An
immune system is a
system
of biological structures and
processes within an
organism that protects against
disease by identifying and killing
pathogens and
tumour cells.
It detects a wide variety of agents, from
viruses to
parasitic
worms, and needs to distinguish them from the organism's own
healthy
cells and
tissues in order to function properly.
Detection is complicated as pathogens can
evolve rapidly, producing
adaptations that avoid the immune system and
allow the pathogens to successfully infect their
hosts.
To survive this challenge, multiple mechanisms evolved that
recognize and neutralize pathogens. Even simple
unicellular organisms such as
bacteria possess
enzyme
systems that protect against
viral
infections. Other basic immune mechanisms evolved in ancient
eukaryotes and remain in their modern
descendants, such as
plants,
fish,
reptiles, and
insects. These mechanisms include
antimicrobial peptides called
defensins,
phagocytosis, and the
complement system.
Vertebrates such as humans have even more
sophisticated defense mechanisms. The immune systems of vertebrates
consist of many types of
proteins, cells,
organs, and tissues, which interact
in an elaborate and dynamic network. As part of this more complex
immune response, the human immune system adapts over time to
recognize specific pathogens more efficiently. This adaptation
process is referred to as "adaptive immunity" or "
acquired immunity" and creates
immunological memory.
Immunological memory created from a primary response to a specific
pathogen, provides an enhanced response to secondary encounters
with that same, specific pathogen. This process of acquired
immunity is the basis of
vaccination.
Disorders in the immune system can result in disease.
Immunodeficiency occurs when the immune
system is less active than normal, resulting in recurring and
life-threatening infections. Immunodeficiency can either be the
result of a
genetic disease, such as
severe combined
immunodeficiency, or be produced by pharmaceuticals or an
infection, such as the
acquired immune deficiency
syndrome (AIDS) that is caused by the
retrovirus HIV. In contrast,
autoimmune diseases result from a
hyperactive immune system attacking normal tissues as if they were
foreign organisms. Common autoimmune diseases include
Hashimoto's Thyroiditis,
rheumatoid arthritis,
diabetes mellitus type 1 and
lupus erythematosus.
Immunology covers the study of all aspects of the
immune system which has significant relevance to
human health and diseases. Further investigation in
this field is expected to play a serious role in promotion of
health and treatment of diseases.
Layered defense
The immune system protects organisms from
infection with layered defenses of increasing
specificity. Most simply, physical barriers prevent pathogens such
as
bacteria and
viruses from entering the organism. If a pathogen
breaches these barriers, the
innate
immune system provides an immediate, but non-specific response.
Innate immune systems are found in all
plants
and
animals. If pathogens successfully evade
the innate response, vertebrates possess a third layer of
protection, the
adaptive immune
system, which is activated by the innate response. Here the
immune system adapts its response during an infection to improve
its recognition of the pathogen. This improved response is then
retained after the pathogen has been eliminated, in the form of an
immunological memory, and
allows the adaptive immune system to mount faster and stronger
attacks each time this pathogen is encountered.
Both innate and adaptive immunity depend on the ability of the
immune system to distinguish between self and non-self
molecules. In
immunology,
self molecules are those components of an organism's body
that can be distinguished from foreign substances by the immune
system. Conversely,
non-self molecules are those
recognized as foreign molecules. One class of non-self molecules
are called
antigens (short for
antibody
generators) and are defined as
substances that bind to specific
immune
receptors and elicit an immune response.
Surface barriers
Several barriers protect organisms from infection, including
mechanical, chemical and biological barriers. The waxy
cuticle of many
leaves,
the
exoskeleton of
insects, the
shell and
membranes of externally deposited
eggs, and
skin are
examples of the mechanical barriers that are the first line of
defense against infection. However, as organisms cannot be
completely sealed against their environments, other systems act to
protect body openings such as the
lungs,
intestines, and the
genitourinary tract. In the lungs,
coughing and
sneezing
mechanically eject pathogens and other
irritants from the
respiratory tract. The flushing action of
tears and
urine also
mechanically expels pathogens, while
mucus
secreted by the respiratory and
gastrointestinal tract serves to trap
and entangle
microorganisms.
Chemical barriers also protect against infection. The skin and
respiratory tract secrete
antimicrobial peptides such as the
β-
defensins.
Enzymes
such as
lysozyme and
phospholipase A2 in
saliva, tears, and
breast
milk are also
antibacterials.
Vaginal secretions serve as a chemical
barrier following
menarche, when they
become slightly
acidic, while
semen contains defensins and
zinc
to kill pathogens. In the
stomach,
gastric acid and
proteases serve as powerful chemical defenses
against ingested pathogens.
