hide from adaptive immune responses and to disseminate throughout the body. Infected
macrophages can be stimulated to clear their load of Mycobacterium, but this needs help
provided by antigen-specific T-cells that recognize the signs of tuberculosis infection in the
MHC molecules and release interreron γ. Here the adaptive and innate immune responses can
be seen to be co-operating to destroy an infection that is hidden within cells.
Adaptive immune responses can also be very important in interrupting the development of
disease. It takes time to produce specific antibodies, because they only develop naturally during
and after an episode of infectious disease. Getting the immune system to generate them, without
suffering from the disease, can be brought about by vaccination as discussed below. If they are
present, antibodies activate the immune system with speed and specificity. Their exceptional
sensitivity facilitates a rapid and targeted response, which can halt an infection before it
provokes any symptoms. Antibodies interrupt the transmission of viruses by binding to surface
proteins needed for cell entry. The different strategies that viruses use to enter cells all depend on
specific molecular recognition. Interfering with this specific binding process will stop the virus
in its tracks. This kind of neutralization is also effective against protein toxins, such as the
diphtheria toxin, that bind to a receptor at the cell surface as the first step in their attack. Specific
antibody that binds the molecules needed for cell entry by a virus or by a toxin prevents disease
developing.
Antibodies do not just interfere with entry into cells. Natural antibodies are all bifunctional
(Figure 1). At one end is the structure that mediates specific recognition (called the Fab
rragment), but at the other is a tail (called the Fc rragment) that engages directly with other
elements of the immune system. This interaction can be a simple ‘eat me’ signal coating bacteria
and attracting the attention of phagocytes, or a ‘kill me’ signal that recruits killer cells. Some Fc
tails bind and activate complement protein that are present in the blood. This starts a powerful
proteolytic cascade that forms pores on the surface of bacteria and punch through their tough cell
walls, killing them and leaving them for disposal by phagocytes. Another type of Fc tail
produces an isotype called IgE, attaches antibodies to the surface of granulocyte cells. If they
encounter an antigen that they recognize they signal the granulocytes to release inflammatory
mediators such as histamines and leukotrienes. These responses are especially relevant in
immunity to parasites and in diseases such as asthma and allergy.
The Fc part of an antibody molecule is also used as a signal to transport it across cell barriers.
The majority of new antibody that a healthy human produces ends up outside the body in the
intestines and in the lungs. Once in these mucosal locations, such antibodies can bind and
neutralize pathogens and toxins, before they have the opportunity to cross into the circulation.
Because all antibodies facilitate specific recognition but have tails that deliver different
functions, they are named on the basis of their tails (Table 2).
The path that immune responses follow does not always lead to the complete elimination of
infection. Cold sores caused by herpesviruses and tuberculosis are two examples of pathogens
that achieve long-term colonization in susceptible individuals. When we study antigen-specific
immune cells in these circumstances, they appear to be very different from both naive cells and
effector cells. Aggressive immune responses are shut down in two ways. The first is intrinsic to
the cells that have been attacking the infection, and depends on the up-regulation of co-
inhibitory receptors on the cell surface. Signals from these co-inhibitory receptors switch off
attacking functions, such as cell killing, and terminate local destruction of tissue and of
pathogen-infected cells. This is a trade-off between continuing damage and tolerating the
presence of infected cells. The extrinsic type of regulation is the expansion of the antigen-
specific T-regulatory cells, which secrete anti-inflammatory cytokines that limit immunity and
promote tissue healing. Regulatory cells, which are stimulated by tissue antigens, play a very
important role in managing the immune system. Mutations that cripple them cause severe
autoimmune disease in animals and people, showing how crucial the control of immune
responses is to health.
These regulating pathways are meant to be beneficial, but they can be exploited by disease. This
is particularly significant in cancer. Tumours are commonly infiltrated by many different
types of immune cell. But although these cells can often respond to cancer antigens, they do not
succeed in killing the tumour, and this is because successful cancers produce signals that drive
the immune system towards self-regulation, shutting off aggressive potentially tumour-
destroying effector mechanisms.
Reviewing how the immune system manages an infection, there is a clear pattern. In the
beginning, signals attract early non-specific cells that can kill and limit spread, then there is an
explosive adaptive immune response that recruits antigen-specific cells and produces high-
affinity antibodies that can block key molecular signals that the pathogen need to thrive. Finally,
either there is a successful resolution that eliminates the danger or the immune cells negotiate a
truce through a delicately adjusted process of regulation that preserves the function of the whole,
even at the expense of tolerating ongoing colonization (see Appendix 1 for a summary).
