Immune system

From Wikipedia, the free encyclopedia

Jump to: navigation, search

A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax

bacteria (orange).
An immune system is a collection of biological 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.[1] 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 recognise 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 diseases occur
when the immune system is less active than normal, resulting in recurring and lifethreatening 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 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.

Contents
[hide]

1 Layered defense
2 Surface barriers
3 Innate
o 3.1 Humoral and chemical barriers
3.1.1 Inflammation
3.1.2 Complement system
o 3.2 Cellular barriers
4 Adaptive
o 4.1 Lymphocytes
4.1.1 Killer T cells
4.1.2 Helper T cells
4.1.3 T cells
4.1.4 B lymphocytes and antibodies
4.1.5 Alternative adaptive immune system
o 4.2 Immunological memory
4.2.1 Passive memory
4.2.2 Active memory and immunization
5 Disorders of human immunity
o 5.1 Immunodeficiencies
o 5.2 Autoimmunity
o 5.3 Hypersensitivity
6 Other mechanisms
7 Tumor immunology
8 Physiological regulation
9 Manipulation in medicine
10 Manipulation by pathogens
11 History of immunology
12 See also
13 References

14 External links

[edit] 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.[2] However, 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.[3]
Components of the immune system

Innate immune system

Adaptive immune system

Response is non-specific

Pathogen and antigen specific response

Exposure leads to immediate maximal

response

Lag time between exposure and maximal

response

Cell-mediated and humoral components

Cell-mediated and humoral components

No immunological memory

Exposure leads to immunological memory

Found in nearly all forms of life

Found only in jawed vertebrates

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.[4] 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.[5]

[edit] 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
shells and membranes of externally deposited eggs, and skin are examples of the
mechanical barriers that are the first line of defense against infection.[5] 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.[6]
Chemical barriers also protect against infection. The skin and respiratory tract secrete
antimicrobial peptides such as the -defensins.[7] Enzymes such as lysozyme and
phospholipase A2 in saliva, tears, and breast milk are also antibacterials.[8][9] Vaginal
secretions serve as a chemical barrier following menarche, when they become slightly
acidic, while semen contains defensins and zinc to kill pathogens.[10][11] 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.[12] 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).[13] 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.[14][15][16]

[edit] Innate
For more details on this topic, see Innate immune system.
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,[17] 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.[18] Innate immune defenses are nonspecific, meaning these systems respond to pathogens in a generic way.[5] 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.[2]

[edit] Humoral and chemical barriers

[edit] Inflammation
For more details on this topic, see Inflammation.
Inflammation is one of the first responses of the immune system to infection.[19] 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).[20][21] 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.[22] 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.[23]
[edit] Complement system
For more details on this topic, see 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.[24][25] Many species have complement systems, including
non-mammals like plants, fish, and some invertebrates.[26]
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.[27] 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.[28] 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.[24]

[edit] Cellular barriers

A scanning electron microscope image of normal circulating human blood. One can see
red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a
neutrophil, and many small disc-shaped platelets.
Leukocytes (white blood cells) act like independent, single-celled organisms and are the
second arm of the innate immune system.[5] 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.[26]
Innate cells are also important mediators in the activation of the adaptive immune system.
[3]

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.[5]
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.[29][30] Phagocytosis evolved as a means of acquiring nutrients, but this
role was extended in phagocytes to include engulfment of pathogens as a defense
mechanism.[31] Phagocytosis probably represents the oldest form of host defense, as
phagocytes have been identified in both vertebrate and invertebrate animals.[32]
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of
invading pathogens.[33] 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.[34] 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.[35] 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.[3]
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.[36] 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.[36]
Mast cells reside in connective tissues and mucous membranes, and regulate the
inflammatory response.[37] They are most often associated with allergy and anaphylaxis.[34]
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.[38] Natural killer (NK cells) cells are leukocytes that attack and destroy tumor
cells, or cells that have been infected by viruses.[39]

[edit] Adaptive
For more details on this topic, see Adaptive immune system.
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.[40] The adaptive immune response is antigenspecific 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.

[edit] 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.[26] 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 T
cells that recognize intact antigens that are not bound to MHC receptors.[41]
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.[26]
[edit] Killer T cells

Killer T cells directly attack other cells carrying foreign or abnormal antigens on their
surfaces.[42]
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.[43] 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.[44] 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).[44]
[edit] Helper T cells

Function of T helper cells: Antigen presenting cells (APCs) present antigen on their Class
II MHC molecules (MHC2). Helper T cells recognize these, with the help of their
expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it
to release cytokines and other stimulatory signals (green arrows) that stimulate the
activity of macrophages, killer T cells and B cells, the latter producing antibodies. The
stimulation of B cells and macrophages succeeds a proliferation of T helper 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.
[45][46]
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
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 200300) 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.[47] 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.[5] 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.[48]
[edit] T cells
T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+
() T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells.
The conditions that produce responses from T cells are not fully understood. Like
other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted
Natural Killer T cells, T cells straddle the border between innate and adaptive
immunity.[49] On one hand, 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 V9/V2 T cells respond within hours to common
molecules produced by microbes, and highly restricted V1+ T cells in epithelia will
respond to stressed epithelial cells.[50]

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.[42]
[edit] B lymphocytes and antibodies
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign
antigen.[51] 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.[52] 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.[53]
[edit] 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.[54]

[edit] Immunological memory

For more details on this topic, see Immunity (medical).
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.
[edit] 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.[55] Breast milk 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.[56] 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.[57]

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.
[edit] 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.[5] 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.[58][26]
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.[5] 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.[59]

[edit] 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.

[edit] Immunodeficiencies
For more details on this topic, see Immunodeficiency.

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.[60][61] In developed countries, obesity, alcoholism,
and drug use are common causes of poor immune function.[61] However, malnutrition is
the most common cause of immunodeficiency in developing countries.[61] 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 B9) also reduces immune responses.[61] 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.[62]
Immunodeficiencies can also be inherited or 'acquired'.[5] 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.[63][64]

[edit] Autoimmunity
For more details on this topic, see 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.[65] 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.[51]

[edit] Hypersensitivity
For more details on this topic, see 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.[66] 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.[66] Immune
complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies)
deposited in various tissues trigger Type III hypersensitivity reactions.[66] 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.[66]

[edit] Other mechanisms

For more details on this topic, see Innate immune system#Other forms of innate
immunity.
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.[1] Many species, however, utilize mechanisms that appear to be precursors of
these aspects of vertebrate immunity. Immune systems appear even in the most
structurally-simple forms of life, with bacteria using a unique defense mechanism, called
the restriction modification system to protect themselves from viral pathogens, called
bacteriophages.[67] 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.[68][69]
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.[1] 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.[70]
Unlike animals, plants lack phagocytic cells, and most plant immune responses involve
systemic chemical signals that are sent through a plant.[71] 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.[71] RNA
silencing mechanisms are particularly important in this systemic response as they can
block virus replication.[72]

[edit] Tumor immunology

Further information: Cancer immunology

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the
cancer cell, the macrophages (smaller white cells) will inject toxins that kill the tumor
cell. Immunotherapy for the treatment of cancer is an active area of medical research.[73]
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;[74] some are derived from oncogenic viruses like human papillomavirus, which
causes cervical cancer,[75] 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.[76][77] 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.[74][78][79]
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.[77][80] 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.[81] 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.[82] Sometimes
antibodies are generated against tumor cells allowing for their destruction by the
complement system.[78]
Clearly, some tumors evade the immune system and go on to become cancers.[83] Tumor
cells often have a reduced number of MHC class I molecules on their surface, thus
avoiding detection by killer T cells.[81] Some tumor cells also release products that inhibit
the immune response; for example by secreting the cytokine TGF-, which suppresses
the activity of macrophages and lymphocytes.[84] In addition, immunological tolerance
may develop against tumor antigens, so the immune system no longer attacks the tumor
cells.[83]
Paradoxically, macrophages can promote tumor growth [85] 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.

[edit] 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[86] and
innate immune responses.[87] Some autoimmune diseases such as lupus erythematosus
strike women preferentially, and their onset often coincides with puberty. By contrast,
male sex hormones such as testosterone seem to be immunosuppressive.[88] Other
hormones appear to regulate the immune system as well, most notably prolactin, growth
hormone and vitamin D.[89][90] It is conjectured that a progressive decline in hormone
levels with age is partially responsible for weakened immune responses in aging
individuals.[91] Conversely, some hormones are regulated by the immune system, notably
thyroid hormone activity.[92]
The immune system is enhanced by sleep and rest,[93] and is impaired by stress.[94]
Diet may affect the immune system; for example, fresh fruits, vegetables, and foods rich
in certain fatty acids may foster a healthy immune system.[95] Likewise, fetal
undernourishment can cause a lifelong impairment of the immune system.[96] In
traditional medicine, some herbs are believed to stimulate the immune system, such as
echinacea, licorice, ginseng, astragalus, sage, garlic, elderberry, shiitake and lingzhi
mushrooms, and hyssop, as well as honey. Studies have suggested that such herbs can
indeed stimulate the immune system,[97] although their mode of action is complex and
difficult to characterize.

[edit] Manipulation in medicine

The immunosuppressive drug dexamethasone

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.[26][98]
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 effects (e.g., central obesity, hyperglycemia, osteoporosis) and
their use must be tightly controlled.[99] 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.[98]
Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals
correctly by inhibiting signal transduction pathways.[100]
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;[101] 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.[102] A
publicly accessible database has been established for the cataloguing of epitopes from
pathogens known to be recognizable by B cells.[103] The emerging field of bioinformaticsbased studies of immunogenicity is referred to as immunoinformatics.[104]

[edit] 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.[105] Bacteria
often overcome physical barriers by secreting enzymes that digest the barrier for
example, by using a type II secretion system.[106] 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.[107]
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.[108] Many pathogens secrete compounds that
diminish or misdirect the host's immune response.[105] 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.[109] 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).[110]
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.[111]
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.[112]
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.[113]

[edit] History of immunology

For more details on this topic, see History of immunology.

Paul Ehrlich
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.[114] This observation of
acquired immunity was later exploited by Louis Pasteur in his development of

vaccination and his proposed germ theory of disease.[115] 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.[116] Viruses were
confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by
Walter Reed.[117]
Immunology made a great advance towards the end of the 19th century, through rapid
developments, in the study of humoral immunity and cellular immunity.[118] 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.[119]

[edit] See also

Wikimedia Commons has media related to: Immunology

Clonal selection
Epitope
Hapten
Human physiology
Immunostimulator
Monoclonal antibodies
Original antigenic sin
Polyclonal antibodies
Tumor antigens
Immune system receptors
Polyclonal response

[edit] References
1. ^ a b c Beck, Gregory; Gail S. Habicht (November 1996). "Immunity and the
Invertebrates" (PDF). Scientific American: 6066.
http://www.scs.carleton.ca/~soma/biosec/readings/sharkimmu-sciamNov1996.pdf. Retrieved on 2007-01-01.
2. ^ a b Litman G, Cannon J, Dishaw L (2005). "Reconstructing immune phylogeny:
new perspectives". Nat Rev Immunol 5 (11): 86679. doi:10.1038/nri1712. PMID
16261174.
3. ^ a b c Mayer, Gene (2006). "Immunology - Chapter One: Innate (non-specific)
Immunity". Microbiology and Immunology On-Line Textbook. USC School of
Medicine. http://pathmicro.med.sc.edu/ghaffar/innate.htm. Retrieved on 2007-0101.

4. ^ Smith A.D. (Ed) Oxford dictionary of biochemistry and molecular biology.

(1997) Oxford University Press. ISBN 0-19-854768-4
5. ^ a b c d e f g h i Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith
Roberts, and Peter Walters (2002). Molecular Biology of the Cell; Fourth Edition.
New York and London: Garland Science. ISBN 0-8153-3218-1.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2.
6. ^ Boyton R, Openshaw P (2002). "Pulmonary defences to acute respiratory
infection". Br Med Bull 61: 112. doi:10.1093/bmb/61.1.1. PMID 11997295.
7. ^ Agerberth B, Gudmundsson G. "Host antimicrobial defence peptides in human
disease". Curr Top Microbiol Immunol 306: 6790. doi:10.1007/3-540-299165_3. PMID 16909918.
8. ^ Moreau J, Girgis D, Hume E, Dajcs J, Austin M, O'Callaghan R (01 Sep 2001).
"Phospholipase A(2) in rabbit tears: a host defense against Staphylococcus
aureus". Invest Ophthalmol Vis Sci 42 (10): 234754. PMID 11527949.
http://www.iovs.org/cgi/content/full/42/10/2347.
9. ^ Hankiewicz J, Swierczek E (1974). "Lysozyme in human body fluids". Clin
Chim Acta 57 (3): 2059. doi:10.1016/0009-8981(74)90398-2. PMID 4434640.
10. ^ Fair W, Couch J, Wehner N (1976). "Prostatic antibacterial factor. Identity and
significance". Urology 7 (2): 16977. doi:10.1016/0090-4295(76)90305-8. PMID
54972.
11. ^ Yenugu S, Hamil K, Birse C, Ruben S, French F, Hall S (2003). "Antibacterial
properties of the sperm-binding proteins and peptides of human epididymis 2
(HE2) family; salt sensitivity, structural dependence and their interaction with
outer and cytoplasmic membranes of Escherichia coli". Biochem J 372 (Pt 2):
47383. doi:10.1042/BJ20030225. PMID 12628001.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1223422&blobtype=pdf.
12. ^ Gorbach S (1990). "Lactic acid bacteria and human health". Ann Med 22 (1):
3741. doi:10.3109/07853899009147239. PMID 2109988.
13. ^ Hill L, Embil J (1986). "Vaginitis: current microbiologic and clinical concepts".
CMAJ 134 (4): 32131. PMID 3510698.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1490817&blobtype=pdf.
14. ^ Reid G, Bruce A (2003). "Urogenital infections in women: can probiotics
help?". Postgrad Med J 79 (934): 42832. doi:10.1136/pmj.79.934.428. PMID
12954951. http://pmj.bmj.com/cgi/content/full/79/934/428.
15. ^ Salminen S, Gueimonde M, Isolauri E (01 May 2005). "Probiotics that modify
disease risk". J Nutr 135 (5): 12948. PMID 15867327.
http://jn.nutrition.org/cgi/content/full/135/5/1294.
16. ^ Reid G, Jass J, Sebulsky M, McCormick J (2003). "Potential uses of probiotics
in clinical practice". Clin Microbiol Rev 16 (4): 65872.
doi:10.1128/CMR.16.4.658-672.2003. PMID 14557292.
17. ^ Medzhitov R (2007). "Recognition of microorganisms and activation of the
immune response". Nature 449 (7164): 81926. doi:10.1038/nature06246. PMID
17943118.
18. ^ Matzinger P (2002). "the danger model: a renewed sense of self". Science 296
(5566): 3015. doi:10.1126/science.1071059. PMID 11951032.