Within the genitourinary and gastrointestinal tracts,
commensal flora serve
as biological barriers by competing with pathogenic bacteria for
food and space and, in some cases, by changing the conditions in
their environment, such as
pH or available iron.
This reduces the probability that pathogens will be able to reach
sufficient numbers to cause illness. However, since most
antibiotics non-specifically target bacteria and
do not affect fungi, oral antibiotics can lead to an “overgrowth”
of
fungi and cause conditions such as a
vaginal
candidiasis (a yeast infection).
There is good evidence that re-introduction of
probiotic flora, such as pure cultures of the
lactobacilli normally found in
unpasteurized
yoghurt, helps restore a
healthy balance of microbial populations in intestinal infections
in children and encouraging preliminary data in studies on
bacterial gastroenteritis,
inflammatory bowel
diseases,
urinary tract
infection and
post-surgical
infections.
Innate
Microorganisms or toxins that successfully enter an organism will
encounter the cells and mechanisms of the innate immune system. The
innate response is usually triggered when microbes are identified
by
pattern recognition
receptors, which recognize components that are conserved among
broad groups of microorganisms, or when damaged, injured or
stressed cells send out alarm signals, many of which (but not all)
are recognized by the same receptors as those that recognize
pathogens. Innate immune defenses are non-specific, meaning these
systems respond to pathogens in a generic way. This system does not
confer long-lasting
immunity
against a pathogen. The innate immune system is the dominant system
of host defense in most organisms.
Humoral and chemical barriers
Inflammation
Inflammation is one of the first responses of the immune system to
infection. The symptoms of inflammation are redness and swelling,
which are caused by increased
blood flow into
a tissue. Inflammation is produced by
eicosanoids and
cytokines, which are released by injured or
infected cells. Eicosanoids include
prostaglandins that produce
fever and the
dilation of
blood vessels associated with
inflammation, and
leukotrienes that
attract certain
white blood cells
(leukocytes). Common cytokines include
interleukins that are responsible for
communication between white blood cells;
chemokines that promote
chemotaxis; and
interferons that have
anti-viral effects, such as shutting down
protein synthesis in the host
cell.
Growth factors and cytotoxic
factors may also be released. These cytokines and other chemicals
recruit immune cells to the site of infection and promote healing
of any damaged tissue following the removal of pathogens.
Complement system
The complement system is a
biochemical cascade that attacks the
surfaces of foreign cells. It contains over 20 different proteins
and is named for its ability to “complement” the killing of
pathogens by
antibodies. Complement is the
major
humoral component of the
innate immune response. Many species have complement systems,
including non-
mammals like plants, fish, and
some
invertebrates.
In humans, this response is activated by complement binding to
antibodies that have attached to these microbes or the binding of
complement proteins to
carbohydrates on
the surfaces of
microbes. This recognition
signal triggers a rapid killing
response. The speed of the response is a result of signal
amplification that occurs following sequential
proteolytic activation of complement molecules,
which are also
proteases. After complement
proteins initially bind to the microbe, they activate their
protease activity, which in turn activates other complement
proteases, and so on. This produces a
catalytic cascade that amplifies the initial
signal by controlled
positive
feedback. The cascade results in the production of peptides
that attract immune cells, increase
vascular permeability, and
opsonize (coat) the surface of a pathogen, marking
it for destruction. This deposition of complement can also kill
cells directly by disrupting their
plasma
membrane.
Cellular barriers
Leukocytes (
white blood cells) act
like independent, single-celled organisms and are the second arm of
the innate immune system. The innate leukocytes include the
phagocytes (
macrophages,
neutrophils, and
dendritic cells),
mast
cells,
eosinophils,
basophils, and
natural killer cells. These cells
identify and eliminate pathogens, either by attacking larger
pathogens through contact or by engulfing and then killing
microorganisms. Innate cells are also important mediators in the
activation of the
adaptive immune
system.
Phagocytosis is an important feature of
cellular innate immunity performed by cells called '
phagocytes' that engulf, or eat, pathogens or
particles. Phagocytes generally patrol the body searching for
pathogens, but can be called to specific locations by
cytokines. Once a pathogen has been engulfed by a
phagocyte, it becomes trapped in an intracellular
vesicle called a
phagosome, which subsequently fuses with another
vesicle called a
lysosome to form a
phagolysosome. The pathogen is killed
by the activity of digestive
enzymes or
following a
respiratory burst that
releases
free radicals into the
phagolysosome. Phagocytosis evolved as a means of acquiring
nutrients, but this role was extended in
phagocytes to include engulfment of pathogens as a defense
mechanism. Phagocytosis probably represents the oldest form of host
defense, as phagocytes have been identified in both vertebrate and
invertebrate animals.