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Memory
Memory is the signature attribute of the immune system. Individuals who recover from a specific
pathogen resist reinfection with the same disease. This striking outcome is the key to
vaccination, so it may be a surprise there is still a great deal to learn about how immunological
memory develops. The benefits of an immune system that can fight off measles more effectively
the second time it tries to attack is obvious. But the ability of the immune system to learn is also
critical for a more subtle reason. One advantage that pathogens have over mammals is that they
can evolve much faster than their hosts. An adaptive immune system that can learn to recognize
a new infection in a few weeks, rather than having to wait a lifetime to develop an effective
defence, provides a bulwark against emerging diseases that have never been encountered before.
The classical measurement of immune memory focuses on the antibody response. Following an
infection (or a vaccination), specific antibody levels rise, with a lag of about a week, to a peak
around 10 days, and then fall off with time to lower levels that are not as low as in the naive state
(Figure 8). Re-challenge with the same stimulus produces a faster (1–3 days), larger (more
antibody is produced) and higher-avidity (as a result of the evolution and selection of higher
affinity antibodies; Figure 7) response. Other changes are also apparent, particularly that the
predominant isotype of the antibody response will usually have shifted to IgG (and sometimes
IgA or IgE).
Figure 8
Antibody responses to vaccination
Following the first immunization, increases in specific antibody can be detected. The levels of
this fall but do not return to baseline. Following the boost, the secondary response is greater and
the baseline is higher. Kinetics and levels vary between individuals and between different
vaccines.
These well-documented and robustly replicable responses are clearly a necessary part of immune
memory, but they are not the whole story. In parallel with changes that are occurring in the
antibody response and can be measured in the serum, other important developments occur in
different populations of antigen-specific lymphocytes.
B-cells develop into two kinds of immune memory cell. Plasma cells localize in bone marrow or
mucosal tissues and produce high-affinity antibodies, for many years. Other B-cells become
memory cells which do not actively secrete antibody, but remain in the circulation and the
mucosal tissue long-term, retaining the potential to develop antibody production. By the time an
individual becomes an adult, their blood contains antibodies produced from cells that have
responded to many different infections.
T-cell populations are also shaped by an individual's history. The simplest change that can be
measured experimentally is that, following an infection or an immunization, there is an increase
in the fraction of the T-cell population with TCRs that recognize that infection. A simple
interpretation of how this is ‘memory’ is that a higher frequency of specific cells means a shorter
time between a new infection occurring and it being recognized. T-cells also undergo changes in
their internal requirements for activation. Cells that have ‘seen’ an antigen are easier to activate.
They have a lower threshold for triggering (responding to antigens at lower concentrations than
naive cells) and become activated by signals that naive cells ignore. Their life expectancy is also
extended, so they hang around longer. Furthermore, some subpopulations of T-cells home to the
tissues where the infection was first detected. For example, if a pathogen enters through the skin,
lymphocytes will take up residence here and remain, as though ‘on guard’. Although
immunologists have been slow to enumerate these components of the memory response, it is
becoming clear that a great deal of the immune resource is devoted to seeding organs with
memory cells, particularly when these tissues are close to the outside world.
All of the changes discussed above seem to occur in a fashion that is independent of whether the
offending infection is still present. But there are still questions here that are hard to answer, such
as how serial infections, with different organisms, are handled. Is there an elastic capacity to
keep all memory cells or do new memory cells drive out old? We know that certain infections
regularly induce life-long protection and other infections do not. Understanding whether we can
convert the latter into the former in some way is an important part of vaccine research.
In spite of all the different mechanisms that the immune response deploys, there are infections
that regularly succeed in establishing long-term colonization. In this situation, can the immune
response do anymore? Chronic infections, and chronic immune responses generally, can induce
the immune system to take a further step. This is the local development of specialized immune
tissue. It produces what is effectively a lymph node at the chronically inflamed site, which
attracts dedicated B-cells and T-cells, and forms a structure that incorporates modified blood
vessels and support tissues to increase the efficiency of local immune responses. However, in
some conditions, such as autoimmune disease, these changes are associated with a poor outcome
for the patient, because they represent a stronger underlying immune drive that does more
damage to healthy tissue.