19. ^ Kawai T, Akira S (2006). "Innate immune recognition of viral infection". Nat
Immunol 7 (2): 1317. doi:10.1038/ni1303. PMID 16424890.
20. ^ Miller, SB (2006). "Prostaglandins in Health and Disease: An Overview".
Seminars in Arthritis and Rheumatism 36 (1): 3749.
doi:10.1016/j.semarthrit.2006.03.005. PMID 16887467.
21. ^ Ogawa Y, Calhoun WJ. (2006). "The role of leukotrienes in airway
inflammation". J Allergy Clin Immunol. 118 (4): 78998.
doi:10.1016/j.jaci.2006.08.009. PMID 17030228.
22. ^ Le Y, Zhou Y, Iribarren P, Wang J (2004). "Chemokines and chemokine
receptors: their manifold roles in homeostasis and disease" (PDF). Cell Mol
Immunol 1 (2): 95104. PMID 16212895.
http://www.nature.com/bjp/journal/v147/n1s/pdf/0706475a.pdf.
23. ^ Martin P, Leibovich S (2005). "Inflammatory cells during wound repair: the
good, the bad and the ugly". Trends Cell Biol 15 (11): 599607.
doi:10.1016/j.tcb.2005.09.002. PMID 16202600.
24. ^ a b Rus H, Cudrici C, Niculescu F (2005). "The role of the complement system
in innate immunity". Immunol Res 33 (2): 10312. doi:10.1385/IR:33:2:103.
PMID 16234578.
25. ^ Mayer, Gene (2006). "Immunology - Chapter Two: Complement".
Microbiology and Immunology On-Line Textbook. USC School of Medicine.
http://pathmicro.med.sc.edu/ghaffar/complement.htm. Retrieved on 2007-01-01.
26. ^ a b c d e f Janeway CA, Jr. et al (2005). Immunobiology. (6th ed.). Garland
Science. ISBN 0-443-07310-4.
27. ^ Liszewski M, Farries T, Lublin D, Rooney I, Atkinson J (1996). "Control of the
complement system". Adv Immunol 61: 20183. doi:10.1016/S00652776(08)60868-8. PMID 8834497.
28. ^ Sim R, Tsiftsoglou S (2004). "Proteases of the complement system" (PDF).
Biochem Soc Trans 32 (Pt 1): 217. doi:10.1042/BST0320021. PMID 14748705.
http://www.biochemsoctrans.org/bst/032/0021/0320021.pdf.
29. ^ Ryter A (1985). "Relationship between ultrastructure and specific functions of
macrophages". Comp Immunol Microbiol Infect Dis 8 (2): 11933.
doi:10.1016/0147-9571(85)90039-6. PMID 3910340.
30. ^ Langermans J, Hazenbos W, van Furth R (1994). "Antimicrobial functions of
mononuclear phagocytes". J Immunol Methods 174 (12): 18594.
doi:10.1016/0022-1759(94)90021-3. PMID 8083520.
31. ^ May R, Machesky L (15 Mar 2001). "Phagocytosis and the actin cytoskeleton".
J Cell Sci 114 (Pt 6): 106177. PMID 11228151.
http://jcs.biologists.org/cgi/reprint/114/6/1061.
32. ^ Salzet M, Tasiemski A, Cooper E (2006). "Innate immunity in
lophotrochozoans: the annelids". Curr Pharm Des 12 (24): 304350.
doi:10.2174/138161206777947551. PMID 16918433.
33. ^ Zen K, Parkos C (2003). "Leukocyte-epithelial interactions". Curr Opin Cell
Biol 15 (5): 55764. doi:10.1016/S0955-0674(03)00103-0. PMID 14519390.
34. ^ a b Stvrtinov, Viera; Jn Jakubovsk and Ivan Huln (1995). Inflammation and
Fever from Pathophysiology: Principles of Disease. Computing Centre, Slovak
Academy of Sciences: Academic Electronic Press.

http://web.archive.org/web/20010711220523/nic.savba.sk/logos/books/scientific/I
nffever.html. Retrieved on 2007-01-01.
35. ^ Bowers, William (2006). "Immunology -Chapter Thirteen: Immunoregulation".
Microbiology and Immunology On-Line Textbook. USC School of Medicine.
http://pathmicro.med.sc.edu/bowers/imm-reg.htm. Retrieved on 2007-01-04.
36. ^ a b Guermonprez P, Valladeau J, Zitvogel L, Thry C, Amigorena S (2002).
"Antigen presentation and T cell stimulation by dendritic cells". Annu Rev
Immunol 20: 62167. doi:10.1146/annurev.immunol.20.100301.064828. PMID
11861614.
37. ^ Krishnaswamy G, Ajitawi O, Chi D. "The human mast cell: an overview".
Methods Mol Biol 315: 1334. PMID 16110146.
38. ^ Kariyawasam H, Robinson D (2006). "The eosinophil: the cell and its weapons,
the cytokines, its locations". Semin Respir Crit Care Med 27 (2): 11727.
doi:10.1055/s-2006-939514. PMID 16612762.
39. ^ Middleton D, Curran M, Maxwell L (2002). "Natural killer cells and their
receptors". Transpl Immunol 10 (23): 14764. doi:10.1016/S09663274(02)00062-X. PMID 12216946.
40. ^ Pancer Z, Cooper M (2006). "The evolution of adaptive immunity". Annu Rev
Immunol 24: 497518. doi:10.1146/annurev.immunol.24.021605.090542. PMID
16551257.
41. ^ Holtmeier W, Kabelitz D. "gammadelta T cells link innate and adaptive immune
responses". Chem Immunol Allergy 86: 15183. PMID 15976493.
42. ^ a b "Understanding the Immune System: How it Works" (PDF). National
Institute of Allergy and Infectious Diseases (NIAID).
http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf.
Retrieved on 2007-01-01.
43. ^ Harty J, Tvinnereim A, White D (2000). "CD8+ T cell effector mechanisms in
resistance to infection". Annu Rev Immunol 18: 275308.
doi:10.1146/annurev.immunol.18.1.275. PMID 10837060.
44. ^ a b Radoja S, Frey A, Vukmanovic S (2006). "T-cell receptor signaling events
triggering granule exocytosis". Crit Rev Immunol 26 (3): 26590. PMID
16928189.
45. ^ Abbas A, Murphy K, Sher A (1996). "Functional diversity of helper T
lymphocytes". Nature 383 (6603): 78793. doi:10.1038/383787a0. PMID
8893001.
46. ^ McHeyzer-Williams L, Malherbe L, McHeyzer-Williams M (2006). "Helper T
cell-regulated B cell immunity". Curr Top Microbiol Immunol 311: 5983.
doi:10.1007/3-540-32636-7_3. PMID 17048705.
47. ^ Kovacs B, Maus M, Riley J, Derimanov G, Koretzky G, June C, Finkel T
(2002). "Human CD8+ T cells do not require the polarization of lipid rafts for
activation and proliferation". Proc Natl Acad Sci U S a 99 (23): 1500611.
doi:10.1073/pnas.232058599. PMID 12419850.
http://www.ncbi.nlm.nih.gov/sites/entrez?
db=pubmed&uid=12419850&cmd=showdetailview.

48. ^ Grewal I, Flavell R (1998). "CD40 and CD154 in cell-mediated immunity".

Annu Rev Immunol 16: 11135. doi:10.1146/annurev.immunol.16.1.111. PMID
9597126.
49. ^ Girardi M (2006). "Immunosurveillance and immunoregulation by T cells".
J Invest Dermatol 126 (1): 2531. doi:10.1038/sj.jid.5700003. PMID 16417214.
50. ^ Holtmeier W, Kabelitz D (2005). " T cells link innate and adaptive immune
responses". Chem Immunol Allergy 86: 151183. doi:10.1159/000086659. PMID
15976493.
51. ^ a b Sproul T, Cheng P, Dykstra M, Pierce S (2000). "A role for MHC class II
antigen processing in B cell development". Int Rev Immunol 19 (23): 13955.
doi:10.3109/08830180009088502. PMID 10763706.
52. ^ Kehry M, Hodgkin P (1994). "B-cell activation by helper T-cell membranes".
Crit Rev Immunol 14 (34): 22138. PMID 7538767.
53. ^ Bowers, William (2006). "Immunology - Chapter nine: Cells involved in
immune responses". Microbiology and Immunology On-Line Textbook. USC
School of Medicine. http://pathmicro.med.sc.edu/bowers/immune%20cells.htm.
Retrieved on 2007-01-04.
54. ^ M.N. Alder, I.B. Rogozin, L.M. Iyer, G.V. Glazko, M.D. Cooper, Z. Pancer
(2005). "Diversity and Function of Adaptive Immune Receptors in a Jawless
Vertebrate". Science 310 (5756): 19701973. doi:10.1126/science.1119420. PMID
16373579.
55. ^ Saji F, Samejima Y, Kamiura S, Koyama M (1999). "Dynamics of
immunoglobulins at the feto-maternal interface" (PDF). Rev Reprod 4 (2): 819.
doi:10.1530/ror.0.0040081. PMID 10357095. http://ror.reproductiononline.org/cgi/reprint/4/2/81.pdf.
56. ^ Van de Perre P (2003). "Transfer of antibody via mother's milk". Vaccine 21
(24): 33746. doi:10.1016/S0264-410X(03)00336-0. PMID 12850343.
57. ^ Keller, Margaret A. and E. Richard Stiehm (2000). "Passive Immunity in
Prevention and Treatment of Infectious Diseases". Clinical Microbiology Reviews
13 (4): 602614. doi:10.1128/CMR.13.4.602-614.2000. PMID 11023960.
http://cmr.asm.org/cgi/content/full/13/4/602.
58. ^ Death and DALY estimates for 2002 by cause for WHO Member States. World
Health Organization. Retrieved on 2007-01-01.
59. ^ Singh M, O'Hagan D (1999). "Advances in vaccine adjuvants". Nat Biotechnol
17 (11): 107581. doi:10.1038/15058. PMID 10545912.
60. ^ Aw D, Silva A, Palmer D (2007). "Immunosenescence: emerging challenges for
an ageing population". Immunology 120 (4): 435446. doi:10.1111/j.13652567.2007.02555.x. PMID 17313487.
61. ^ a b c d Chandra, RK (01 Aug 1997). "Nutrition and the immune system: an
introduction". American Journal of Clinical Nutrition Vol 66 (2): 460S463S.
PMID 9250133. http://www.ajcn.org/cgi/content/abstract/66/2/460S. Free fulltext pdf available
62. ^ Miller JF (2002). "The discovery of thymus function and of thymus-derived
lymphocytes". Immunol. Rev. 185: 714. PMID 12190917. http://www.blackwellsynergy.com/doi/abs/10.1034/j.1600-065X.2002.18502.x.

63. ^ Joos L, Tamm M (2005). "Breakdown of pulmonary host defense in the

immunocompromised host: cancer chemotherapy". Proc Am Thorac Soc 2 (5):
4458. doi:10.1513/pats.200508-097JS. PMID 16322598.
http://pats.atsjournals.org/cgi/content/full/2/5/445.
64. ^ Copeland K, Heeney J (1996). "T helper cell activation and human retroviral
pathogenesis". Microbiol Rev 60 (4): 72242. PMID 8987361.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=239461&blobtype=pdf.
65. ^ Miller J (1993). "Self-nonself discrimination and tolerance in T and B
lymphocytes". Immunol Res 12 (2): 11530. doi:10.1007/BF02918299. PMID
8254222.
66. ^ a b c d Ghaffar, Abdul (2006). "Immunology - Chapter Seventeen:
Hypersensitivity Reactions". Microbiology and Immunology On-Line Textbook.
USC School of Medicine. http://pathmicro.med.sc.edu/ghaffar/hyper00.htm.
Retrieved on 2007-01-01.
67. ^ Bickle T, Krger D (1993). "Biology of DNA restriction". Microbiol Rev 57 (2):
43450. PMID 8336674. http://www.pubmedcentral.nih.gov/picrender.fcgi?
artid=372918&blobtype=pdf.
68. ^ Barrangou R, Fremaux C, Deveau H, et al (March 2007). "CRISPR provides
acquired resistance against viruses in prokaryotes". Science (journal) 315 (5819):
170912. doi:10.1126/science.1138140. PMID 17379808.
69. ^ Brouns SJ, Jore MM, Lundgren M, et al (August 2008). "Small CRISPR RNAs
guide antiviral defense in prokaryotes". Science (journal) 321 (5891): 9604.
doi:10.1126/science.1159689. PMID 18703739.
70. ^ Stram Y, Kuzntzova L. (2006). "Inhibition of viruses by RNA interference".
Virus Genes 32 (3): 299306. doi:10.1007/s11262-005-6914-0. PMID 16732482.
71. ^ a b Schneider, David (Spring 2005). "Innate Immunity - Lecture 4: Plant immune
responses". Stanford University Department of Microbiology and Immunology.
http://cmgm.stanford.edu/micro/Schneider-lab/Innate%20immunity
%20course.html. Retrieved on 2007-01-01.
72. ^ Baulcombe D (2004). "RNA silencing in plants". Nature 431 (7006): 35663.
doi:10.1038/nature02874. PMID 15372043.
73. ^ Morgan R et al. (2006). "Cancer regression in patients after transfer of
genetically engineered lymphocytes". Science 314: 126129.
doi:10.1126/science.1129003. PMID 16946036.
74. ^ a b Andersen MH, Schrama D, Thor Straten P, Becker JC (2006). "Cytotoxic T
cells". J Invest Dermatol 126 (1): 3241. doi:10.1038/sj.jid.5700001. PMID
16417215.
75. ^ Boon T, van der Bruggen P (1996). "Human tumor antigens recognized by T
lymphocytes". J Exp Med 183: 72529. doi:10.1084/jem.183.3.725. PMID
8642276.
76. ^ Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G
(2000). "T cell recognition of melanoma-associated antigens". J Cell Physiol 182:
32331. doi:10.1002/(SICI)1097-4652(200003)182:3<323::AID-JCP2>3.0.CO;2#. PMID 10653598.

77. ^ a b Romero P, Cerottini JC, Speiser DE (2006). "The human T cell response to
melanoma antigens". Adv Immunol. 92: 187224. doi:10.1016/S00652776(06)92005-7. PMID 17145305.
78. ^ a b Guevara-Patino JA, Turk MJ, Wolchok JD, Houghton AN (2003). "Immunity
to cancer through immune recognition of altered self: studies with melanoma".
Adv Cancer Res. 90: 15777. doi:10.1016/S0065-230X(03)90005-4. PMID
14710950.
79. ^ Renkvist N, Castelli C, Robbins PF, Parmiani G (2001). "A listing of human
tumor antigens recognized by T cells". Cancer Immunol Immunother 50: 315.
doi:10.1007/s002620000169. PMID 11315507.
80. ^ Gerloni M, Zanetti M. (2005). "CD4 T cells in tumor immunity". . Springer
Semin Immunopathol 27 (1): 3748. doi:10.1007/s00281-004-0193-z. PMID
15965712.
81. ^ a b Seliger B, Ritz U, Ferrone S (2006). "Molecular mechanisms of HLA class I
antigen abnormalities following viral infection and transformation". Int J Cancer
118 (1): 12938. doi:10.1002/ijc.21312. PMID 16003759.
82. ^ Hayakawa Y, Smyth MJ. (2006). "Innate immune recognition and suppression
of tumors

Allergy
From Wikipedia, the free encyclopedia

Jump to: navigation, search

Allergy
Classification and external
resources

ICD-10

T78.4

ICD-9

995.3

DiseasesDB

33481

MedlinePlus

000812

eMedicine

med/1101

MeSH

D006967

Allergy is a disorder of the immune system often also referred to as atopy. Allergic
reactions occur to environmental substances known as allergens; these reactions are
acquired, predictable and rapid. Strictly, allergy is one of four forms of hypersensitivity

and is called type I (or immediate) hypersensitivity. It is characterized by excessive

activation of certain white blood cells called mast cells and basophils by a type of
antibody known as IgE, resulting in an extreme inflammatory response. Common allergic
reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the
venom of stinging insects such as wasps and bees.[1]
Mild allergies like hay fever are highly prevalent in the human population and cause
symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a
major role in conditions such as asthma. In some people, severe allergies to
environmental or dietary allergens or to medication may result in life-threatening
anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin
for responses to known allergens or analyzing the blood for the presence and levels of
allergen-specific IgE. Treatments for allergies include allergen avoidance, use of antihistamines, steroids or other oral medications, immunotherapy to desensitize the response
to allergen, and targeted therapy.