Neutrophils and macrophages are phagocytes that travel throughout
the body in pursuit of invading pathogens. Neutrophils are normally
found in the
bloodstream and are
the most abundant type of phagocyte, normally representing 50% to
60% of the total circulating leukocytes. During the acute phase of
inflammation, particularly as a result of bacterial infection,
neutrophils migrate toward the site of inflammation in a process
called chemotaxis, and are usually the first cells to arrive at the
scene of infection. Macrophages are versatile cells that reside
within tissues and produce a wide array of chemicals including
enzymes,
complement proteins, and
regulatory factors such as
interleukin
1. Macrophages also act as scavengers, ridding the body of
worn-out cells and other debris, and as
antigen-presenting cells that
activate the adaptive immune system.
Dendritic cells (DC) are phagocytes in tissues that are in contact
with the external environment; therefore, they are located mainly
in the
skin,
nose,
lungs,
stomach, and
intestines. They are named for their resemblance
to
neuronal dendrites, as both have many spine-like
projections, but dendritic cells are in no way connected to the
nervous system. Dendritic cells serve
as a link between the bodily tissues and the innate and adaptive
immune systems, as they
present
antigen to
T cells, one of the key cell
types of the adaptive immune system.
Mast cells reside in
connective
tissues and
mucous membranes,
and regulate the inflammatory response. They are most often
associated with
allergy and
anaphylaxis. Basophils and eosinophils are
related to neutrophils. They secrete chemical mediators that are
involved in defending against
parasites
and play a role in allergic reactions, such as
asthma. Natural killer (
NK
cells) cells are leukocytes that attack and destroy
tumor cells, or cells that have been infected by
viruses.
Adaptive
The adaptive immune system evolved in early vertebrates and allows
for a stronger immune response as well as immunological memory,
where each pathogen is "remembered" by a signature antigen. The
adaptive immune response is antigen-specific and requires the
recognition of specific “non-self” antigens during a process called
antigen presentation. Antigen
specificity allows for the generation of responses that are
tailored to specific pathogens or pathogen-infected cells. The
ability to mount these tailored responses is maintained in the body
by "memory cells". Should a pathogen infect the body more than
once, these specific memory cells are used to quickly eliminate
it.
Lymphocytes
The cells of the adaptive immune system are special types of
leukocytes, called
lymphocytes.
B cells and
T cells are the
major types of lymphocytes and are derived from
hematopoietic stem cells in the
bone marrow. B cells are involved in the
humoral immune response, whereas T
cells are involved in
cell-mediated immune response.
Association of a T cell with MHC class
I or MHC class II, and antigen (in red)
Both B cells and T cells carry receptor molecules that recognize
specific targets. T cells recognize a “non-self” target, such as a
pathogen, only after antigens (small fragments of the pathogen)
have been processed and presented in combination with a “self”
receptor called a
major
histocompatibility complex (MHC) molecule. There are two major
subtypes of T cells: the
killer T
cell and the
helper T cell. Killer
T cells only recognize antigens coupled to
Class I MHC
molecules, while helper T cells only recognize antigens coupled to
Class II
MHC molecules. These two mechanisms of antigen presentation
reflect the different roles of the two types of T cell. A third,
minor subtype are the
γδ T cells
that recognize intact antigens that are not bound to MHC
receptors.
In contrast, the B cell antigen-specific receptor is an
antibody molecule on the B cell surface, and
recognizes whole pathogens without any need for
antigen processing. Each lineage of B
cell expresses a different antibody, so the complete set of B cell
antigen receptors represent all the antibodies that the body can
manufacture.
Killer T cells
Killer T cells directly attack other
cells carrying foreign or abnormal antigens on their
surfaces.
Killer T cell are a sub-group of T
cells that kill cells infected with viruses (and other pathogens),
or are otherwise damaged or dysfunctional. As with B cells, each
type of T cell recognises a different antigen. Killer T cells are
activated when their
T cell receptor
(TCR) binds to this specific antigen in a complex with the MHC
Class I receptor of another cell. Recognition of this MHC:antigen
complex is aided by a
co-receptor on the
T cell, called
CD8. The T cell then travels
throughout the body in search of cells where the MHC I receptors
bear this antigen. When an activated T cell contacts such cells, it
releases
cytotoxins, such as
perforin, which form pores in the target cell's
plasma membrane, allowing
ions, water and toxins to enter. The entry of another
toxin called
granulysin (a protease)
induces the target cell to undergo
apoptosis. T cell killing of host cells is
particularly important in preventing the replication of viruses. T
cell activation is tightly controlled and generally requires a very
strong MHC/antigen activation signal, or additional activation
signals provided by "helper" T cells (see below).