Immune responses are not just concerned with driving immunity forward; there are many
negative-feedback loops that shut responses down. Humoral responses, mediated by antibody,
use a specific type of receptor (a special type of Fc receptor) that senses the levels of Ig in the
environment and shuts down its production once it reaches a certain level. T regulatory cells
limit exuberant immune responses to self-antigens.
In summary, although the importance of immune memory is unquestionable, its implementation
is a subtle interplay of cell types, effector molecules and timing at least as complex as the acute
immune response and equally fascinating.
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Immunodericiency
One argument for the importance of immune systems, i.e. that every living thing devotes
precious resources to them, does not address how crucial this is at different stages of life.
Furthermore, animals and people with crippled immune systems grow, develop and reproduce
fairly normally, if they are protected from pathogenic infections, so there is no intrinsic need for
a functional immune system for life. This raises a question of how fundamental to good health
the immune response is? Experiments of Nature have given us a very clear answer.
Rarely, but regularly, individuals are born without an effective immune system. This arises when
uncommon mutations prevent immune cells from maturing. Such children have a very limited
life expectancy. Without immunity, they are repeatedly attacked by the organisms that afflict all
of us. For individuals with severe immunodeficiency, a successful bone marrow transplant is a
standard life-saving treatment, using donor cells that do not harbour the dangerous mutation, or
their own cells modified by genetic engineering to correct the defect.
Less dangerous, but still severe, are mutations that cripple a particular arm of the immune
response. Patients whose complement proteins do not work suffer from repeated infections with
bacteria that cause abscesses and pneumonia; patients with deficiencies in their natural killer
cells are highly susceptible to herpesvirus infections. Patients who have macrophages that cannot
digest the bacteria that they eat, develop recurrent abscesses that are difficult to treat. The most
common are defects that arise in antibody-producing cells, and these conditions are often X-
linked, i.e. encoded on the female X chromosome and so commoner in men than women.
Clearly, in the wild, adequate immunity is crucial to a healthy childhood.
What about adults; does the ability to mount an immune response continue to be important as we
age? Here, again, the answer is delivered through our study of disease. HIV infection cripples
the immune system, producing profoundly immunocompromised individuals. Before the
development of effective anti-retroviral therapy, HIV that reached the stage of AIDS was a death
sentence. This was because patients developed uncommon infections and cancers, which could
no longer be tackled by the ravaged immune system that had been destroyed by HIV.
Immunosuppression for other reasons is becoming increasingly common, because it is a useful
treatment for many different diseases. Immunosuppression may be profound when patients have
received transplanted organs or bone marrow. Sometimes it is more focused, for example
targeting specific cytokines such as tumour necrosis ractor (TNF) and interleukin (IL)-17 or
targeting molecules that regulate how immune cells migrate around the body. For example, drugs
used to treat multiple sclerosis, which inhibit T-cell trafficking into the brain, are effective in
reducing autoimmune disease, but occasionally lead to the re-emergence of previously
suppressed infection, which was being held in check. Therapies that neutralize TNF give great
relief to patients with rheumatoid arthritis, but, in some cases, this promotes the re-emergence of
tuberculosis. These immunodeficiencies, arising because of infection or therapy in adults,
indicate that an active immune response remains an important guardian of health throughout life.
Autoinrlammation
Defects in innate immunity, in complement pathways, which presented with recurrent infection,
were identified in the 1970s. More recently, we have come to understand that mutations in the
sensing systems that the innate immune system uses to calibrate danger, can lead to inherited
illness. One important sensor is called the inrlammasome, an intracytoplasmic structure that
assembles from several proteins when the cell detects danger. Subunits of the inflammasome
come together and activate an enzyme that then releases inflammation promoting cytokines.
Once in the circulation, these cytokines can cause sickness and fever.
Inflammasome activation is triggered by changes in the environment that cause the subunits to
assemble. The disease gout, which follows the deposition of crystals in small joints such as the
toe, depends on inflammasome activation by these crystals, which lead to inflammation.
Inherited diseases arise as a result of gain-or-runction mutations in part of the inflammasome
machinery that leads to spontaneous assembly, or assembly following mild environmental
change such as exposure to cold. Some of these mutations are compatible with a relatively
normal life expectancy, and have a 50:50 chance of being passed on to the affected parent's
offspring. Other related diseases are much more severe. And, although the underlying cause may
be a mutation in a molecular pathway that is part of the innate immune system, large-scale and
persistent inflammation can, in time, lead to the development of autoimmunity too.