Contents
[hide]

1 Classification and history

2 Signs and symptoms
3 Cause
o 3.1 Genetic basis
o 3.2 Hygiene Hypothesis
o 3.3 Other Environmental factors
4 Pathophysiology
o 4.1 Acute response
o 4.2 Late-phase response
5 Diagnosis
o 5.1 Skin testing
o 5.2 Blood testing
6 Treatment
o 6.1 Pharmacotherapy
o 6.2 Immunotherapy
o 6.3 Unproven and ineffective treatments
7 Epidemiology
8 Medical specialty
9 See also
10 References

11 External links

[edit] Classification and history

The concept of "allergy" was originally introduced in 1906 by the Viennese pediatrician
Clemens von Pirquet, after he noted that some of his patients were hypersensitive to
normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this
phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning
"work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all
were thought to be caused by an improper activation of the immune system. Later, it
became clear that several different disease mechanisms were implicated, with the
common link to a disordered activation of the immune system. In 1963, a new
classification scheme was designed by Philip Gell and Robin Coombs that described four
types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With
this new classification, the word "allergy" was restricted to only type I hypersensitivities
(also called immediate hypersensitivity), which are characterized as rapidly developing
reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of
the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers
were the first to isolate and describe IgE in the 1960s.[5]

[edit] Signs and symptoms

Common symptoms of allergy

Affected organ

Symptom

Nose

swelling of the nasal mucosa

(allergic rhinitis)

Sinuses

allergic sinusitis

Eyes

redness and itching of the

conjunctiva (allergic
conjunctivitis)

Airways

Sneezing, coughing,
bronchoconstriction, wheezing
and dyspnea, sometimes
outright attacks of asthma, in
severe cases the airway
constricts due to swelling

known as angioedema

Ears

feeling of fullness, possibly

pain, and impaired hearing due
to the lack of eustachian tube
drainage.

Skin

rashes, such as eczema and

hives (urticaria)

Gastrointestinal abdominal pain, bloating,

tract
vomiting, diarrhea

Many allergens such as dust or pollen are airborne particles. In these cases, symptoms
arise in areas in contact with air, such as eyes, nose and lungs. For instance, allergic
rhinitis, also known as hay fever, causes irritation of the nose, sneezing, and itching and
redness of the eyes.[6] Inhaled allergens can also lead to asthmatic symptoms, caused by
narrowing of the airways (bronchoconstriction) and increased production of mucus in the
lungs, shortness of breath (dyspnea), coughing and wheezing.[7]
Aside from these ambient allergens, allergic reactions can result from foods, insect stings,
and reactions to medications like aspirin and antibiotics such as penicillin. Symptoms of
food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and
swelling of the skin during hives. Food allergies rarely cause respiratory (asthmatic)
reactions, or rhinitis.[8] Insect stings, antibiotics, and certain medicines produce a systemic
allergic response that is also called anaphylaxis; multiple organ systems can be affected,
including the digestive system, the respiratory system, and the circulatory system.[9][10][11]
Depending of the rate of severity, it can cause cutaneous reactions, bronchoconstriction,
edema, hypotension, coma, and even death. This type of reaction can be triggered
suddenly, or the onset can be delayed. The severity of this type of allergic response often
requires injections of epinephrine, sometimes through a device known as the EpiPen
auto-injector. The nature of anaphylaxis is such that the reaction can seem to be
subsiding, but may recur throughout a prolonged period of time. [11]
Substances that come into contact with the skin, such as latex, are also common causes of
allergic reactions, known as contact dermatitis or eczema.[12] Skin allergies frequently
cause rashes, or swelling and inflammation within the skin, in what is known as a "wheal
and flare" reaction characteristic of hives and angioedema.[13]

[edit] Cause

Risk factors for allergy can be placed in two general categories, namely host and
environmental factors. Host factors include heredity, sex, race, and age, with heredity
being by far the most significant. However, there have been recent increases in the
incidence of allergic disorders that cannot be explained by genetic factors alone. Four
major environmental candidates are alterations in exposure to infectious diseases during
early childhood, environmental pollution, allergen levels, and dietary changes.[14]

[edit] Genetic basis

Allergic diseases are strongly familial: identical twins are likely to have the same allergic
diseases about 70% of the time; the same allergy occurs about 40% of the time in nonidentical twins.[15] Allergic parents are more likely to have allergic children,[16] and their
allergies are likely to be more severe than those from non-allergic parents. Some
allergies, however, are not consistent along genealogies; parents who are allergic to
peanuts may have children who are allergic to ragweed. It seems that the likelihood of
developing allergies is inherited and related to an irregularity in the immune system, but
the specific allergen is not.[16]
The risk of allergic sensitization and the development of allergies varies with age, with
young children most at risk.[17] Several studies have shown that IgE levels are highest in
childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of
hay fever is highest in children and young adults and the incidence of asthma is highest in
children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16]
although for some diseases, namely asthma in young adults, females are more likely to be
affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in
some allergies, however racial factors have been difficult to separate from environmental
influences and changes due to migration.[16] Interestingly, it has been suggested that
different genetic loci are responsible for asthma, specifically, in people of Caucasian,
Hispanic, Asian, and African origins.[20]

[edit] Hygiene Hypothesis

According to the hygiene hypothesis, proposed by David P. Strachan, allergic diseases are
caused by inappropriate immunological responses to harmless antigens driven by a TH2mediated immune response. Many bacteria and viruses elicit a TH1-mediated immune
response, which down-regulates TH2 responses. The first proposed mechanism of action
of the hygiene hypothesis stated that insufficient stimulation of the TH1 arm of the
immune system lead to an overactive TH2 arm, which in turn led to allergic disease.[21] In
other words, individuals living in too sterile an environment are not exposed to enough
pathogens to keep the immune system busy. Since our bodies evolved to deal with a
certain level of such pathogens, when it is not exposed to this level the immune system
will attack harmless antigens, and thus normally benign microbial objects, like pollen,
will trigger an immune response. [22]
The hygiene hypothesis was developed to explain the observation that hay fever and
eczema, both allergic diseases, were less common in children from larger families, which

were presumably exposed to more infectious agents through their siblings, than in
children from families with only one child. The hygiene hypothesis has been extensively
investigated by immunologists and epidemiologists and has become an important
theoretical framework for the study of allergic disorders. It is used to explain the increase
in allergic diseases that has been seen since industrialization, and the higher incidence of
allergic diseases in more developed countries. The hygiene hypothesis has now expanded
to include exposure to symbiotic bacteria and parasites as important modulators of
immune system development, along with infectious agents.
Epidemiological data supports the hygiene hypothesis. Studies have shown that various
immunological and autoimmune diseases are much less common in the developing world
than the industrialized world and that immigrants to the industrialized world from the
developing world increasingly develop immunological disorders in relation to the length
of time since arrival in the industrialized world.[23] Longitudinal studies in the third world
demonstrate an increase in immunological disorders as a country grows more affluent
and, presumably, cleaner[24]. The use of antibiotics in the first year of life has been linked
to asthma and other allergic diseases.[25] The use of antibacterial cleaning products has
also been associated with higher incidence of asthma, as has birth by Caesarean section
rather than vaginal birth.[26][27]

[edit] Other Environmental factors

International differences have been associated with the number of individuals within a
population that suffer from allergy. Allergic diseases are more common in industrialized
countries than in countries that are more traditional or agricultural, and there is a higher
rate of allergic disease in urban populations versus rural populations, although these
differences are becoming less defined.[28]
Exposure to allergens, especially in early life, is an important risk factor for allergy.
Alterations in exposure to microorganisms is another plausible explanation, at present, for
the increase in atopic allergy.[14] Endotoxin exposure reduces release of inflammatory
cytokines such as TNF-, IFN, interleukin-10, and interleukin-12 from white blood cells
(leukocytes) that circulate in the blood.[29] Certain microbe-sensing proteins, known as
Toll-like receptors, found on the surface of cells in the body are also thought to be
involved in these processes.[30]
Gutworms and similar parasites are present in untreated drinking water in developing
countries, and were present in the water of developed countries until the routine
chlorination and purification of drinking water supplies.[31] Recent research has shown
that some common parasites, such as intestinal worms (e.g. hookworms), secrete
chemicals into the gut wall (and hence the bloodstream) that suppress the immune system
and prevent the body from attacking the parasite.[32] This gives rise to a new slant on the
hygiene hypothesis theory that co-evolution of man and parasites has led to an
immune system that only functions correctly in the presence of the parasites. Without
them, the immune system becomes unbalanced and oversensitive.[33] In particular,
research suggests that allergies may coincide with the delayed establishment of gut flora

in infants.[34] However, the research to support this theory is conflicting, with some
studies performed in China and Ethiopia showing an increase in allergy in people infected
with intestinal worms.[28] Clinical trials have been initiated to test the effectiveness of
certain worms in treating some allergies.[35] It may be that the term 'parasite' could turn
out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[35] For
more information on this topic, see Helminthic therapy.

[edit] Pathophysiology
The pathophysiology of allergic responses can be divided into two phases. The first is an
acute response that occurs immediately after exposure to an allergen. This phase can
either subside or progress into a "late phase reaction" which can substantially prolong the
symptoms of a response, and result in tissue damage.

[edit] Acute response

Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcRI receptor; 4 preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast
cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
In the early stages of allergy, a type I hypersensitivity reaction against an allergen,
encountered for the first time, causes a response in a type of immune cell called a TH2
lymphocyte, which belongs to a subset of T cells that produce a cytokine called
interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells,
whose role is production of antibodies. Coupled with signals provided by IL-4, this
interaction stimulates the B cell to begin production of a large amount of a particular type
of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgEspecific receptor (a kind of Fc receptor called FcRI) on the surface of other kinds of
immune cells called mast cells and basophils, which are both involved in the acute
inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules
held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc
receptors occurs when more than one IgE-receptor complex interacts with the same
allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils
undergo a process called degranulation, during which they release histamine and other
inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and

prostaglandins) from their granules into the surrounding tissue causing several systemic
effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle
contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on
the individual, allergen, and mode of introduction, the symptoms can be system-wide
(classical anaphylaxis), or localized to particular body systems; asthma is localized to the
respiratory system and eczema is localized to the dermis.[14]

[edit] Late-phase response

After the chemical mediators of the acute response subside, late phase responses can
often occur. This is due to the migration of other leukocytes such as neutrophils,
lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen
2-24 hours after the original reaction.[36] Cytokines from mast cells may also play a role in
the persistence of long-term effects. Late phase responses seen in asthma are slightly
different from those seen in other allergic responses, although they are still caused by
release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[37]

[edit] Diagnosis

An allergy testing machine being operated in the diagnostic immunology lab at Lackland
Air Force Base
Before a diagnosis of allergic disease can be confirmed, the other possible causes of the
presenting symptoms should be carefully considered.[38] Vasomotor rhinitis, for example,
is one of many maladies that shares symptoms with allergic rhinitis, underscoring the
need for professional differential diagnosis.[39] Once a diagnosis of asthma, rhinitis,
anaphylaxis, or other allergic disease has been made, there are several methods for
discovering the causative agent of that allergy.

[edit] Skin testing

Skin testing on arm

Skin testing on back

For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is
preferred over blood allergy tests because it is more sensitive and specific, simpler to use,
and less expensive.[40] Skin testing is also known as "puncture testing" and "prick testing"
due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of
suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.)
are introduced to sites on the skin marked with pen or dye (the ink/dye should be
carefully selected, lest it cause an allergic response itself). A small plastic or metal device
is used to puncture or prick the skin. Sometimes, the allergens are injected
"intradermally" into the patient's skin, with a needle and syringe. Common areas for
testing include the inside forearm and the back. If the patient is allergic to the substance,
then a visible inflammatory reaction will usually occur within 30 minutes. This response
will range from slight reddening of the skin to a full-blown hive (called "wheal and
flare") in more sensitive patients. Interpretation of the results of the skin prick test is
normally done by allergists on a scale of severity, with +/- meaning borderline reactivity,
and 4+ being a large reaction. Increasingly, allergists are measuring and recording the
diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often
guided by relevant literature.[41] Some patients may believe they have determined their
own allergic sensitivity from observation, but a skin test has been shown to be much
better than patient observation to detect allergy.[42]
If a serious life threatening anaphylactic reaction has brought a patient in for evaluation,
some allergists will prefer an initial blood test prior to performing the skin prick test. Skin
tests may not be an option if the patient has widespread skin disease or has taken
antihistamines sometime the last several days.

[edit] Blood testing

Various blood allergy testing methods are also available for detecting allergy to specific
substances. This kind of testing measures a "total IgE level" - an estimate of IgE
contained within the patient's serum. This can be determined through the use of
radiometric and colormetric immunoassays. Radiometric assays include the
radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE)
antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in
the blood.[40] Other newer methods use colorimetric or fluorometric technology in the
place of radioactive isotopes. Some "screening" test methods are intended to provide
qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic
sensitization. One such method has a sensitivity of about 70.8% and a positive predictive
value of 72.6% according to a large study.[43]
A low total IgE level is not adequate to rule out sensitization to commonly inhaled
allergens.[44] Statistical methods, such as ROC curves, predictive value calculations, and
likelihood ratios have been used to examine the relationship of various testing methods to
each other. These methods have shown that patients with a high total IgE have a high
probability of allergic sensitization, but further investigation with specific allergy tests for
a carefully chosen allergens is often warranted.

[edit] Treatment
There have been enormous improvements in the medical treatments used to treat allergic
conditions. With respect to anaphylaxis and hypersensitivity reactions to foods, drugs,
and insects and in allergic skin diseases, advances have included the identification of
food proteins to which IgE binding is associated with severe reactions and development
of low-allergen foods, improvements in skin prick test predictions; evaluation of the
atopy patch test; in wasp sting outcomes predictions and a rapidly disintegrating
epinephrine tablet, and anti-IL-5 for eosinophilic diseases.[45]
Traditionally treatment and management of allergies involved simply avoiding the
allergen in question or otherwise reducing exposure. For instance, people with cat
allergies were encouraged to avoid them. While avoidance may help to reduce symptoms
and avoid life-threatening anaphylaxis, it is difficult to achieve for those with pollen or
similar air-borne allergies. Strict avoidance still has a role in management though, and is
often used in managing food allergies.

[edit] Pharmacotherapy
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent
activation of cells and degranulation processes. These include antihistamines, cortisone,
dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn
sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are
FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics,
decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil
chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of

allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in
chronic treatment of allergic disorders.