Helper T cells
Helper T cells regulate both the
innate and adaptive immune responses and help determine which types
of immune responses the body will make to a particular pathogen.
These cells have no cytotoxic activity and do not kill infected
cells or clear pathogens directly. They instead control the immune
response by directing other cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize
antigen bound to Class II MHC molecules. The MHC:antigen complex is
also recognized by the helper cell's
CD4
co-receptor, which recruits molecules inside the T cell (e.g.
Lck) that are responsible for the T cell's
activation. Helper T cells have a weaker association with the
MHC:antigen complex than observed for killer T cells, meaning many
receptors (around 200–300) on the helper T cell must be bound by an
MHC:antigen in order to activate the helper cell, while killer T
cells can be activated by engagement of a single MHC:antigen
molecule. Helper T cell activation also requires longer duration of
engagement with an antigen-presenting cell. The activation of a
resting helper T cell causes it to release cytokines that influence
the activity of many cell types. Cytokine signals produced by
helper T cells enhance the microbicidal function of macrophages and
the activity of killer T cells. In addition, helper T cell
activation causes an upregulation of molecules expressed on the T
cell's surface, such as CD40 ligand (also called
CD154), which provide extra stimulatory signals
typically required to activate antibody-producing B cells.
γδ T cells
γδ T cells possess an
alternative
T cell receptor (TCR) as
opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics
of helper T cells, cytotoxic T cells and NK cells. The conditions
that produce responses from γδ T cells are not fully understood.
Like other 'unconventional' T cell subsets bearing invariant TCRs,
such as
CD1d-restricted
Natural Killer T cells, γδ T cells
straddle the border between innate and adaptive immunity. On one
hand, γδ T cells are a component of
adaptive immunity as they
rearrange TCR genes to produce receptor
diversity and can also develop a memory phenotype. On the other
hand, the various subsets are also part of the innate immune
system, as restricted TCR or NK receptors may be used as
pattern recognition receptors.
For example, large numbers of human Vγ9/Vδ2 T cells respond within
hours to
common molecules
produced by microbes, and highly restricted Vδ1+ T cells in
epithelia will respond to stressed
epithelial cells.
An antibody is made up of two heavy
chains and two light chains.
The unique variable region allows an antibody to recognize its
matching antigen.
B lymphocytes and antibodies
A
B cell identifies pathogens when antibodies
on its surface bind to a specific foreign antigen. This
antigen/antibody complex is taken up by the B cell and processed by
proteolysis into peptides. The B cell
then displays these antigenic peptides on its surface MHC class II
molecules. This combination of MHC and antigen attracts a matching
helper T cell, which releases
lymphokines
and activates the B cell. As the activated B cell then begins to
divide, its offspring (
plasma cells)
secrete
millions of copies of the antibody that recognizes this antigen.
These antibodies circulate in blood plasma and
lymph, bind to pathogens expressing the
antigen and mark them for destruction by
complement activation or for uptake and
destruction by phagocytes. Antibodies can also neutralize
challenges directly, by binding to bacterial toxins or by
interfering with the receptors that viruses and bacteria use to
infect cells.
Alternative adaptive immune system
Although the classical molecules of the adaptive immune system
(e.g. antibodies and
T cell
receptors) exist only in jawed vertebrates, a distinct
lymphocyte-derived molecule has been discovered
in primitive
jawless vertebrates, such as
the
lamprey and
hagfish. These animals possess a large array of
molecules called variable lymphocyte receptors (VLRs) that, like
the antigen receptors of jawed vertebrates, are produced from only
a small number (one or two) of
genes. These
molecules are believed to bind pathogenic
antigens in a similar way to antibodies, and with
the same degree of specificity.
Immunological memory
When B cells and T cells are activated and begin to replicate, some
of their offspring will become long-lived memory cells. Throughout
the lifetime of an animal, these memory cells will remember each
specific pathogen encountered and can mount a strong response if
the pathogen is detected again. This is "adaptive" because it
occurs during the lifetime of an individual as an adaptation to
infection with that pathogen and prepares the immune system for
future challenges. Immunological memory can either be in the form
of passive short-term memory or active long-term memory.
Passive memory
Newborn
infants have no prior exposure to
microbes and are particularly vulnerable to infection. Several
layers of passive protection are provided by the mother. During
pregnancy, a particular type of antibody,
called
IgG, is transported from
mother to baby directly across the
placenta, so human babies have high levels of
antibodies even at birth, with the same range of antigen
specificities as their mother.