Autoimmunity
Autoimmune disease occurs when the adaptive immune system mounts an attack against healthy
tissue. Recent research indicates that resistance to infection and susceptibility to autoimmune
disease are intimately connected. Individuals with a ‘stronger’ immune system, which reacts
aggressively to infection, are also more likely to develop autoimmune disease. This is another
example of the delicate balance the immune system strikes between its response to the safe or the
dangerous environment.
As with all other adaptive immune discrimination, the antigen that is targeted determines that
pattern of disease. This means that some autoimmune diseases affect a number of different
organs [e.g. systemic lupus erythaematosus (SLE), where the targets are common components of
nucleus and cytoplasm components], whereas others attack a single organ, for example the brain
in the disease multiple sclerosis (where the targets are proteins found only in the brain). Early
theories of autoimmunity postulated that it occurred because of the escape from the thymus of
aberrant T-cells that could see autoantigens. But it has been well established that all individuals
harbour potentially dangerous T-cells and the key question is not how they escape from the
thymus, but how they become activated to a state that causes disease.
There are two situations in which this has been shown to happen. The first follows a sudden
change in a tissue. This might be an infection that kills cells or an accident that causes local
damage. This tissue damage releases signals that trigger an immune response against itself. This
would usually be contained by feedback inhibition, but, when it is not, autoimmune disease can
follow. The second is when antigens derived from the tissue and those produced by an infection
are very similar and the host has a TCR that can recognize both. If the T-cell is activated and
expands, discrimination between the infection and the tissue fails and the normal tissue antigens
provoke an ongoing immune response. Both of these processes can be demonstrated in animal
models of autoimmune disease.
However, in human disease, we rarely know by which of these pathways disease has developed.
Infections that contain cross-reactive antigens probably also always cause tissue damage, and an
accident that is bad enough to damage tissue is often accompanied by broken skin and the
possibility of infection. Triggering events are also often clinically trivial. When patients receive
their first diagnosis of autoimmune disease, they often have a history of recent illness. But it is
unusual that they have been sick enough to have seen a doctor. So there is no connection
between the seriousness of the triggering event and the severity of the autoimmune disease that
follows.
After an autoimmune has been diagnosed, more often than not, it becomes a chronic problem. It
is also likely to wax and wane. This ‘relapsing and remitting’ pattern reflects underlying waves
of activation and regulation, changing the level of autoimmune attack (Figure 9).
Allergy
On the other hand, antigen-specific therapies have proved to be useful in allergy. Like
autoimmune disease, allergy is caused by an inappropriate immune response. In this case,
however, the triggering antigen is not an autoantigen, but a usually innocuous environmental
protein. Allergic responses can arise to a very broad range of different stimuli. These might be
natural, such as the pollens that cause hay fever, or they may be drugs, such as the antibiotic
penicillin. Allergic responses are very specific, as you would expect, because they are adaptive
immune responses. Every individual's hay fever is triggered by one type of pollen, not by any
pollen. Patients with an allergy to penicillin are safe taking other kinds of antibiotic.
Allergies are the commonest type of acquired immune disease. They usually depend on an IgE-
mediated immune response to the environmental antigen. As with triggering autoimmune
disease, the initial sensitizing event may not even be perceived, but it leads to high-affinity IgE
antibodies being generated. The IgE binds to granulocyte cells and acts as a receptor for the
allergen, releasing powerful inflammatory mediators when they are triggered. Such cells are
abundant at mucosal surfaces where it is thought that their normal role is to eliminate dangerous
toxins, which explains the sometimes rapid and dramatic symptoms that their activation
produces.
Allergies have been successfully treated for many years by a technique called desensitization:
starting from tiny doses, a patient is gradually exposed to increasing amounts of the triggering
antigen. This gradual escalation stimulates negative-feedback mechanisms that keep the allergic
reaction in check. For patients with severe reactions, this treatment will protect them from a
potentially fatal reaction if they encounter the allergen in the environment.
Both allergy and autoimmune disease are becoming much more common in first-world
populations. Studies have consistently shown that the fraction of people developing these
diseases is increasing. Why this should be the case has not been proved, but one suggestion, the
‘hygiene hypothesis’, postulates that modern standards of public health, which have had a
profound impact on the timing and type of infections that children encounter as they grow up,
have changed the overall balance of the immune response. Childhood mortality is much lower
because of better public health, but immune systems that develop in this cleaner world may be
less educated and more prone to errors in discrimination. Such ideas are difficult to prove
conclusively, but have received partial support in numerous experiments and epidemiological
investigations that highlight the subtle and complicated interplay between an individual immune
system and the environment.