[edit] Immunotherapy
Desensitization or hyposensitization is a treatment in which the patient is gradually
vaccinated with progressively larger doses of the allergen in question. This can either
reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive
skewing of IgG antibody production, to block excessive IgE production seen in atopys. In
a sense, the person builds up immunity to increasing amounts of the allergen in question.
Studies have demonstrated the long-term efficacy and the preventive effect of
immunotherapy in reducing the development of new allergy.[46] Meta-analyses have also
confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation
needed]
A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of
allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma,
and stinging insect based on numerous well-designed scientific studies.[47] Additionally,
national and international guidelines confirm the clinical efficacy of injection
immunotherapy in rhinitis and asthma, as well as the safety, provided that
recommendations are followed.[48]
A second form of immunotherapy involves the intravenous injection of monoclonal antiIgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction.
They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as
this would stimulate the allergic inflammatory response. The first agent of this class is
Omalizumab. While this form of immunotherapy is very effective in treating several
types of atopy, it should not be used in treating the majority of people with food allergies.
[citation needed]

A third type, Sublingual immunotherapy, is an orally-administered therapy which takes

advantage of oral immune tolerance to non-pathogenic antigens such as foods and
resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in
Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support
among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]
Allergy shot treatment is the closest thing to a cure for allergic symptoms. This therapy
requires a long-term commitment.

[edit] Unproven and ineffective treatments

An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for
decades but is not generally accepted as effective.[49] EPD uses dilutions of allergen and
an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to
respond by favouring desensitization, or down-regulation, rather than sensitization. EPD
has also been tried for the treatment of autoimmune diseases but again is not approved by
the U.S. Food and Drug Administration or of proven effectiveness.[49]

In alternative medicine, a number of allergy treatments are described by its practitioners,

particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and
applied kinesiology. Systematic literature searches conducted by the Mayo Clinic through
2006, involving hundreds of articles studying multiple conditions, including asthma and
upper respiratory tract infection showed no effectiveness of any alternative treatments,
and no difference compared with placebo. The authors concluded that, based on rigorous
clinical trials of all types of homeopathy for childhood and adolescence ailments, there is
no convincing evidence that supports the use of alternative treatments.[50]

[edit] Epidemiology
Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and
allergic diseaseshay fever and asthmahave increased in the Western world over the
past 2-3 decades.[51] Rapid increases in allergic asthma and other atopic disorders in
industrialized nations probably began in the 1960s and 1970s, with further increases
occurring during the 1980s and 1990s,[52] although some suggest that a steady rise in
sensitization has been occurring since the 1920s.[53] The incidence of atopy in developing
countries has generally remained much lower.[52]
Allergic conditions: Statistics and Epidemiology

Allergy type

United States

United Kingdom[54]

Allergic
rhinitis

35.9 million[55] (about 11% of 3.3 million (about 5.5%

the population[56])
of the population[57])

Asthma

10 million suffer from

allergic asthma (about 3% of
the population). The
prevalence of asthma
increased 75% from 19801994. Asthma prevalence is
39% higher in African
Americans than in Anglo
Saxons.[58]

Atopic
eczema

5.7 million (about

9.4%). In six and seven
year olds asthma
increased from 18.4%
to 20.9% over five
years, during the same
time the rate decreased
from 31% to 24.7% in
13 to 14 year olds.

About 9% of the population.

Between 1960 and 1990
5.8 million (about 1%
prevalence has increased
severe).
from 3% to 10% in children.
[59]

At least 40 deaths per year

due to insect venom. About
400 deaths due to penicillin
Between 1999 and
anaphylaxis. About 220
2006, 48 deaths
cases of anaphylaxis and 3
Anaphylaxis
occurred in people
deaths per year are due to
ranging from five
latex allergy.[60] An estimated
months to 85 years old.
150 people die annually from
anaphylaxis due to food
allergy.[61]

Around 15% of adults have

mild, localized allergic
Insect venom reactions. Systemic reactions Unknown
occur in 3% of adults and
less than 1% of children. [62]

Anaphylactic reactions to
Drug allergies penicillin cause 400 deaths
per year.

Unknown

About 6% of US children
under age 3 and 3.5-4% of
the overall US population.
[citation needed]
Peanut and/or tree
Food allergies
nut (e.g. walnut, almond and
cashew) allergy affects about
three million Americans, or
1.1% of the population.[61]

5-7% of infants and 12% of adults. A 117.3%

increase in peanut
allergies was observed
from 2001 to 2005, an
estimated 25,700
people in England are
affected.

Multiple
allergies
(Asthma,
eczema and
allergic
rhinitis
together)

2.3 million (about

3.7%), prevalence has
increased by 48.9%
between 2001 and
2005.

Unknown

Although genetic factors fundamentally govern susceptibility to atopic disease, increases

in atopy have occurred within too short a time frame to be explained by a genetic change
in the population, thus pointing to environmental or lifestyle changes.[52] Several
hypotheses have been identified to explain this increased prevalence; increased exposure

to perennial allergens due to housing changes and increasing time spent indoors, and
changes in cleanliness or hygiene that have resulted in the decreased activation of a
common immune control mechanism, coupled with dietary changes, obesity and decline
in physical exercise.[51] The hygiene hypothesis maintains[63] that high living standards
and hygienic conditions exposes children to fewer infections. It is thought that reduced
bacterial and viral infections early in life direct the maturing immune system away from
TH1 type responses, leading to unrestrained TH2 responses that allow for an increase in
allergy.[64][65]
Changes in rates and types of infection alone however, have been unable to explain the
observed increase in allergic disease, and recent evidence has focused attention on the
importance of the gastrointestinal microbial environment. Evidence has shown that
exposure to food and fecal-oral pathogens, such as hepatitis A, Toxoplasma gondii, and
Helicobacter pylori (which also tend to be more prevalent in developing countries), can
reduce the overall risk of atopy by more than 60%,[66] and an increased prevalence of
parasitic infections has been associated with a decreased prevalence of asthma.[67] It is
speculated that these infections exert their effect by critically altering TH1/TH2 regulation.
[68]
Important elements of newer hygiene hypotheses also include exposure to endotoxins,
exposure to pets and growing up on a farm.[68]

[edit] Medical specialty

In the United States physicians who hold certification by the American Board of Allergy
and Immunology (ABAI) have successfully completed an accredited educational program
and an evaluation process, including a secure, proctored examination to demonstrate the
knowledge, skills, and experience to the provision of patient care in allergy and
immunology.[69] An allergist-immunologist is a physician specially trained to manage
and treat asthma and the other allergic diseases. Becoming an allergist-immunologist
requires completion of at least nine years of training. After completing medical school
and graduating with a medical degree, a physician will then undergo three years of
training in internal medicine (to become an internist) or pediatrics (to become a
pediatrician). Once physicians have finished training in one of these specialties, they
must pass the exam of either the American Board of Pediatrics (ABP) or the American
Board of Internal Medicine (ABIM). Internists or pediatricians who wish to focus on the
sub-specialty of allergy-immunology then complete at least an additional two years of
study, called a fellowship, in an allergy-immunology training program. Allergistimmunologists who are listed as ABAI-certified have successfully passed the certifying
examination of the American Board of Allergy and Immunology (ABAI), following their
fellowship.[70]
In the United Kingdom, allergy is a subspecialty of general medicine or pediatrics. After
obtaining postgraduate exams (MRCP or MRCPCH respectively) a doctor works as
several years as a specialist registrar before qualifying for the General Medical Council
specialist register. Allergy services may also be delivered by immunologists. A 2003
Royal College of Physicians report presented a case for improvement of what were felt to
be inadequate allergy services in the UK.[71] In 2006, the House of Lords convened a

subcommittee that reported in 2007. It concluded likewise that allergy services were
insufficient to deal with what the Lords referred to as an "allergy epidemic" and its social
cost; it made several other recommendations.[72]

[edit] See also

Allergic inflammation
Basophil activation
Allergen
Hypersensitivity
Hypoallergenic
IgE
Immunoglobulin
Multiple chemical sensitivity (MCS)
Oral allergy syndrome
Urticaria
Medical tattoo

[edit] References
1. ^ Kay AB (2000). "Overview of 'allergy and allergic diseases: with a view to the
future'". Br. Med. Bull. 56 (4): 84364. doi:10.1258/0007142001903481. PMID
11359624.
2. ^ Clemens Peter Pirquet von Cesenatico at Who Named It?
3. ^ Von Pirquet C (1906). "Allergie". Munch Med Wochenschr 53: 1457.
4. ^ Gell PGH, Coombs RRA. (1963). Clinical Aspects of Immunology. London:
Blackwell.
5. ^ Ishizaka K, Ishizaka T, Hornbrook MM (1966). "Physico-chemical properties of
human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of
reaginic activity". J. Immunol. 97 (1): 7585. PMID 4162440.
6. ^ Bope, Edward T.; Rakel, Robert E.. Conn's Current Therapy 2005. Philadelphia,
PA: W.B. Saunders Company. pp. 880. ISBN 0721 6386 43.
7. ^ Holgate ST (1998). "Asthma and allergy--disorders of civilization?". QJM 91
(3): 17184. doi:10.1093/qjmed/91.3.171. PMID 9604069.
8. ^ Rusznak C, Davies RJ (1998). "ABC of allergies. Diagnosing allergy". BMJ
316 (7132): 6869. PMID 9522798.
9. ^ Golden DB (2007). "Insect sting anaphylaxis". Immunol Allergy Clin North Am
27 (2): 26172, vii. doi:10.1016/j.iac.2007.03.008. PMID 17493502.
10. ^ Schafer JA, Mateo N, Parlier GL, Rotschafer JC (2007). "Penicillin allergy skin
testing: what do we do now?". Pharmacotherapy 27 (4): 5425.
doi:10.1592/phco.27.4.542. PMID 17381381.
11. ^ a b Tang AW (2003). "A practical guide to anaphylaxis". Am Fam Physician 68
(7): 132532. PMID 14567487.

12. ^ Brehler R, Ktting B (2001). "Natural rubber latex allergy: a problem of

interdisciplinary concern in medicine". Arch. Intern. Med. 161 (8): 105764.
doi:10.1001/archinte.161.8.1057. PMID 11322839.
13. ^ Muller BA (2004). "Urticaria and angioedema: a practical approach". Am Fam
Physician 69 (5): 11238. PMID 15023012.
14. ^ a b c d Janeway, Charles; Paul Travers, Mark Walport, and Mark Shlomchik
(2001). Immunobiology; Fifth Edition. New York and London: Garland Science.
pp. e-book. ISBN 0-8153-4101-6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
call=bv.View..ShowTOC&rid=imm.TOC&depth=10..
15. ^ Galli SJ (2000). "Allergy". Curr. Biol. 10 (3): R935. doi:10.1016/S09609822(00)00322-5. PMID 10679332.
16. ^ a b c d e De Swert LF (1999). "Risk factors for allergy". Eur. J. Pediatr. 158 (2):
8994. PMID 10048601.
17. ^ a b Croner S (1992). "Prediction and detection of allergy development: influence
of genetic and environmental factors". J. Pediatr. 121 (5 Pt 2): S5863. PMID
1447635.
18. ^ Jarvis D, Burney P (1997) Epidemiology of atopy and atopic disease In: Kay
AB (ed) Allergy and allergic diseases, vol 2. Blackwell Science London, pp 1208
1224
19. ^ Anderson HR, Pottier AC, Strachan DP (1992). "Asthma from birth to age 23:
incidence and relation to prior and concurrent atopic disease". Thorax 47 (7):
53742. PMID 1412098.
20. ^ Barnes KC, Grant AV, Hansel NN, Gao P, Dunston GM (2007). "African
Americans with asthma: genetic insights". Proc Am Thorac Soc 4 (1): 5868.
doi:10.1513/pats.200607-146JG. PMID 17202293.
http://pats.atsjournals.org/cgi/content/full/4/1/58.
21. ^ Folkerts G, Walzl G, Openshaw PJ. Do common childhood infections 'teach' the
immune system not to be allergic? Immunol Today 2000; 21(3):118-120. PubMed
22. ^ [1]
23. ^ Gibson PG, Henry RL, Shah S, Powell H, Wang H (September 2003).
"Migration to a western country increases asthma symptoms but not eosinophilic
airway inflammation". Pediatr. Pulmonol. 36 (3): 20915.
doi:10.1002/ppul.10323. PMID 12910582.
24. ^ Addo-Yobo EO, Woodcock A, Allotey A, Baffoe-Bonnie B, Strachan D,
Custovic A (February 2007). "Exercise-induced bronchospasm and atopy in
Ghana: two surveys ten years apart". PLoS Med. 4 (2): e70.
doi:10.1371/journal.pmed.0040070. PMID 17326711. PMC: 1808098.
http://medicine.plosjournals.org/perlserv/?request=getdocument&doi=10.1371/journal.pmed.0040070. Retrieved on 2008-07-06.
25. ^ Marra F, Lynd L, Coombes M "et al." (2006). "Does antibiotic exposure during
infancy lead to development of asthma?: a systematic review and metaanalysis".
Chest 129 (3): 6108. doi:10.1378/chest.129.3.610. PMID 16537858.
26. ^ Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell, CR (2007). "A
meta-analysis of the association between Caesarean section and childhood
asthma". Clin. And Exper. Allergy online ahead of print: 629.
doi:10.1111/j.1365-2222.2007.02780.x.

27. ^ Zock JP, Plana E, Jarvis D "et al." (2007). "The use of household cleaning
sprays and adult asthma: an international longitudinal study". Am J Respir Crit
Care Med 176 (8): 73541. doi:10.1164/rccm.200612-1793OC. PMID 17585104.
28. ^ a b Cooper PJ (2004). "Intestinal worms and human allergy". Parasite Immunol.
26 (11-12): 45567. doi:10.1111/j.0141-9838.2004.00728.x. PMID 15771681.
29. ^ Braun-Fahrlnder C, Riedler J, Herz U, et al (2002). "Environmental exposure
to endotoxin and its relation to asthma in school-age children". N. Engl. J. Med.
347 (12): 86977. doi:10.1056/NEJMoa020057. PMID 12239255.
30. ^ Garn H, Renz H (2007). "Epidemiological and immunological evidence for the
hygiene hypothesis". Immunobiology 212 (6): 44152.
doi:10.1016/j.imbio.2007.03.006. PMID 17544829.
31. ^ Macpherson CN, Gottstein B, Geerts S (2000). "Parasitic food-borne and waterborne zoonoses". Rev. - Off. Int. Epizoot. 19 (1): 24058. PMID 11189719.
32. ^ Carvalho EM, Bastos LS, Arajo MI (2006). "Worms and allergy". Parasite
Immunol. 28 (10): 52534. doi:10.1111/j.1365-3024.2006.00894.x. PMID
16965288.
33. ^ Yazdanbakhsh M, Kremsner PG, van Ree R (2002). "Allergy, parasites, and the
hygiene hypothesis". Science 296 (5567): 4904.
doi:10.1126/science.296.5567.490. PMID 11964470.
34. ^ Emanuelsson C, Spangfort MD (2007). "Allergens as eukaryotic proteins
lacking bacterial homologues". Mol. Immunol. 44 (12): 325660.
doi:10.1016/j.molimm.2007.01.019. PMID 17382394.
35. ^ a b Falcone FH, Pritchard DI (2005). "Parasite role reversal: worms on trial".
Trends Parasitol. 21 (4): 15760. doi:10.1016/j.pt.2005.02.002. PMID 15780835.
36. ^ Grimbaldeston MA, Metz M, Yu M, Tsai M, Galli SJ (2006). "Effector and
potential immunoregulatory roles of mast cells in IgE-associated acquired
immune responses". Curr. Opin. Immunol. 18 (6): 75160.
doi:10.1016/j.coi.2006.09.011. PMID 17011762.
37. ^ Holt PG, Sly PD (2007). "Th2 cytokines in the asthma late-phase response".
Lancet 370 (9596): 13968. doi:10.1016/S0140-6736(07)61587-6. PMID
17950849.
38. ^ Allergic and Environmental Asthma at eMedicine - Includes discussion of
differentials
39. ^ Wheeler PW, Wheeler SF (2005). "Vasomotor rhinitis". American family
physician 72 (6): 105762. PMID 16190503.
http://www.aafp.org/afp/20050915/1057.html.
40. ^ a b Ten RM, Klein JS, Frigas E (1995). "Allergy skin testing". Mayo Clin. Proc.
70 (8): 7834. PMID 7630219.
http://www.mayoclinicproceedings.com/inside.asp?AID=3978&UID=.
41. ^ Verstege A, Mehl A, Rolinck-Werninghaus C, et al (2005). "The predictive
value of the skin prick test weal size for the outcome of oral food challenges".
Clin. Exp. Allergy 35 (9): 12206. doi:10.1111/j.1365-2222.2005.2324.x. PMID
16164451.
42. ^ Li JT, Andrist D, Bamlet WR, Wolter TD (2000). "Accuracy of patient
prediction of allergy skin test results". Ann. Allergy Asthma Immunol. 85 (5): 382
4. PMID 11101180.