Breast
milk or
colostrum also contains
antibodies that are transferred to the gut of the infant and
protect against bacterial infections until the newborn can
synthesize its own antibodies. This is
passive immunity because the
fetus does not actually make any memory cells or
antibodies—it only borrows them. This passive immunity is usually
short-term, lasting from a few days up to several months. In
medicine, protective passive immunity can also be
transferred artificially from one
individual to another via antibody-rich
serum.
The time-course of an immune response
begins with the initial pathogen encounter, (or initial
vaccination) and leads to the formation and maintenance of active
immunological memory.
Active memory and immunization
Long-term
active memory is acquired following infection by
activation of B and T cells. Active immunity can also be generated
artificially, through
vaccination. The
principle behind vaccination (also called
immunization) is to introduce an
antigen from a pathogen in order to stimulate the
immune system and develop
specific
immunity against that particular pathogen without causing
disease associated with that organism. This deliberate induction of
an immune response is successful because it exploits the natural
specificity of the immune system, as well as its inducibility. With
infectious disease remaining one of the leading causes of death in
the human population, vaccination represents the most effective
manipulation of the immune system mankind has developed.
Most viral
vaccines are based on live
attenuated viruses, while many
bacterial vaccines are based on
acellular components of micro-organisms,
including harmless
toxin components. Since
many antigens derived from acellular vaccines do not strongly
induce the adaptive response, most bacterial vaccines are provided
with additional
adjuvants that
activate the
antigen-presenting
cells of the
innate immune
system and maximize
immunogenicity.
Disorders of human immunity
The immune system is a remarkably effective structure that
incorporates specificity, inducibility and adaptation. Failures of
host defense do occur, however, and fall into three broad
categories: immunodeficiencies, autoimmunity, and
hypersensitivities.
Immunodeficiencies
Immunodeficiencies occur when one
or more of the components of the immune system are inactive. The
ability of the immune system to respond to pathogens is diminished
in both the young and the
elderly, with
immune responses beginning to decline at around 50 years of age due
to
immunosenescence. In
developed countries,
obesity,
alcoholism,
and drug use are common causes of poor immune function. However,
malnutrition is the most common cause
of immunodeficiency in
developing
countries. Diets lacking sufficient protein are associated with
impaired cell-mediated immunity, complement activity, phagocyte
function,
IgA antibody
concentrations, and cytokine production. Deficiency of single
nutrients such as
iron;
copper;
zinc;
selenium;
vitamins A,
C,
E, and
B6;
and
folic acid (vitamin B
9)
also reduces immune responses. Additionally, the loss of the
thymus at an early age through
genetic mutation or surgical removal results in
severe immunodeficiency and a high susceptibility to
infection.
Immunodeficiencies can also be inherited or '
acquired'.
Chronic granulomatous
disease, where
phagocytes have a
reduced ability to destroy pathogens, is an example of an
inherited, or
congenital,
immunodeficiency.
AIDS and some types of
cancer cause acquired immunodeficiency.
Autoimmunity
Overactive immune responses comprise the other end of immune
dysfunction, particularly the
autoimmune
disorders. Here, the immune system fails to properly
distinguish between self and non-self, and attacks part of the
body. Under normal circumstances, many T cells and antibodies react
with “self” peptides. One of the functions of specialized cells
(located in the
thymus and
bone marrow) is to present young lymphocytes
with self antigens produced throughout the body and to eliminate
those cells that recognize self-antigens, preventing
autoimmunity.
Hypersensitivity
Hypersensitivity is an immune
response that damages the body's own tissues. They are divided into
four classes (Type I – IV) based on the mechanisms involved and the
time course of the hypersensitive reaction. Type I hypersensitivity
is an immediate or
anaphylactic
reaction, often associated with
allergy.
Symptoms can range from mild discomfort to death. Type I
hypersensitivity is mediated by
IgE
released from
mast cells and
basophils.Type II hypersensitivity
occurs when antibodies bind to antigens on the patient's own cells,
marking them for destruction. This is also called
antibody-dependent (or cytotoxic) hypersensitivity, and is mediated
by
IgG and
IgM antibodies.
Immune complexes (aggregations of antigens,
complement proteins, and IgG and IgM antibodies) deposited in
various tissues trigger Type III hypersensitivity reactions. Type
IV hypersensitivity (also known as cell-mediated or
delayed
type hypersensitivity) usually takes between two and three
days to develop. Type IV reactions are involved in many autoimmune
and infectious diseases, but may also involve
contact dermatitis (
poison ivy). These reactions are mediated by
T cells,
monocytes,
and
macrophages.