Go to:
Applications or immunology
Table 3.
Blood group incompatibilities
Blood group Serum contains antibodies against Serum lacks antibodies against
A B A and O
B A B and O
O A and B O
AB Nil O, A and B
Transplanting whole tissues was a much more difficult challenge. Ensuring that blood groups
matched was not enough to prevent rejection. In 1944, it was not even generally accepted that
rejection involved an immune response. Peter Medawar, working on skin grafting in rabbits,
demonstrated that this was the case by establishing that second grafts were rejected more rapidly
than first grafts. He then went on to estimate a minimum number of antigens that was necessary
to explain the fact that no rabbit accepted a graft from any other. He showed that the fewest
number of antigens that could produce this result was seven, a finding he described as
“astonishing”. Although there were three major blood groups, he concluded that, for skin
transplantation groups, there must be at least 127. Although as we now know, because this
process is regulated by thousands of different MHC alleles, this was a large underestimate, it set
the scene for scientists and surgeons to understand that successful transplantation strategies must
always incorporate a plan to manage the immune system. Since then tissue typing has played a
key role in this process, first using methods detecting antigen expression on white blood cells
and more recently by using DNA sequencing to detect HLA genes to find well-matched organ
donors.
Vaccination
In 2014, the Centers for Disease Control and Prevention in the U.S.A. published an estimate of
the impact of their national vaccination programme over the previous 20 years. They concluded
that over the lifetime of the immunized individuals that there would be 21 million fewer
hospitalizations and 732000 fewer deaths. The success of vaccination is rarely emphasized in
media coverage, but it is an enormous and cost-effective benefit. Vaccination, as a public health
strategy to harness the immune response, pre-dates by at least a century acceptance of the germ
theory of disease, which provides a mechanistic understanding of why it is effective. It has a
crucial and continuing role in the fight against both ancient and emerging infections.
The most notorious disease against which vaccination has been applied is smallpox. A scourge
among humans since at least 1100 years BCE, it was a terrifying condition, transmitted through
the air, which killed 20–30% of individuals who became infected and left the survivors severely
disfigured by scarring. Among naive populations, i.e. those which had never encountered the
infection, it was even more deadly. In 1738, smallpox killed half of all the Cherokee Indians in
the U.S.A. Vaccination against smallpox was pioneered by Edward Jenner in the 18th Century,
and in 1958, the World Health Organization (WHO) adopted a resolution to attempt global
eradication. The disease was cornered by a combination of vaccination, surveillance and
containment of epidemic hotspots. Factors that helped successful eradication included that
humans played an essential role in the life cycle of the virus, that there was no natural reservoir
in the animal kingdom, and that smallpox did not establish a carrier state, in which symptomless
individuals were contagious. As progress reducing smallpox outbreaks continued and the number
of victims fell, the WHO optimized a strategy of tracing and vaccinating contacts, working
outwards from the patient to contain the disease. Through the dedicated work of many
individuals, the world was certified free of the smallpox in 1979. This great success has been
challenging to replicate with other diseases. To date, the only other infection to be exterminated
entirely from the wild by vaccination is rinderpest. This was caused by a virus related to measles
which affected cattle, and had a mortality approaching 100% in non-immune populations.
Local eradication of other diseases through vaccination has proved possible. Polio has also been
eradicated in almost all countries, thanks to vaccination. Following a programme in Finland,
starting in 1982, measles, mumps and rubella were eliminated from the indigenous population
between 1996 and 1997. Maintaining this freedom from disease remains an ongoing challenge;
as the immunity of the population wanes and the memory of how dangerous these illnesses were
fades, uptake of vaccination falls, but these viruses continue to circulate in other countries, from
which they could be reintroduced to a now susceptible population.
Vaccination works by immunizing individuals with a ‘safe’ version of the infectious agent, to
educate the immune system without causing severe illness. Some vaccines, for example that for
polio, use weakened (attenuated) strains of live virus. For other conditions, heat-killed
preparations may be preferred or the vaccine may contain recombinant proteins that have been
synthesized and purified from cell culture (e.g. hepatitis and human papillomavirus vaccines).