43. ^ Vidal C, Gude F, Boquete O, et al (2005). "Evaluation of the phadiatop test in

the diagnosis of allergic sensitization in a general adult population". Journal of
investigational allergology & clinical immunology 15 (2): 12430. PMID
16047713.
44. ^ Kerkhof M, Dubois AE, Postma DS, Schouten JP, de Monchy JG (2003). "Role
and interpretation of total serum IgE measurements in the diagnosis of allergic
airway disease in adults". Allergy 58 (9): 90511. doi:10.1034/j.13989995.2003.00230.x. PMID 12911420.
45. ^ Sicherer SH, Leung DY (2007). "Advances in allergic skin disease,
anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects". J.
Allergy Clin. Immunol. 119 (6): 14629. doi:10.1016/j.jaci.2007.02.013. PMID
17412401.
46. ^ Ross RN, Nelson HS, Finegold I (2000). "Effectiveness of specific
immunotherapy in the treatment of allergic rhinitis: an analysis of randomized,
prospective, single- or double-blind, placebo-controlled studies". Clinical
therapeutics 22 (3): 34250. doi:10.1016/S0149-2918(00)80038-7. PMID
10963288.
47. ^ Rank MA, Li JT (September 2007). "Allergen immunotherapy". Mayo Clin.
Proc. 82 (9): 111923. PMID 17803880.
48. ^ Passalacqua G, Durham SR (2007). "Allergic rhinitis and its impact on asthma
update: allergen immunotherapy". J. Allergy Clin. Immunol. 119 (4): 88191.
doi:10.1016/j.jaci.2007.01.045. PMID 17418661.
49. ^ a b Terr AI (2004). "Unproven and controversial forms of immunotherapy".
Clinical allergy and immunology 18: 70310. PMID 15042943.
50. ^ Altun U, Pittler MH, Ernst E (2007). "Homeopathy for childhood and
adolescence ailments: systematic review of randomized clinical trials". Mayo
Clin. Proc. 82 (1): 6975. PMID 17285788.
51. ^ a b Platts-Mills TA, Erwin E, Heymann P, Woodfolk J (2005). "Is the hygiene
hypothesis still a viable explanation for the increased prevalence of asthma?".
Allergy 60 Suppl 79: 2531. doi:10.1111/j.1398-9995.2005.00854.x. PMID
15842230.
52. ^ a b c Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J (2006). "Too clean,
or not too clean: the hygiene hypothesis and home hygiene". Clin. Exp. Allergy 36
(4): 40225. doi:10.1111/j.1365-2222.2006.02463.x. PMID 16630145.
53. ^ Isolauri E, Huurre A, Salminen S, Impivaara O (2004). "The allergy epidemic
extends beyond the past few decades". Clin. Exp. Allergy 34 (7): 100710.
doi:10.1111/j.1365-2222.2004.01999.x. PMID 15248842.
54. ^ "Chapter 4: The Extent and Burden of Allergy in the United Kingdom". House
of Lords - Science and Technology - Sixth Report. 2007-07-24.
http://www.publications.parliament.uk/pa/ld200607/ldselect/ldsctech/166/16607.h
tm. Retrieved on 2007-12-03.
55. ^ "AAAAI - rhinitis, sinusitis, hay fever, stuffy nose, watery eyes, sinus
infection". http://www.aaaai.org/patients/gallery/rhinitissinusitis.asp?item=1a.
Retrieved on 2007-12-03.
56. ^ Based on an estimated population of 303 million in 2007 U.S. POPClock. U.S.
Census Bureau.

57. ^ Based on an estimated population of 60.6 million UK population grows to 60.6

million
58. ^ "AAAAI - asthma, allergy, allergies, prevention of allergies and asthma,
treatment for allergies and asthma".
http://www.aaaai.org/patients/gallery/prevention.asp?item=1a. Retrieved on 200712-03.
59. ^ "AAAAI - skin condition, itchy skin, bumps, red irritated skin, allergic reaction,
treating skin condition". http://www.aaaai.org/patients/gallery/skinallergies.asp?
item=1a. Retrieved on 2007-12-03.
60. ^ "AAAAI - anaphylaxis, cause of anaphylaxis, prevention, allergist, anaphylaxis
statistics". http://www.aaaai.org/patients/gallery/anaphylaxis.asp?item=1a.
Retrieved on 2007-12-03.
61. ^ a b "AAAAI - food allergy, food reactions, anaphylaxis, food allergy
prevention". http://www.aaaai.org/patients/gallery/foodallergy.asp?item=1a.
Retrieved on 2007-12-03.
62. ^ "AAAAI - stinging insect, allergic reaction to bug bite, treatment for insect
bite". http://www.aaaai.org/patients/gallery/insect.asp?item=1a. Retrieved on
2007-12-03.
63. ^ Strachan DP (1989). "Hay fever, hygiene, and household size". BMJ 299
(6710): 125960. PMID 2513902. Full text at PMC: 1838109
64. ^ Yazdanbakhsh M, Kremsner PG, van Ree R (2002). "Allergy, parasites, and the
hygiene hypothesis". Science 296 (5567): 4904.
doi:10.1126/science.296.5567.490. PMID 11964470.
65. ^ Renz H, Blmer N, Virna S, Sel S, Garn H (2006). "The immunological basis of
the hygiene hypothesis". Chem Immunol Allergy 91: 3048.
doi:10.1159/000090228. PMID 16354947.
66. ^ Matricardi PM, Rosmini F, Riondino S, et al (2000). "Exposure to foodborne
and orofecal microbes versus airborne viruses in relation to atopy and allergic
asthma: epidemiological study". BMJ 320 (7232): 4127.
doi:10.1136/bmj.320.7232.412. PMID 10669445. Full text at PMC: 27285
67. ^ Masters S, Barrett-Connor E (1985). "Parasites and asthma--predictive or
protective?". Epidemiol Rev 7: 4958. PMID 4054238.
68. ^ a b Sheikh A, Strachan DP (2004). "The hygiene theory: fact or fiction?". Curr
Opin Otolaryngol Head Neck Surg 12 (3): 2326. PMID 15167035.
69. ^ "ABAI: American Board of Allergy and Immunology".
http://www.abai.org/training.asp. Retrieved on 2007-08-05.
70. ^ "AAAAI - What is an Allergist?".
http://www.aaaai.org/media/resources/allergist.asp. Retrieved on 2007-08-05.
71. ^ Royal College of Physicians (2003). Allergy: the unmet need. London, UK:
Royal College of Physicians. ISBN 1-86016-183-9. PDF versionPDF (1.03 MiB)
72. ^ House of Lords - Science and Technology Committee (2007). Allergy - HL 166I, 6th Report of Session 2006-07 - Volume 1: Report. London, UK: TSO (The
Stationery Office). ISBN 0104011491.
http://www.publications.parliament.uk/pa/ld200607/ldselect/ldsctech/166/16602.h
tm.

Short Contents | Full Contents

Navigation

About this book

Part V. The
Immune System
in Health and
Disease
12. Allergy and
Hypersensitivity
The production
of IgE.
Effector
mechanisms in
allergic
reactions.
Hypersensitivity
diseases.
Summary to
Chapter 12.
References

Other books @ NCBI

Immunobiology Part V. The Immune System in Health and

Disease 12. Allergy and Hypersensitivity Effector mechanisms in
allergic reactions.

Search

This book
books
PubMed

All

Figure 12.10. Molecules released by mast cells on activation. Mast

cells produce a wide variety of biologically active proteins and other
chemical mediators. The enzymes and toxic mediators listed in the first
two rows are released from the preformed granules. The cytokines,
chemokines, and lipid mediators are synthesized after activation.
2001 by Garland Science

The enzymes and toxic mediators listed in the first two rows are released from the

preformed granules. The cytokines, chemokines, and lipid mediators are synthesized after
activation.

Effector mechanisms in allergic reactions.

Allergic reactions are triggered when allergens cross-link preformed IgE bound to the
high-affinity receptor Fc RI on mast cells. Mast cells line the body surfaces and serve to
alert the immune system to local infection. Once activated, they induce inflammatory
reactions by secreting chemical mediators stored in preformed granules, and by
synthesizing leukotrienes and cytokines after activation occurs. In allergy, they provoke
very unpleasant reactions to innocuous antigens that are not associated with invading
pathogens that need to be expelled. The consequences of IgE-mediated mast-cell
activation depend on the dose of antigen and its route of entry; symptoms range from the
irritating sniffles of hay fever when pollen is inhaled, to the life-threatening circulatory
collapse that occurs in systemic anaphylaxis (Fig. 12.9). The immediate allergic reaction
caused by mast-cell degranulation is followed by a more sustained inflammation, known
as the late-phase response. This late response involves the recruitment of other effector
cells, notably TH2 lymphocytes, eosinophils, and basophils, which contribute significantly
to the immunopathology of an allergic response.
12-5. Most IgE is cell-bound and engages effector mechanisms of the immune system
by different pathways from other antibody isotypes.
Most antibodies are found in body fluids and engage effector cells, through receptors
specific for the Fc constant regions, only after binding specific antigen through the
antibody variable regions. IgE, however, is an exception as it is captured by the highaffinity Fc receptor in the absence of bound antigen. This means that IgE is mostly found
fixed in the tissues on mast cells that bear this receptor, as well as on circulating basophils
and activated eosinophils. The ligation of cell-bound IgE antibody by specific antigen
triggers activation of these cells at the site of antigen entry into the tissues. The release of
inflammatory lipid mediators, cytokines, and chemokines at sites of IgE-triggered
reactions results in the recruitment of eosinophils and basophils to augment the type I
response.
There are two types of IgE-binding Fc receptor. The first, Fc RI, is a high-affinity
receptor of the immunoglobulin superfamily that binds IgE on mast cells, basophils, and
activated eosinophils (see Section 9-22). When the cell-bound IgE antibody is crosslinked by a specific antigen, Fc RI transduces an activating signal. High levels of IgE,
such as those that exist in subjects with allergic diseases or parasite infections, can result
in a marked increase in Fc RI on the surface of mast cells, enhanced sensitivity of such
cells to activation by low concentrations of specific antigen, and markedly increased IgEdependent release of chemical mediators and cytokines.
The second IgE receptor, Fc RII, usually known as CD23, is a C-type lectin and is
structurally unrelated to Fc RI; it binds IgE with low affinity. CD23 is present on many
different cell types, including B cells, activated T cells, monocytes, eosinophils, platelets,
follicular dendritic cells, and some thymic epithelial cells. This receptor was thought to be

crucial for the regulation of IgE antibody levels; however, knockout mouse strains lacking
the CD23 gene show no major abnormality in the development of polyclonal IgE
responses. However the CD23 knockout mice have demonstrated a role for CD23 in
enhancing the antibody response to a specific antigen in the presence of that same antigen
complexed with IgE. This antigen-specific, IgE-mediated enhancement of antibody
responses fails to occur in mice lacking the CD23 gene. This demonstrates a role for
CD23 on antigen-presenting cells in the capture of antigen by specific IgE.
12-6. Mast cells reside in tissues and orchestrate allergic reactions.
Mast cells were described by Ehrlich in the mesentery of rabbits and named Mastzellen
(fattened cells'). Like basophils, mast cells contain granules rich in acidic proteoglycans
that take up basic dyes. However, in spite of this resemblance, and the similar range of
mediators stored in these basophilic granules, mast cells are derived from a different
myeloid lineage than basophils and eosinophils. Mast cells are highly specialized cells,
and are prominent residents of mucosal and epithelial tissues in the vicinity of small blood
vessels and postcapillary venules, where they are well placed to guard against invading
pathogens (see Sections 9-20 and 9-21). Mast cells are also found in subendothelial
connective tissue. They home to tissues as agranular cells; their final differentiation,
accompanied by granule formation, occurs after they have arrived in the tissues. The
major growth factor for mast cells is stem-cell factor (SCF), which acts on the cell-surface
receptor c-Kit (see Section 7-2). Mice with defective c-Kit lack differentiated mast cells
and cannot make IgE-mediated inflammatory responses. This shows that such responses
depend almost exclusively on mast cells.
Mast cells express Fc RI constitutively on their surface and are activated when antigens
cross-link IgE bound to these receptors (see Fig. 9.35). Degranulation occurs within
seconds, releasing a variety of preformed inflammatory mediators (Fig. 12.10). Among
these are histaminea short-lived vasoactive amine that causes an immediate increase in
local blood flow and vessel permeabilityand enzymes such as mast-cell chymase,
tryptase, and serine esterases. These enzymes can in turn activate matrix
metalloproteinases, which break down tissue matrix proteins, causing tissue destruction.
Large amounts of tumor necrosis factor (TNF)- are also released by mast cells after
activation. Some comes from stores in mast-cell granules; some is newly synthesized by
the activated mast cells themselves. TNF- activates endothelial cells, causing increased
expression of adhesion molecules, which promotes the influx of inflammatory leukocytes
and lymphocytes into tissues (see Section 2-22).
On activation, mast cells synthesize and release chemokines, lipid mediators such as
leukotrienes and platelet-activating factor (PAF), and additional cytokines such as IL-4
and IL-13 which perpetuate the TH2 response. These mediators contribute to both the
acute and the chronic inflammatory responses. The lipid mediators, in particular, act
rapidly to cause smooth muscle contraction, increased vascular permeability, and mucus
secretion, and also induce the influx and activation of leukocytes, which contribute to the
late-phase response. The lipid mediators derive from membrane phospholipids, which are