Other mechanisms
It is likely that a multicomponent, adaptive immune system arose
with the first
vertebrates, as
invertebrates do not generate lymphocytes or an
antibody-based humoral response. Many species, however, utilize
mechanisms that appear to be precursors of these aspects of
vertebrate immunity. Immune systems appear even in the structurally
most simple forms of life, with bacteria using a unique defense
mechanism, called the
restriction modification
system to protect themselves from viral pathogens, called
bacteriophages. Prokaryotes also
possess acquired immunity, through a system that uses
CRISPR sequences to retain fragments of the genomes
of phage that they have come into contact with in the past, which
allows them to block virus replication through a form of
RNA interference.
Pattern recognition
receptors are proteins used by nearly all organisms to identify
molecules associated with pathogens.
Antimicrobial peptides called
defensins are an evolutionarily conserved component of the innate
immune response found in all animals and plants, and represent the
main form of
invertebrate systemic
immunity. The
complement system and phagocytic cells are
also used by most forms of invertebrate life.
Ribonucleases and the
RNA interference pathway are conserved
across all
eukaryotes, and are thought to
play a role in the immune response to viruses.
Unlike animals, plants lack phagocytic cells, and most plant immune
responses involve systemic chemical signals that are sent through a
plant. When a part of a plant becomes infected, the plant produces
a localized
hypersensitive
response, whereby cells at the site of infection undergo rapid
apoptosis to prevent the spread of the
disease to other parts of the plant.
Systemic acquired resistance
(SAR) is a type of defensive response used by plants that renders
the entire plant
resistant to a
particular infectious agent.
RNA
silencing mechanisms are particularly important in this
systemic response as they can block virus replication.
Tumor immunology
Another important role of the immune system is to identify and
eliminate
tumors. The
transformed
cells of tumors express
antigens that are not found on normal
cells. To the immune system, these antigens appear foreign, and
their presence causes immune cells to attack the transformed tumor
cells. The antigens expressed by tumors have several sources; some
are derived from
oncogenic viruses like
human papillomavirus, which
causes
cervical cancer, while others
are the organism's own proteins that occur at low levels in normal
cells but reach high levels in tumor cells. One example is an
enzyme called
tyrosinase that, when expressed at high levels,
transforms certain skin cells (e.g.
melanocytes) into tumors called
melanomas. A third possible source of tumor
antigens are proteins normally important for regulating
cell growth and survival, that commonly mutate
into cancer inducing molecules called
oncogenes.
The main response of the immune system to tumors is to destroy the
abnormal cells using killer T cells, sometimes with the assistance
of helper T cells. Tumor antigens are presented on MHC class I
molecules in a similar way to viral antigens. This allows killer T
cells to recognize the tumor cell as abnormal. NK cells also kill
tumorous cells in a similar way, especially if the tumor cells have
fewer MHC class I molecules on their surface than normal; this is a
common phenomenon with tumors. Sometimes antibodies are generated
against tumor cells allowing for their destruction by the
complement system.
Clearly, some tumors evade the immune system and go on to become
cancers. Tumor cells often have a reduced number of MHC class I
molecules on their surface, thus avoiding detection by killer T
cells. Some tumor cells also release products that inhibit the
immune response; for example by secreting the cytokine
TGF-β, which suppresses the activity of
macrophages and
lymphocytes. In addition,
immunological tolerance may develop against
tumor antigens, so the immune system no longer attacks the tumor
cells.
Paradoxically, macrophages can promote tumor growth when tumor
cells send out cytokines that attract macrophages which then
generate cytokines and growth factors that nurture tumor
development. In addition, a combination of hypoxia in the tumor and
a cytokine produced by macrophages induces tumor cells to decrease
production of a protein that blocks
metastasis and thereby assists spread of cancer
cells.
Physiological regulation
Hormones can act as
immunomodulators, altering the sensitivity
of the immune system. For example,
female sex hormones are known
immunostimulators of both adaptive and
innate immune responses.
Some autoimmune diseases such as
lupus erythematosus strike women
preferentially, and their onset often coincides with
puberty. By contrast,
male sex
hormone such as
testosterone seem
to be
immunosuppressive. Other
hormones appear to regulate the immune system as well, most notably
prolactin,
growth hormone and
vitamin D. It is conjectured that a progressive
decline in hormone levels with age is partially responsible for
weakened immune responses in aging individuals. Conversely, some
hormones are regulated by the immune system, notably
thyroid hormone activity.
Sleep
The immune system is enhanced by sleep and rest, and is impaired by
stress.
Sleep deprivation is
detrimental to immune function, and sleep can be considered a vital
part of the immune system. Viewed in this light, decreases in the
length and quality of sleep in the population have far-reaching
public health implications. Complex
feedback loops exist between the sleep cycle and immune response:
acute infection causes changes in the sleep cycle, including an
increase in
slow-wave sleep relative
to
REM sleep.