Vaccines are remarkably safe, but each new vaccine is unique and occasional unanticipated
complications do occur. Where these are common, they will be detected early in clinical trials,
but if they are rare they will only become evident after millions of doses of the vaccine have
been given. These rare outcomes are impossible to predict and must be identified by monitoring
the vaccinated. Such complications do less damage than the diseases that they are a protection
from when these infections are at large. But as the illnesses themselves become rarer, the
benefits that vaccination produces become more difficult to appreciate.
Devising vaccines for new infections is not straightforward. It is instructive to set against the
astonishing success that is the eradication of smallpox, the failure to date to discover a vaccine of
similar efficacy that is effective against malaria or HIV. This does not reflect a lack of effort, but
does illustrate that our ability to harness and manipulate the immune response remains limited.
There is still much to learn.
Immunotherapy
Immunotherapy is treatment that exploits our understanding the immune response in animals or
people to achieve a medical benefit. It may use the specificity of the immune response or target
general mechanisms such as co-stimulation, either enhancing or inhibiting them. The earliest
example of effective immunotherapy is vaccination against smallpox, discussed above, but there
are many other areas into which these techniques extend. One of the first clinical applications of
immunotherapy was the development of passive immunity against diphtheria toxin, introduced
by Emil Behring and based on work reported in 1890. Behring and Kitasato Sibasaburo
immunized guinea pigs with attenuated toxin and discovered that their serum could cure animals
infected with virulent strains of the disease. In 1891, this approach was used to save a child with
diphtheria (at the time, this disease was killing more than 50000 children a year in Germany). By
1892, this antitoxin was being produced commercially, first in Germany and later in London.
Such anti-toxins continue to have a role in modern therapy to this day.
In autoimmune diseases, the goal of immunotherapy is to shut off the immune response. The
gold standard would be a treatment that selectively disables only the antigen-specific response
directed at self, leaving the rest of the immune system intact to defend the patient against
infection. This has proven to be extremely difficult to achieve in human populations, where
immune responses are mediated through a myriad of overlapping antigen specificities, but it can
be demonstrated in animal models of autoimmune disease, which provides hope that such
therapies can be developed. The overarching idea is that it should be possible to reprogramme
the immune response to ignore specific autoantigens, something that might be considered the
reverse of immunization.
In the absence of effective autoantigen-specific therapies for autoimmune disease, other
approaches have proved useful. One is to neutralize the soluble mediators that signal
inflammation. This has been applied to rheumatoid arthritis, an autoimmune disease that attacks
the joints. Blocking the cytokine TNF brings rapid and long-lasting benefit to patients. This is
done in a number of ways, but one is a modern reinvention of Behring's approach. Mouse
monoclonal antibodies that recognize and neutralize TNF were identified and then engineered so
that the backbone of the antibody was human. These can then be injected into patients to
neutralize the actions of the cytokine. Of course, TNF is not just important for mediating arthritis
and patients who receive this treatment are immunosuppressed. Although this suppression is not
as profound as it would be following an organ transplant, there is still an increased risk of
reactivation of infections such as tuberculosis. Other anti-cytokine antibodies have also proved
useful, for example they are used to treat autoinflammatory diseases (anti-IL-1 and anti-IL-6)
and skin diseases such as psoriasis (anti-IL-17).
As well as blocking soluble mediators, antibodies can block interactions between molecules on
the surface of cells. This effect is used in a treatment that stops T-cells moving out of the blood
and into the brain of patients with multiple sclerosis. This therapy developed from research in
mice that showed that lymphocytes used specific receptors to regulate how they moved into
different organs. The equivalent molecules are used by lymphocytes in humans and blocking
them with antibody reduces the number of attacks of disease in patients with multiple sclerosis.
A side effect of these drugs is that they limit immunosurveillance. In rare cases, this precipitates
the emergence of dangerous infections in the brain, which were previously held in check by the
immune system.
Cancer can also be treated by exploiting the immune response. One early strategy for successful
immunotherapy for cancer used monoclonal antibodies that blocked receptors which the tumour
cells used to receive growth-promoting signals. These treatments are beneficial when the cancer
cells express these receptors, but their impact is generally of only a limited duration and is
eventually followed by a relapse. This is because, similar to the way that viruses live many
lifetimes to that of a human, a growing cancer is a fast-evolving threat to health. Cancers arise
when mutations that permit unrestrained growth develop, and this growth is associated with
much less reliable checking of genetic fidelity. Modern techniques have allowed researchers to
develop family trees based on mutations in a cancer's genes, showing how they consist of related
lineages of cells that peel off from the parental line and expand through time. Every mutation
that develops is an opportunity for the immune system to push back, by recognizing tumour
antigens on their surface in their MHC molecules. If this mechanism were failsafe, tumours
would never progress beyond this stage. But cancer can escape the immune system by deploying
a number of mechanisms that shut the immune responses down. Understanding how this occurs
has stimulated the development of a number of new therapies that are having an astonishing
impact against some types of cancer.