cleaved to release the precursor molecule arachidonic acid. This molecule can be modified
by two pathways to give rise to prostaglandins, thromboxanes, and leukotrienes. The
leukotrienes, especially C4, D4, and E4, are important in sustaining inflammatory
responses in the tissues. Many anti-inflammatory drugs are inhibitors of arachidonic acid
metabolism. Aspirin, for example, is an inhibitor of the enzyme cyclooxygenase and
blocks the production of prostaglandins.
IgE-mediated activation of mast cells thus orchestrates an important inflammatory
cascade that is amplified by the recruitment of eosinophils, basophils, and TH2
lymphocytes. The physiological importance of this reaction is as a defense mechanism
against certain types of infection (see Section 9-23). In allergy, however, the acute and
chronic inflammatory reactions triggered by mast-cell activation have important
pathophysiological consequences, as seen in the diseases associated with allergic
responses to environmental antigens.
12-7. Eosinophils are normally under tight control to prevent inappropriate toxic
responses.
Eosinophils are granulocytic leukocytes that originate in bone marrow. They are so called
because their granules, which contain arginine-rich basic proteins, are colored bright
orange by the acidic stain eosin (Fig. 12.11). Only very small numbers of these cells are
normally present in the circulation; most eosinophils are found in tissues, especially in the
connective tissue immediately underneath respiratory, gut, and urogenital epithelium,
implying a likely role for these cells in defense against invading organisms. Eosinophils
have two kinds of effector function. First, on activation they release highly toxic granule
proteins and free radicals, which can kill microorganisms and parasites but can also cause
significant tissue damage in allergic reactions. Second, activation induces the synthesis of
chemical mediators such as prostaglandins, leukotrienes, and cytokines, which amplify the
inflammatory response by activating epithelial cells, and recruiting and activating more
eosinophils and leukocytes (Fig. 12.12).
The activation and degranulation of eosinophils is strictly regulated, as their inappropriate
activation would be very harmful to the host. The first level of control acts on the
production of eosinophils by the bone marrow. Few eosinophils are produced in the
absence of infection or other immune stimulation. But when TH2 cells are activated,
cytokines such as IL-5 are released that increase the production of eosinophils in the bone
marrow and their release into the circulation. However, transgenic animals overexpressing
IL-5 have increased numbers of eosinophils (eosinophilia) in the circulation but not in
their tissues, indicating that migration of eosinophils from the circulation into tissues is
regulated separately, by a second set of controls. The key molecules in this case are CC
chemokines (see Section 2-20). Most of these cause chemotaxis of several types of
leukocyte, but two are specific for eosinophils and have been named eotaxin 1 and
eotaxin 2.
The eotaxin receptor on eosinophils, CCR3, is a member of the chemokine family of

receptors (see Section 6-16). This receptor also binds the CC chemokines MCP-3, MCP-4,
and RANTES, which also induce eosinophil chemotaxis. The eotaxins and these other CC
chemokines also activate eosinophils. Identical or similar chemokines also stimulate mast
cells and basophils. For example, eotaxin attracts basophils and causes their
degranulation, and MCP-1, which binds to CCR2, similarly activates mast cells in both
the presence or absence of antigen. MCP-1 can also promote the differentiation of naive
TH0 cells to TH2 cells; TH2 cells also carry CCR3 and migrate toward eotaxin. These
findings show that families of chemokines, as well as cytokines, can coordinate certain
kinds of immune response.
A third set of controls regulates the state of eosinophil activation. In their nonactivated
state, eosinophils do not express high-affinity IgE receptors and have a high threshold for
release of their granule contents. After activation by cytokines and chemokines, this
threshold drops, Fc RI is expressed, and the number of Fc receptors and complement
receptors on the cell surface also increases. The eosinophil is now primed to carry out its
effector activity, for example degranulation in response to antigen that cross-links specific
IgE bound to Fc RI on the eosinophil surface.
The potential of eosinophils to cause tissue injury is illustrated by rare syndromes due to
abnormally large numbers of eosinophils in the blood (hypereosinophilia). These
syndromes are sometimes seen in association with T-cell lymphomas, in which
unregulated IL-5 secretion drives a marked increase in the numbers of circulating
eosinophils. The clinical manifestations of hypereosinophilia are damage to the
endocardium (Fig. 12.13) and to nerves, leading to heart failure and neuropathy, both
thought to be caused by the toxic effects of eosinophil granule proteins.
12-8. Eosinophils and basophils cause inflammation and tissue damage in allergic
reactions.
In a local allergic reaction, mast-cell degranulation and TH2 activation cause eosinophils
to accumulate in large numbers and to become activated. Their continued presence is
characteristic of chronic allergic inflammation and they are thought to be major
contributors to tissue damage.
Basophils are also present at the site of an inflammatory reaction. Basophils share a
common stem-cell precursor with eosinophils; growth factors for basophils are very
similar to those for eosinophils and include IL-3, IL-5, and GM-CSF. There is evidence
for reciprocal control of the maturation of the stem-cell population into basophils or
eosinophils. For example, transforming growth factor (TGF)- in the presence of IL-3
suppresses eosinophil differentiation and enhances that of basophils. Basophils are
normally present in very low numbers in the circulation and seem to have a similar role to
eosinophils in defense against pathogens. Like eosinophils, they are recruited to the sites
of allergic reactions. Basophils express Fc RI on the cell surface and, on activation by
cytokines or antigen, they release histamine and IL-4 from the basophilic granules after

which they are named.

Eosinophils, mast cells, and basophils can interact with each other. Eosinophil
degranulation releases major basic protein, which in turn causes degranulation of mast
cells and basophils. This effect is augmented by any of the cytokines that affect eosinophil
and basophil growth, differentiation, and activation, such as IL-3, IL-5, and GM-CSF.
12-9. An allergic reaction is divided into an immediate response and a late-phase
response.
The inflammatory response after IgE-mediated mast-cell activation occurs as an
immediate reaction, starting within seconds, and a late reaction, which takes up to 812
hours to develop. These reactions can be distinguished clinically (Fig. 12.14). The
immediate reaction is due to the activity of histamine, prostaglandins, and other
preformed or rapidly synthesized mediators that cause a rapid increase in vascular
permeability and the contraction of smooth muscle. The late-phase reaction is caused by
the induced synthesis and release of mediators including leukotrienes, chemokines, and
cytokines from the activated mast cells (see Fig. 12.10). These recruit other leukocytes,
including eosinophils and TH2 lymphocytes, to the site of inflammation. Although the latephase reaction is clinically less marked than the immediate response, it is associated with
a second phase of smooth muscle contraction, sustained edema, and the development of
one of the cardinal features of allergic asthma: airway hyperreactivity to nonspecific
bronchoconstrictor stimuli such as histamine and methacholine.
The late-phase reaction is an important cause of much serious long-term illness, as for
example in chronic asthma. This is because the late reaction induces the recruitment of
inflammatory leukocytes, especially eosinophils and TH2 lymphocytes, to the site of the
allergen-triggered mast-cell response. This late response can easily convert into a chronic
inflammatory response if antigen persists and stimulates allergen-specific TH2 cells, which
in turn promote eosinophilia and further IgE production.
12-10. The clinical effects of allergic reactions vary according to the site of mast-cell
activation.
When reexposure to allergen triggers an allergic reaction, the effects are focused on the
site at which mast-cell degranulation occurs. In the immediate response, the preformed
mediators released are short-lived, and their potent effects on blood vessels and smooth
muscles are therefore confined to the vicinity of the activated mast cell. The more
sustained effects of the late-phase response are also focused on the site of initial allergentriggered activation, and the particular anatomy of this site may determine how readily the
inflammation can be resolved. Thus, the clinical syndrome produced by an allergic
reaction depends critically on three variables: the amount of allergen-specific IgE present;
the route by which the allergen is introduced; and the dose of allergen (Fig. 12.15).

If an allergen is introduced directly into the bloodstream or is rapidly absorbed from

the gut, the connective tissue mast cells associated with all blood vessels can
become activated. This activation causes a very dangerous syndrome called systemic
anaphylaxis. Disseminated mast-cell activation has a variety of potentially fatal effects:
the widespread increase in vascular permeability leads to a catastrophic loss of blood
pressure; airways constrict, causing difficulty in breathing; and swelling of the epiglottis
can cause suffocation. This potentially fatal syndrome is called anaphylactic shock. It can
occur if drugs are administered to people who have IgE specific for that drug, or after an
insect bite in individuals allergic to insect venom. Some foods, for example peanuts or
brazil nuts, can cause systemic anaphylaxis in susceptible individuals. This syndrome can
be rapidly fatal but can usually be controlled by the immediate injection of epinephrine,
which relaxes the smooth muscle and inhibits the cardiovascular effects of anaphylaxis.
The most frequent allergic reactions to drugs occur with penicillin and its relatives. In
people with IgE antibodies against penicillin, administration of the drug by injection can
cause anaphylaxis and even death. Great care should be taken to avoid giving a drug to
patients with a past history of allergy to that drug or one that is closely related structurally.
Penicillin acts as a hapten (see Section 9-2); it is a small molecule with a highly reactive
-lactam ring that is crucial for its antibacterial activity. This ring reacts with amino
groups on host proteins to form covalent conjugates. When penicillin is ingested or
injected, it forms conjugates with self proteins, and the penicillin-modified self peptides
can provoke a TH2 response in some individuals. These TH2 cells then activate penicillinbinding B cells to produce IgE antibody to the penicillin hapten. Thus, penicillin acts both
as the B-cell antigen and, by modifying self peptides, as the T-cell antigen. When
penicillin is injected intravenously into an allergic individual, the penicillin-modified
proteins can cross-link IgE molecules on the mast cells and cause anaphylaxis.
12-11. Allergen inhalation is associated with the development of rhinitis and asthma.
Inhalation is the most common route of allergen entry. Many people have mild allergies to
inhaled antigens, manifesting as sneezing and a runny nose. This is called allergic rhinitis,
and results from the activation of mucosal mast cells beneath the nasal epithelium by
allergens such as pollens that release their protein contents, which can then diffuse across
the mucus membranes of the nasal passages. Allergic rhinitis is characterized by intense
itching and sneezing, local edema leading to blocked nasal passages, a nasal discharge,
which is typically rich in eosinophils, and irritation of the nose as a result of histamine
release. A similar reaction to airborne allergens deposited on the conjunctiva of the eye is
called allergic conjunctivitis. Allergic rhinitis and conjunctivitis are commonly caused by
environmental allergens that are only present during certain seasons of the year. For
example, hay fever is caused by a variety of allergens, including certain grass and tree
pollens. Autumnal symptoms may be caused by weed pollen, such as that of ragweed.
These reactions are annoying but cause little lasting damage.
A more serious syndrome is allergic asthma, which is triggered by allergen-induced
activation of submucosal mast cells in the lower airways (Fig. 12.16). This leads within

seconds to bronchial constriction and increased secretion of fluid and mucus, making
breathing more difficult by trapping inhaled air in the lungs. Patients with allergic asthma
often need treatment, and asthmatic attacks can be life-threatening. An important feature
of asthma is chronic inflammation of the airways, which is characterized by the continued
presence of increased numbers of TH2 lymphocytes, eosinophils, neutrophils, and other
leukocytes (Fig. 12.17).
Although allergic asthma is initially driven by a response to a specific allergen, the
subsequent chronic inflammation seems to be perpetuated even in the apparent absence of
further exposure to allergen. The airways become characteristically hyperreactive and
factors other than reexposure to antigen can trigger asthma attacks. For example, the
airways of asthmatics characteristically show hyperresponsiveness to environmental
chemical irritants such as cigarette smoke and sulfur dioxide; viral or, to a lesser extent,
bacterial respiratory tract infections can exacerbate the disease by inducing a TH2dominated local response.
12-12. Skin allergy is manifest as urticaria or chronic eczema.
The same dichotomy between immediate and delayed responses is seen in cutaneous
allergic responses. The skin forms an effective barrier to the entry of most allergens but it
can be breached by local injection of small amounts of allergen, for example by a stinging
insect. The entry of allergen into the epidermis or dermis causes a localized allergic
reaction. Local mast-cell activation in the skin leads immediately to a local increase in
vascular permeability, which causes extravasation of fluid and swelling. Mast-cell
activation also stimulates the release of chemicals from local nerve endings by a nerve
axon reflex, causing the vasodilation of surrounding cutaneous blood vessels, which
causes redness of the surrounding skin. The resulting skin lesion is called a wheal-andflare reaction. About 8 hours later, a more widespread and sustained edematous response
appears in some individuals as a consequence of the late-phase response (see Fig. 12.14).
A disseminated form of the wheal-and-flare reaction, known as urticaria or hives,
sometimes appears when ingested allergens enter the bloodstream and reach the skin.
Histamine released by mast cells activated by allergen in the skin causes large, itchy, red
swellings of the skin.
Allergists take advantage of the immediate response to test for allergy by injecting minute
amounts of potential allergens into the epidermal layer of the skin. Although the reaction
after the administration of antigen by intraepidermal injection is usually very localized,
there is a small risk of inducing systemic anaphylaxis. Another standard test for allergy is
to measure levels of IgE antibody specific for a particular allergen in a sandwich ELISA
(see Appendix I, Section A-6).
Although acute urticaria is commonly caused by allergens, the causes of chronic urticaria,
in which the urticarial rash can recur over long periods, are less well understood. In up to
a third of cases, it seems likely that chronic urticaria is an autoimmune disease caused by
autoantibodies against the chain of Fc RI. This is an example of a type II

hypersensitivity reaction in which an autoantibody against a cellular receptor

triggers cellular activation, in this case causing mast-cell degranulation with
resulting urticaria.
A more prolonged inflammatory response is sometimes seen in the skin, most often in
atopic children. They develop a persistent skin rash called eczema or atopic dermatitis,
due to a chronic inflammatory response similar to that seen in the bronchial walls of
patients with asthma. The etiology of eczema is not well understood. TH2 cells and IgE are
involved, and it usually clears in adolescence, unlike rhinitis and asthma, which can
persist throughout life.
12-13. Allergy to foods causes symptoms limited to the gut and systemic reactions.
When an allergen is eaten, two types of allergic response are seen. Activation of mucosal
mast cells associated with the gastrointestinal tract leads to transepithelial fluid loss and
smooth muscle contraction, causing diarrhea and vomiting. For reasons that are not
understood, connective tissue mast cells in the dermis and subcutaneous tissues can also
be activated after ingestion of allergen, presumably by allergen that has been absorbed
into the bloodstream, and this results in urticaria. Urticaria is a common reaction when
penicillin is given orally to a patient who already has penicillin-specific IgE antibodies.
Ingestion of food allergens can also lead to the development of generalized anaphylaxis,
accompanied by cardiovascular collapse and acute asthmatic symptoms. Certain foods,
most importantly peanuts, tree nuts, and shellfish, are particularly associated with this
type of life-threatening response.
12-14. Allergy can be treated by inhibiting either IgE production or the effector
pathways activated by cross-linking of cell-surface IgE.
The approaches to the treatment and prevention of allergy are set out in Fig. 12.18. Two
treatments are commonly used in clinical practiceone is desensitization and the other is
blockade of the effector pathways. There are also several approaches still in the
experimental stage. In desensitization the aim is to shift the antibody response away from
one dominated by IgE toward one dominated by IgG; the latter can bind to the allergen
and thus prevent it from activating IgE-mediated effector pathways. Patients are injected
with escalating doses of allergen, starting with tiny amounts. This injection schedule
gradually diverts the IgE-dominated response, driven by TH2 cells, to one driven by TH1
cells, with the consequent downregulation of IgE production. Recent evidence shows that
desensitization is also associated with a reduction in the numbers of late-phase
inflammatory cells at the site of the allergic reaction. A potential complication of the
desensitization approach is the risk of inducing IgE-mediated allergic responses.
An alternative, and still experimental, approach to desensitization is vaccination with
peptides derived from common allergens. This procedure induces T-cell anergy (see
Section 8-11), which is associated with multiple changes in the T-cell phenotype,
including downregulation of cytokine production and reduced expression of the CD3:T-