Cytokines, a class of
peptides, appear to be one of the main mechanisms
through which the immune system and sleep cycle interact, as
cytokines are produced by the immune system in response to
infection, and also play a role in the normal sleep cycle.
Nutrition and diet
The functioning of the immune system, like most systems in the
body, is dependent on proper nutrition. It has been long known that
severe malnutrition leads to
immunodeficiency.
Overnutrition is also associated with diseases
such as
diabetes and
obesity which are known to affect immune function.
More moderate malnutrition, as well as certain specific trace
mineral and nutrient deficiencies, can also compromise the immune
response.
Specific foods may also affect the immune system; for example,
fresh
fruits,
vegetables, and foods rich in certain
fatty acids may foster a healthy immune system.
Likewise,
fetal
undernourishment can cause a lifelong impairment of the immune
system. In
traditional
medicine, some herbs are believed to stimulate the immune
system, such as
echinacea,
licorice,
ginseng,
astragalus,
sage,
garlic,
elderberry,
and
hyssop, as well as
honey.
Medicinal mushrooms like
Shiitake,
Lingzhi mushrooms,, the
Turkey tail mushroom,
Agaricus blazei, and
Maitake have shown evidence of immune system
up-regulation
in vitro,
in vivo, as well as in
people. An isolated compound from Shiitake, known as
Active Hexose Correlated
Compound has also shown evidence of being able to up-regulate
certain aspects of the immune system. Research suggests the
compounds in medicinal mushrooms most responsible for up-regulating
the immune system, are a diverse collection of
polysaccharides, particularly
beta-glucans, and to a lesser extent,
alpha-glucans. Specifically, beta-glucans stimulate the
innate branch of the immune system.
Research has shown beta-glucans have the potential to stimulate
dendritic cells macrophage,
NK cells,
T cells, and immune system
cytokines.The mechanisms in which beta-glucans
stimulate the immune system is only partially understood. One
mechanism in which beta-glucans are able to activate the immune
system, is by interacting with the
Macrophage-1 antigen (
CD18)
receptor on immune
cells. Other human
receptors
have been identified as being able to receive signals from
beta-glucans such as
Toll-like
receptor 2, Dectin-1, lactosylceramide, and
scavenger receptors.
Published research has suggested that certain herbs can stimulate
aspects of the immune system,
although further research is often needed to discover their
mode of action.
Manipulation in medicine
The immune response can be manipulated to suppress unwanted
responses resulting from autoimmunity, allergy, and
transplant rejection, and to stimulate
protective responses against pathogens that largely elude the
immune system (see
immunization).
Immunosuppressive drugs are used to
control autoimmune disorders or
inflammation when excessive tissue damage
occurs, and to prevent
transplant
rejection after an
organ
transplant.
Anti-inflammatory drugs are often
used to control the effects of inflammation. The
glucocorticoids are the most powerful of
these drugs; however, these drugs can have many undesirable
side effect (
e.g.,
central obesity,
hyperglycemia,
osteoporosis) and their use must be tightly
controlled. Therefore, lower doses of anti-inflammatory drugs are
often used in conjunction with
cytotoxic or
immunosuppressive drugs such as
methotrexate or
azathioprine.
Cytotoxic
drugs inhibit the immune response by killing dividing cells
such as activated T cells. However, the killing is indiscriminate
and other
constantly dividing
cells and their organs are affected, which causes toxic side
effects. Immunosuppressive drugs such as
ciclosporin prevent T cells from responding to
signals correctly by inhibiting
signal transduction pathways.
Larger drugs (>500
Da) can
provoke a neutralizing immune response, particularly if the drugs
are administered repeatedly, or in larger doses. This limits the
effectiveness of drugs based on larger peptides and proteins (which
are typically larger than 6000 Da). In some cases, the drug itself
is not immunogenic, but may be co-administered with an immunogenic
compound, as is sometimes the case for
Taxol. Computational methods have been developed
to predict the immunogenicity of peptides and proteins, which are
particularly useful in designing therapeutic antibodies, assessing
likely virulence of mutations in viral coat particles, and
validation of proposed peptide-based drug treatments. Early
techniques relied mainly on the observation that
hydrophilic amino acids
are overrepresented in
epitope regions than
hydrophobic amino acids; however, more
recent developments rely on
machine
learning techniques using databases of existing known epitopes,
usually on well-studied virus proteins, as a
training set. A publicly accessible database
has been established for the cataloguing of epitopes from pathogens
known to be recognizable by B cells. The emerging field of
bioinformatics-based studies of
immunogenicity is referred to as
immunoinformatics.