Two lines of research were important in reaching these conclusions. One came from studies that
showed that a cancer, which evolved through time, in an environment where there was an intact
immune response gradually developed the ability to grow despite immune system control. This
suggested that the immune response kept the cancer in check for a while and exerted a pressure
that selected mutations which permitted escape. The second strand came from workers interested
in co-inhibitory cell-surface molecules regulating lymphocyte activation. It was discovered that
these were an abundant family of different molecular receptors, which could limit immune
activation or even shut it down completely. Cancers learn to use the signals that turn
lymphocytes off, persuading them not to kill. But the tumours cannot eliminate the immune cells
and so they remain in an uneasy truce with the tumour, present but not activated.
Once it was realized that some tumours were constantly delivering negative signals to immune
cells, it became feasible to devise strategies to interfere with these signalling pathways. Once
again, targeting them with antibodies to block this signalling was an obvious and appropriate
approach. Drugs that do this have now been tested in patients and, in some cases, the results have
been quite remarkable. As of 2015, two pathways have been successfully targeted in clinical
trials, inhibiting molecules called CTLA4 and PD1. There is some evidence that attacking both
together is even more effective than either used alone. Following treatment with these drugs,
some patients thought to have weeks or months to live have developed long-term remissions that
have been so striking that the possibility that some of them are cured is beginning to be
considered. Such powerful interventions are not without side effects. Unleashing immune
responses can be intolerable and sometimes fatal; patients who cannot control lymphocyte
activation may develop autoimmune diseases, unrelated to their cancer, as a result of subclinical
disease that was previously held in check. However, in cancer cases, the benefits often outweigh
the side effects, and, as we learn more about how to apply such treatment, we will learn how to
better manage the accompanying autoimmunity.
Cancer immunotherapy that uses killer cells to selectively target the tumour cells is also being
tested in clinical trials. By combining genetic engineering with cell culture techniques, a number
of small studies have established that it is possible to create T-cells that will target tumour cells
and cannot be turned off. These cells [chimaeric antigen receptor (CAR) T-cells] are genetically
engineered and grown outside that patient's body and then reinfused. On their return, they
expand and destroy tumour cells. Although side effects due to extensive cytokine release are an
important complication, these therapies too can lead to very long-term remissions. This proof of
principle raises the possibility in the future of making an individual's unique cancer antigens the
target of an immune response. The barriers to these types of treatment are many, not least their
cost, but they are a very real opportunity for effective, immune-based and individually tailored
cures for cancer.
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Conclusion
Immunity works in a co-ordinated fashion to respond to numerous threats from the environment.
It is essential to good health, from the moment of conception, when the mother's immune system
starts protecting the growing baby, until old age. As medicine has progressed, physicians have
slowly learned how to apply an understanding of the fundamentals of immunology to reinforce
and repurpose the immune response, providing greater protection against infection or targeting
cancers. Immunotherapy has been improving human health since Edward Jenner coined the term
vaccination and it will have much more to contribute in the future.
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Abbreviations
Ig immunoglobulin
IL interleukin
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Appendix 1. Overview or the immune process
This article is a reviewed, revised and updated version of the following ‘Biochemistry Across the
School Curriculum’ (BASC) booklet: Davey, B. Immunology. For further information and to
provide feedback on this or any other Biochemical Society education resource, please
contact education@biochemistry.org. For further information on other Biochemical Society
publications, please visit www.biochemistry.org/publications.
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Competing Interests
The Author declares that there are no competing interests associated with this article.
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Recommended reading and key publications
Go to:
Immunology
1. Abbas A.K., Lichtman A.H., Pillai S. Basic Immunology: Functions and Disorders of the
Immune System. Amsterdam: Elsevier; 2016. [Google Scholar]
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1989. [Google Scholar]
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General reading
1. Ferry G., Sulston J. The Common Thread. London: Random House; 2002. [Google
Scholar]
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