cell receptor complex. IgE-mediated responses are not induced by the peptides because
IgE, in contrast to T cells, can only recognize the intact antigen. A major difficulty with
this approach is that an individual's responses to peptides are restricted by their MHC
class II alleles (see Section 5-12); therefore, patients with different MHC class II
molecules respond to different allergen-derived peptides. As the human population is
outbred and expresses a wide variety of MHC class II alleles, the number of peptides
required to treat all allergic individuals might be very large.
Another vaccination strategy that shows promise in experimental models of allergy is the
use of oligodeoxynucleotides rich in unmethylated cytosine guanine dinucleotides (CpG)
as adjuvants (see Section 14-19) for desensitization regimes. These oligonucleotides
mimic bacterial DNA sequences known as CpG motifs and strongly promote TH1
responses. Their mechanism of action is discussed in Sections 14-19 and 8-6 and
Appendix I, Section A-4.
The signaling pathways that enhance the IgE response in allergic disease are also potential
targets for therapy. Inhibitors of IL-4, IL-5, and IL-13 would be predicted to reduce IgE
responses, but redundancy between some of the activities of these cytokines might make
this approach difficult to implement in practice. A second approach to manipulating the
response is to give cytokines that promote TH1-type responses. IFN-, IFN-, IL-10, IL12, and TGF- have each been shown to reduce IL-4-stimulated IgE synthesis in vitro,
and IFN- and IFN- have been shown to reduce IgE synthesis in vivo.
Another target for therapeutic intervention might be the high-affinity IgE receptor. An
effective competitor for IgE at this receptor could prevent the binding of IgE to the
surfaces of mast cells, basophils, and eosinophils. Candidate competitors include
humanized anti-IgE monoclonal antibodies, which bind to IgE and block its binding to the
receptor, and modified IgE Fc constructs that bind to the receptor but lack variable regions
and thus cannot bind antigen. Yet another approach would be to block the recruitment of
eosinophils to sites of allergic inflammation. The eotaxin receptor CCR3 is a potential
target for this type of therapy. The production of eosinophils in bone marrow and their exit
into the circulation might also be reduced by a blockade of IL-5 action.
The mainstays of therapy at present, however, are drugs that treat the symptoms of
allergic disease and limit the inflammatory response. Anaphylactic reactions are treated
with epinephrine, which stimulates the reformation of endothelial tight junctions,
promotes the relaxation of constricted bronchial smooth muscle, and also stimulates the
heart. Inhaled bronchodilators that act on -adrenergic receptors to relax constricted
muscle are also used to relieve acute asthma attacks. Antihistamines that block the
histamine H1 receptor reduce the urticaria that follows histamine release from mast cells
and eosinophils. Relevant H1 receptors include those on blood vessels that cause increased
permeability of the vessel wall, and those on unmyelinated nerve fibers that are thought to
mediate the itching sensation. In chronic allergic disease it is extremely important to treat
and prevent the chronic inflammatory tissue injury. Topical or systemic corticosteroids
(see Section 14-1) are used to suppress the chronic inflammatory changes seen in asthma,

rhinitis, and eczema. However, what is really needed is a means of converting the T-cell
response to the allergenic peptide antigen from predominantly TH2 to predominantly TH1.
This topic is also discussed in Chapter 14.
Summary.
The allergic response to innocuous antigens reflects the pathophysiological aspects of a
defensive immune response whose physiological role is to protect against helminthic
parasites. It is triggered by antigen binding to IgE antibodies bound to the high-affinity
IgE receptor Fc RI on mast cells. Mast cells are strategically distributed beneath the
mucosal surfaces of the body and in connective tissue. Antigen cross-linking the IgE on
their surface causes them to release large amounts of inflammatory mediators. The
resulting inflammation can be divided into early events, characterized by short-lived
mediators such as histamine, and later events that involve leukotrienes, cytokines, and
chemokines, which recruit and activate eosinophils and basophils. The late phase of this
response can evolve into chronic inflammation, characterized by the presence of effector
T cells and eosinophils, which is most clearly seen in chronic allergic asthma.
2001 by Garland Science

Allergic Cascade
Common Allergy Triggers Slideshow

Who are the "players" in the allergic cascade?

What about a more detailed look at the "players?"
What are cytokines?
What is the "early phase" of an allergic reaction?
What is the "late phase" of an allergic reaction?
What are the consequences of the allergic cascade?
How does understanding the allergic cascade help?
Allergic Cascade At A Glance
Pictures of Common Allergy Triggers - Slideshow

The immune system is very specific and goal oriented. Although you may be allergic to a
number of substances, allergic reactions are directed at specific allergens. For example,
you may be allergic to Bermuda grass, but not oysters. At times, however, two or more
foreign substances might appear similar in nature to the immune system, which may
mistake one for the other and react to both. For example, if you are allergic to birch trees,
your immune system may also react to apples or other fruits, which it mistakes for birch
pollen. These cross-reactions occur because of similar allergens that are produced by a

variety of plants. The allergic response, however, is by no means vague or ill-defined. It

is a definite, vigorous attack aimed, unfortunately, at harmless agents. The end result is
well-defined symptoms and disorders.
The deeper our understanding of the intricate nature of the allergic reaction, the more
likely we are to find more effective treatments. We need to look more closely at the chain
of events from the initial response to allergens to the many symptoms that may result.
Although misguided, it is an efficient, well-orchestrated, and potentially explosive
sequence of cellular and chemical interactions. This is the so-called "allergic cascade."
Who are the "players" in the allergic cascade?
Our body's immune system is designed to constantly be on the lookout for intruders. It
has the remarkable ability to distinguish between "self" and "non-self" (foreign
substances, which it tirelessly protects us from). Let us look more closely at this complex
process. Take for example an exposure to ragweed pollen. Once in the body, the ragweed
pollen is engulfed by the immune system's scouts, the so-called Antigen Preventing Cells
or APC's. These APC's slice up the ragweed pollen into small fragments, which then
combine with special proteins in the cell, called human leukocyte antigens or HLA's.
HLA's function like a guideline to help the body distinguish "self" from "non-self." When
combined with the HLAs, the fragments become visible to a key player in the allergic
cascade (the lymphocytes), which recognizes them as foreign. This ragweed pollen
fragment-HLA combination is exposed on the surface of the APC's in full view of these
specialized white blood cells.
Before we review details of how the various players in the allergic cascade fulfill their
roles, let's note these basic concepts of types of important cells and messenger proteins of
the immune reaction:
The term white blood cells or leukocytes is derived from Greek words "leukos" meaning
white and "cytes" meaning cells. The white blood cells are essential to the immune
system and include the monocytes, macrophages, neutrophils, and lymphocytes.
Lymphocytes are white blood cells that play a key role in both immunity and allergy.
They are divided into two types, the T and B lymphocytes. Each type is responsible for a
particular branch of the immune system. It is the duty of the T-lymphocytes to be ready to
directly shift into action to attack foreign substances (cell-mediated immunity). Some Tlymphocytes are experts at "killing" (cytotoxic or killer T cells) while others assist the
immune response and are termed "helper" cells (TH cells). The TH cells are further
divided into TH1 (infection fighters) and TH2 (allergy promoters), depending on the
proteins they release. The partners of the T-lymphocytes are the B-lymphocytes. Blymphocytes are tiny antibody factories that produce antibodies to help destroy foreign
substances when stimulated to do so by the TH cells.

Basophils and eosinophils are other white blood cells that play an important role in
allergy. T cells often call these cells into action in allergic conditions. Blood levels of
eosinophils are commonly elevated in people with asthma and other allergic diseases.
Cytokines are a diverse group of proteins that are released by lymphocytes and
macrophages in response to an injury or activation, such as by an allergen. They act as
chemical signals that "step up" or "step down" the immune reaction.
What about a more detailed look at the "players?"
Lymphocytes - T's & B's
Lymphocytes are part of the white blood cell family and consist of T and B varieties.
Each T lymphocyte, or T cell, is like a specially trained detective. The T cell examines the
evidence that is exposed by the APC. When specific T cells come into contact with the
ragweed pollen fragment on the APC and recognize it as foreign, an army of specialized
T cells called "helper" cells (actually TH2 cells) is activated, thus releasing chemicals
(cytokines) that stimulate B lymphocytes. B lymphocytes produce IgE antibodies that
bind to the allergens (such as the pollen fragment).
Once the IgE is produced, it specifically recognizes the ragweed pollen and will
recognize it on future exposure.
The balance between allergy-promoting TH2 cells and infection-fighting TH1 cells has
recently been found to be a critical component of our immune system. Whereas allergy
reactions involve large numbers of TH2 cells, infections generate an army of TH1 cells,
which then release chemicals that help destroy microbes.
Allergy and asthma rates have been increasing in recent decades. One currently favored
theory explaining the increase is that it is a consequence of inadequately "geared up"
human immune systems because of the relatively sterilized environment of modern man,
possibly due to antibiotics and vaccinations! This has been referred to as the "hygiene
hypothesis." What this concept implies is that the immune systems of individuals who
have been exposed to sufficient microbes make TH1 cells when stimulated. But, if an
individual's immune system is inadequately stimulated to produce TH1 cells by exposure
to microbes, it will instead lean toward the allergy-producing system and make TH2 cells.
A tendency toward allergic reactions is the result.
Although this appears complicated, an understanding of the different lymphocyte
responses is important in treating allergies. Ideally, we would like to respond to ragweed
pollen with TH1 lymphocytes and not TH2 lymphocytes, which promote allergic
reactions and produce IgE in large amounts. Allergic individuals summon a large number
of TH2 cells in response to allergens, whereas non-allergic people do not.
Finally, the tendency to develop allergic conditions (i.e., to develop strong TH2 responses
to allergens) is thought to be partially inherited from our parents. At birth, there seems to

be a balance between the infection-fighting TH1 cells and the allergy-promoting TH2
cells. Current thinking is that allergy develops after birth when a child is exposed to
certain substances in the environment. The immune system is stimulated by these
exposures so that the scales are now tipped toward the production of allergy-promoting
TH2 cells. They are especially tipped toward allergy promotion in individuals that have
inherited the genetic tendency from their parents.
Mast Cells & Basophils
Mast cells and basophils are the next key players in the allergic cascade. They are volatile
cells with potentially explosive behavior. Mast cells reside in tissues while basophils are
found in the blood. Each of these cells has over 100,000 receptor sites for IgE, which
binds on their surfaces. The binding of IgE to these cells acts like the fuse on a bomb.
The cells are now sensitized or primed with the IgE. When this allergic or sensitized
individual is exposed to ragweed pollen again, the IgE is ready to bind to this pollen.
When this occurs, the mast cells and basophils are activated and explosively release a
number of chemicals that ultimately produce the allergic reaction we can see and feel.
Wherever these chemicals are released in the body will display the allergy symptoms. In
the ragweed pollen example, when the mast cells are activated in the nose by exposure to
the pollen, the release of chemicals will likely result in sneezing, nasal congestion, and a
runny nose - the typical symptoms of hay fever. Once sensitized, mast cells and basophils
can remain ready to ignite with IgE for months or even years!
Chemical Mediators
Each mast cell and basophil may contain over 1000 tiny packets (granules). Each of these
granules holds more than 30 allergy chemicals, called chemical mediators. Many of these
chemical mediators are already prepared and are released from the granules as they burst
in an allergic response. The most important of these chemical mediators is histamine.
Once released into the tissues or blood stream, histamine attaches to histamine receptors
(H1 receptors) that are present on the surface of most cells. This attachment results in
certain effects on the blood vessels, mucous glands, and bronchial tubes. These effects
cause typical allergic symptoms such as swelling, sneezing, and itching of the nose,
throat, and roof of the mouth.
Some chemical mediators are not formed until 5 to 30 minutes after activation of the mast
cells or basophils. The most prominent of these are the leukotrienes. Leukotriene D4 is 10
times more potent than histamine. Its effects are similar to those of histamine, but
leukotriene D4 also attracts other cells to tarea, thereby aggravating the inflammation.
Allergy Facts
Leukotrienes were initially discovered in 1938 and were called the "slow reacting
substances of anaphylaxis (SRS-A)." Forty years later, Samuelsen in Sweden identified
them as playing an important role in allergic inflammation.
Recently, a new family of medicines, called leukotriene modifiers, have been found to be
helpful in treating asthma. Examples are Singulair (monlelukast) and Accolate (zafirlukast).

The other group of inflammation-causing chemical mediators that form after mast cell stimulation is the prostaglandins. Prostaglandin
D2, in particular, is a very potent contributor to the inflammation of the lung airways (bronchial tubes) in allergic asthma.

What are cytokines?

Cytokines are small proteins that can either step-up or step-down the immune response. One of the cytokines, interleukin 4 (IL4), is essential for the production of I
cells, particularly eosinophils, which then promote inflammation. This spectrum of cytokines is also released by the TH2 lymphocytes, thus further promoting allerg
What is the "early phase" of an allergic reaction?

We have seen how the first encounter with ragweed pollen sensitizes the body with the help of lymphocytes and results in the IgE coating of the mast cells and baso
chemical mediators that cause the various symptoms of allergy. This process is the "early phase" of the allergic reaction. It can occur within seconds or minutes of e
hypersensitivity reaction, which in this case is to the ragweed pollen allergen.

In the context of allergy, hypersensitivity refers to a condition in a previously exposed person in which tissue inflammation results from an immune reaction upon r
What is the "late phase" of an allergic reaction?

About 50% of the time, the allergic reaction progresses into a "late phase." This "late phase" occurs about 4 to 6 hours after the exposure. In the late phase reaction,
the area, including the eosinophils, neutrophils, and lymphocytes. Cytokines that are released by the mast cells and basophils act as tiny messengers to call these oth
released by the TH2 lymphocytes and they attract even more of these cells of inflammation.

The eosinophils appear to be particularly troublesome cells of inflammation. Eosinophils evolved to defend the body against parasites, much like IgE. Nevertheless
allergies. When they arrive at the site of the allergic reaction, they release chemicals that cause damage to the tissues and continue to promote the inflammation. Re
allergic symptoms and make the tissues even more sensitive to subsequent exposure!

Font Size
A
A
A
Previous
1
2
3
4
5
6
Next

Allergic Cascade Index

Glossary

Allergic Cascade (cont.)

In this Article
Who are the "players" in the allergic cascade?

 What about a more detailed look at the "players?"

What are cytokines?
What is the "early phase" of an allergic reaction?
What is the "late phase" of an allergic reaction?
What are the consequences of the allergic cascade?
How does understanding the allergic cascade help?
Allergic Cascade At A Glance
Pictures of Common Allergy Triggers - Slideshow
Allergic Cascade Glossary
Allergic Cascade Index

How does understanding the allergic cascade help?