Manipulation by pathogens
The success of any pathogen is dependent on its ability to elude
host immune responses. Therefore, pathogens have developed several
methods that allow them to successfully infect a host, while
evading detection or destruction by the immune system. Bacteria
often overcome physical barriers by secreting
enzymes that digest the barrier — for example, by
using a
type II secretion
system. Alternatively, using a
type III secretion system, they
may insert a hollow tube into the host cell, providing a direct
route for proteins to move from the pathogen to the host. These
proteins are often used to shut down host defenses.
An evasion strategy used by several pathogens to avoid the innate
immune system is to hide within the cells of their host (also
called
intracellular pathogenesis). Here, a pathogen spends most of
its
life-cycle inside host
cells, where it is shielded from direct contact with immune cells,
antibodies and complement. Some examples of intracellular pathogens
include viruses, the
food
poisoning bacterium Salmonella and the
eukaryotic parasites that cause
malaria (
Plasmodium falciparum) and
leishmaniasis (
Leishmania spp.). Other bacteria, such as
Mycobacterium
tuberculosis, live inside a protective capsule that
prevents
lysis by complement. Many pathogens
secrete compounds that diminish or misdirect the host's immune
response. Some bacteria form
biofilms to
protect themselves from the cells and proteins of the immune
system. Such biofilms are present in many successful infections,
e.g., the chronic
Pseudomonas
aeruginosa and
Burkholderia cenocepacia
infections characteristic of
cystic
fibrosis. Other bacteria generate surface proteins that bind to
antibodies, rendering them ineffective; examples include
Streptococcus (protein G),
Staphylococcus aureus
(protein A), and
Peptostreptococcus magnus (protein
L).
The mechanisms used to evade the adaptive immune system are more
complicated. The simplest approach is to rapidly change
non-essential
epitopes (
amino acids and/or sugars) on the surface of the
pathogen, while keeping essential epitopes concealed. This is
called
antigenic variation. An
example is HIV, which mutates rapidly, so the proteins on its
viral envelope that are essential for
entry into its host target cell are constantly changing. These
frequent changes in antigens may explain the failures of
vaccines directed at this virus. The parasite
Trypanosoma brucei uses
a similar strategy, constantly switching one type of surface
protein for another, allowing it to stay one step ahead of the
antibody response. Masking antigens with host molecules is another
common strategy for avoiding detection by the immune system. In
HIV, the envelope that covers the
viron is
formed from the outermost membrane of the host cell; such
"self-cloaked" viruses make it difficult for the immune system to
identify them as "non-self" structures.
History of immunology
Immunology is a science that examines the
structure and function of the immune system. It originates from
medicine and early studies on the causes of
immunity to disease. The earliest known mention of immunity was
during the
plague of Athens in 430
BC.
Thucydides noted that people who had
recovered from a previous bout of the disease could nurse the sick
without contracting the illness a second time. In the 18th century,
Pierre-Louis Moreau de
Maupertuis made experiments with scorpion venom and observed
that certain dogs and mice were immune to this venom. This and
other observations of acquired immunity was later exploited by
Louis Pasteur in his development of
vaccination and his proposed
germ theory of disease. Pasteur's
theory was in direct opposition to contemporary theories of
disease, such as the
miasma
theory. It was not until
Robert
Koch's 1891
proofs, for which
he was awarded a
Nobel Prize in 1905,
that
microorganisms were confirmed as
the cause of
infectious disease.
Viruses were confirmed as human pathogens in 1901, with the
discovery of the
yellow fever virus by
Walter Reed.
Immunology made a great advance towards the end of the 19th
century, through rapid developments, in the study of
humoral immunity and
cellular immunity. Particularly important
was the work of
Paul Ehrlich, who
proposed the
side-chain theory to
explain the specificity of the antigen-antibody reaction; his
contributions to the understanding of humoral immunity were
recognized by the award of a Nobel Prize in 1908, which was jointly
awarded to the founder of cellular immunology,
Elie Metchnikoff.
See also
References
- Smith A.D. (Ed) Oxford dictionary of biochemistry and
molecular biology. (1997) Oxford University Press. ISBN
0-19-854768-4
- Death and DALY estimates for 2002 by cause for WHO
Member States. World Health Organization.
Retrieved on 1 January 2007.
- R.M. Suskind, C.L. Lachney, J.N. Udall, Jr.,
"Malnutrition and the Immune Response", in: Dairy products in
human health and nutrition, M. Serrano-Ríos, ed., CRC Press,
1994.
- The Nobel Prize in Physiology or Medicine 1905
Nobelprize.org Accessed 8 January 2007.
- Major Walter Reed, Medical Corps, U.S. Army
Walter Reed Army Medical Center. Accessed 8 January 2007.
- The Nobel Prize in Physiology or Medicine 1908
Nobelprize.org Accessed 8 January 2007
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