How can we put this new understanding of allergic reaction to good use? By looking closely at the com
scientists have been able to find new and innovative treatments for common and troub

The most basic, and best, approach to caring for allergies is avoidance of the substances causing them, the
foods, and medications are relatively easy to avoid. However, many other allergens, such as dust mites, m
Measures to reduce exposure to them, however, are still essential for the optimal t

The most convenient approach to the treatment of allergies involves taking various medications. A clas

Allergies and your immune system

When it comes to allergy, your immune system acts like the Incredible Hulk, senselessly
following good intentions gone wrong. In allergic individuals, genetics and environment
have conspired to make cells that are essential for normal immune function become
overactive and respond to otherwise innocuous substances.
Key to this process are two important immune system cells: helper T cells 1 (Th1) and 2
(Th2). These white blood cells circulate in the bloodstream and alert other immune
system players that the body may be under attack from invading germs. Th1 cells handle
certain types of bacterial infection, while Th2 cells help in eliminating certain parasites.
In allergic diseases, this process goes awry in at least two ways. First, Th2 cells dominate
(a process called immune deviation), meaning they are more likely to respond than Th1
cells. Second, the body mounts these Th2 responses to substances that are not actually
harmful, such as pollen and dust mites. During the response, Th2 cells produce
substances and recruit cells and molecules mast cells and eosinophils that lead to
an allergic reaction. The proteins produced by the Th2 cell, called cytokines, orchestrate
the allergic response. One of the consequences of Th2 cell activation is that another type
of white blood cell, the B cell, essential to normal immune function, is stimulated to
produce an antibody called immunoglobulin E (IgE).

The role of antibodies

Antibodies account for the astounding versatility of the immune system. Each antibody is
programmed to recognize a particular foreign molecule or antigen. Since the immune
system produces millions of antibodies, it is prepared to recognize any antigen that enters
the body. Without the surveillance capability of antibodies, the human body would be
devastated by disease-causing microorganisms (pathogens). Antibodies are made of a
type of protein called immunoglobulin.
Although the antibody family consists of five different types of antibodies IgA, IgD,
IgE, IgG, and IgM the majority of allergic reactions are caused by IgE. For instance,
the IgE antibody that recognizes ragweed causes symptoms of hay fever in early fall.
Indeed, some purists in the field say that only an IgE-mediated response should be
considered to be an allergic response. However, since other allergic responses are IgGmediated (such as serum sickness) or T cellmediated (for instance, poison ivy), this
report takes the broader position that an allergy involves an immune response be it
IgE-mediated or not.
Normally, antibodies are produced when B cells recognize an antigen on the surface of
specific harmful invading pathogens, such as the bacteria that cause pneumonia. This
recognition causes B cells to mature into antibody-producing plasma cells. Like a
battalion of medieval archers, these plasma cells let fly their antibodies, which travel to
their targets on the outer surface of harmful bacteria. After finding their mark, IgG
antibodies neutralize the bacterial toxins or make the bacteria ingestible by other cells of

the immune system, neutrophils and macrophages that eat and destroy the bacteria. In a
similar way, IgE antibodies set in motion the events that kill and eliminate parasites.

Antibodies behaving badly

On the whole, antibodies do a stunning job at keeping bacteria and viruses at bay.
However, the downside of their efficiency is what happens in an allergic response, when
certain antibodies, in particular IgE, are produced inappropriately. IgE antibodies like to
link up with their receptors on mast cells, specialized cells found in great numbers at
points of entry into the body such as the linings of the airways, the eyes, the gut, and the
dermis (one of the layers of the skin). The trouble starts when an innocuous, often
inhaled, allergen meets up with the IgE on a mast cell.
From this moment, the mast cell prompts an allergic reaction by releasing histamine and
other chemicals such as leukotrienes and prostaglandins, which within minutes trigger
sneezing, runny nose, itchy eyes and skin, and wheezing. One of the reasons the response
is so fast is that histamine is good to go even before the mast cell that houses it is
activated. This means that upon activation, the mast cell quickly releases histamine into
the surrounding tissue like the contents of an exploding suitcase. This release is followed
by leukotrienes and prostaglandins that are rapidly generated by the activated mast cell.
Allergy: A 2-step process

Even worse, when an acute allergic reaction spirals out of control, it can set in motion a
life-threatening bodywide reaction called anaphylaxis or allergic shock, which requires
immediate action.
But thats not the only danger. Mast cells produce other chemicals, such as proteases, that
cause tissue damage. And activated mast cells produce their own cytokines that stimulate
B cells to produce more IgE, which leads to more IgE on the mast cells and more
opportunity to release the inflammatory chemicals. At the same time, other cytokines
recruit eosinophils to the site of the allergic response, setting up local inflammation.
What is inflammation?

Doctors first described inflammation as painful, hot, red swelling of tissues in the body
such as that seen around a boil or an insect bite. These early physicians used the Latin
words rubor (red), calor (heat), dolor (pain), and tumor (swelling) to describe
inflammation. We now know that inflammation that lasts for hours or days represents
white blood cells trying to fight off an invading pathogen or deal with a foreign body such
as a splinter. Over time, the process leads to lasting damage with formation of scar tissue
as the body attempts to heal itself. When todays physicians see the characteristic cellular
changes of inflammation under a microscope, they call it inflammation without needing
to see the classic signs (redness, heat, pain, swelling) originally described by the early
physicians.

The cascade effect

Meanwhile, the allergen continues to stimulate the Th2 cells, stirring up more production
of IgE and inflammation and fueling the allergic reaction even further. In other words, a
cascade effect is now in motion that, unless stopped, may lead to what are called latephase reactions, typically peaking six to nine hours after exposure to the allergen. Left
unchecked and with repeated encounters with the allergen, this perpetuating cycle can
lead to continual allergic reactions, which over time may cause lasting tissue damage.
Mast cells, which are so instrumental in most allergic attacks, are something of a mystery.
For quite a while, their purpose was unclear. But evidence suggests that they not only
fight parasites but also help the body deal with harmful bacteria. So although mast cells
seem to do more harm than good by setting off annoying allergic reactions, they probably
play an important role in protecting the body against unwelcome parasitic and bacterial
guests.
The mast cells protective function explains why they are positioned so close to where
any microorganism might get into the body, for example, in the membranes lining the
digestive and respiratory tracts. Packed as they are with chemicals, mast cells are
designed to respond fast within minutes. Mast cells activated in the digestive tract can
cause abdominal pain, diarrhea, and vomiting; in the airways, the effect can be
congestion and blockage that cause wheezing, coughing, and mucus; and their effect on
blood vessels is to increase blood flow, which increases fluid in the surrounding tissues
the cause of swelling and, when severe, anaphylaxis. Mast cells are aided by
eosinophils, another type of immune system cell that plays an important role in
inflammation.

Delayed hypersensitivity
So far, we have focused on IgE and its role in allergic reactions. We also indicated that a
broader use of the word allergy includes other immunological hypersensitivity
reactions that are not IgE-mediated. For example, a reaction called contact
hypersensitivity or delayed hypersensitivity is the mechanism of contact dermatitis, a
type of rash caused by certain chemicals, such as those found in poison ivy. The process

begins in much the same way as in many other immunological processes, with the
chemical substance being taken up by immune cells in the skin, called dendritic cells, that
present the chemical to T cells, rather like a host introducing an arriving guest to family
members. The T cell population recognizes the chemical and increases its numbers,
creating a new population of cells called memory T cells. The next time you come into
contact with the chemical, these primed memory T cells are ready to react to the
chemical and generate an inflammatory response as though they were fighting off an
infection. This reaction is not immediate like that generated by mast cells and IgE, but
takes 4872 hours to reach its peak; hence the term delayed hypersensitivity. If youve
ever had poison ivy, youll remember that the rash didnt appear immediately but
emerged a day or two later.

Serum sickness
A third type of reaction is serum sickness. This is a reaction due to IgG antibodies rather
than IgE antibodies. IgG, or immunoglobulin G, is the main type of antibody produced by
the body. Some people make large and inappropriate quantities of IgG antibodies to
medications they receive. When these people receive those medications a second time,
the antibodies attach to the medication as though it were an invading microorganism,
forming very large molecule complexes of antigen (the medication) and antibody. These
molecules get stuck in the bloodstream, where they activate another part of the bodys
defense system, a group of proteins called a complement. The complement system is
another part of the bodys defense against microorganisms. When activated, it initiates an
inflammatory response, recruiting cells that eat and kill the invading bugs. The upshot is
serum sickness, marked by widespread signs of inflammation with a rash, enlarged lymph
nodes, and damage to the kidneys. Serum sickness was first described in individuals who
received horse serum as part of their treatment for pneumococcal pneumonia. While
penicillin can cause allergic reactions because of mast cells and IgE, it can also cause
serum sickness.

Innate immune system

From Wikipedia, the free encyclopedia

Jump to: navigation, search

See also: Immune system and Adaptive immune system
The innate immune system comprises the cells and mechanisms that defend the host
from infection by other organisms, in a non-specific manner. This means that the cells of
the innate system recognize and respond to pathogens in a generic way, but unlike the
adaptive immune system, it does not confer long-lasting or protective immunity to the
host.[1] Innate immune systems provide immediate defense against infection, and are
found in all classes of plant and animal life.

Contents

[hide]

1 Functions
2 Inflammation
3 Complement system
4 Cells of the innate immune response
o 4.1 Mast cells
o 4.2 Phagocytes
4.2.1 Macrophages
4.2.2 Neutrophils
4.2.3 Dendritic cells
o 4.3 Basophils and eosinophils
o 4.4 Natural killer cells
o 4.5 T cells
5 Pathogen-specificity
6 Innate immune evasion
7 Other forms of innate immunity
o 7.1 Host defense in prokaryotes
o 7.2 Host defense in invertebrates
o 7.3 Host defense in plants
8 See also

9 References

[edit] Functions
The innate system is thought to constitute an evolutionarily older defense strategy, and is
the dominant immune system found in plants, fungi, insects, and in primitive
multicellular organisms (see Other forms of innate immunity).[2]
The major functions of the vertebrate innate immune system include:

Recruiting immune cells to sites of infection and inflammation, through the

production of chemical factors, including specialized chemical mediators, called
cytokines.
Activation of the complement cascade to identify bacteria, activate cells and to
promote clearance of dead cells or antibody complexes.
The identification and removal of foreign substances present in organs, tissues,
the blood and lymph, by specialized white blood cells.
Activation of the adaptive immune system through a process known as antigen
presentation.

[edit] Inflammation

Main article: Inflammation

Inflammation is one of the first responses of the immune system to infection or irritation.
Inflammation is stimulated by chemical factors released by injured cells and serves to
establish a physical barrier against the spread of infection, and to promote healing of any
damaged tissue following the clearance of pathogens.[3]
Chemical factors produced during inflammation (histamine, bradykinin, serotonin,
leukotrienes also prostaglandins) sensitize pain receptors, cause vasodilation of the blood
vessels at the scene, and attract phagocytes, especially neutrophils.[3] Neutrophils then
trigger other parts of the immune system by releasing factors that summon other
leukocytes and lymphocytes.
The inflammatory response is characterized by the following symptom quintet: Redness
(rubor) Heat (calor) Swelling (tumor) Pain (dolor) and possible dysfunction of the
organs or tissues involved (functio laesa).

[edit] Complement system

Main article: Complement system
The complement system is a biochemical cascade of the immune system that helps, or
complements, the ability of antibodies to clear pathogens or mark them for destruction
by other cells. The cascade is composed of many plasma proteins, synthesized in the
liver, primarily by hepatocytes. The proteins work together to:

trigger the recruitment of inflammatory cells.

"tag" pathogens for destruction by other cells by opsonizing, or coating, the
surface of the pathogen.
disrupt the plasma membrane of an infected cell, resulting in cytolysis of the
infected cell, causing the death of the pathogen.
rid the body of neutralized antigen-antibody complexes.

Elements of the complement cascade can be found in many species evolutionarily older
than mammals including plants, birds, fish and some species of invertebrates.[4]

[edit] Cells of the innate immune response

Main article: Leukocyte

A scanning electron microscope image of normal circulating human blood. One can see
red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a
neutrophil, and many small disc-shaped platelets.
All white blood cells (WBC) are known as leukocytes. Leukocytes are different from
other cells of the body in that they are not tightly associated with a particular organ or
tissue; thus, they function similar to independent, single-celled organisms. Leukocytes are
able to move freely and interact and capture cellular debris, foreign particles, or invading
microorganisms. Unlike many other cells in the body, most innate immune leukocytes
cannot divide or reproduce on their own, but are the products of pluripotent
hematopoietic stem cells present in the bone marrow.[1]
The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and
the phagocytic cells including macrophages, neutrophils and dendritic cells, and function
within the immune system by identifying and eliminating pathogens that might cause
infection.[2]

[edit] Mast cells

Main article: Mast cell
Mast cells are a type of innate immune cell that resides in the connective tissue and in the
mucous membranes, and are intimately associated with defense against pathogens, wound
healing, but are also often associated with allergy and anaphylaxis.[3] When activated,
mast cells rapidly release characteristic granules, rich in histamine and heparin, along
with various hormonal mediators, and chemokines, or chemotactic cytokines into the
environment. Histamine dilates blood vessels, causing the characteristic signs of
inflammation, and recruits neutrophils and macrophages.[3]

[edit] Phagocytes

Main article: Phagocytosis

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, i.e.
phagocytose, pathogens or particles. To engulf a particle or pathogen, a phagocyte
extends portions of its plasma membrane, wrapping the membrane around the particle
until it is enveloped (i.e. the particle is now inside the cell). Once inside the cell, the
invading pathogen is contained inside an endosome which merges with a lysosome.[2] The
lysosome contains enzymes and acids that kill and digest the particle or organism.
Phagocytes generally patrol the body searching for pathogens, but are also able to react to
a group of highly specialized molecular signals produced by other cells, called cytokines.
The phagocytic cells of the immune system include macrophages, neutrophils, and
dendritic cells.
Phagocytosis of the hosts own cells is common as part of regular tissue development and
maintenance. When host cells die, either internally induced by processes involving
programmed cell death (also called apoptosis), or caused by cell injury due to a bacterial
or viral infection, phagocytic cells are responsible for their removal from the affected site.
[1]
By helping to remove dead cells preceding growth and development of new healthy
cells, phagocytosis is an important part of the healing process following tissue injury.

A macrophage
[edit] Macrophages
Macrophages, from the Greek, meaning "large eating cell", are large phagocytic
leukocytes, which are able to move outside of the vascular system by moving across the
cell membrane of capillary vessels and entering the areas between cells in pursuit of
invading pathogens. In tissues, organ-specific macrophages are differentiated from
phagocytic cells present in the blood called monocytes. Macrophages are the most
efficient phagocytes, and can phagocytose substantial numbers of bacteria or other cells
or microbes.[2] The binding of bacterial molecules to receptors on the surface of a
macrophage triggers it to engulf and destroy the bacteria through the generation of a
respiratory burst, causing the release of reactive oxygen species. Pathogens also
stimulate the macrophage to produce chemokines, which summons other cells to the site
of infection.[2]
[edit] Neutrophils

A neutrophil
Neutrophils, along with two other cell types; eosinophils and basophils (see below), are
known as granulocytes due to the presence of granules in their cytoplasm, or as
polymorphonuclear cells (PMNs) due to their distinctive lobed nuclei. Neutrophil
granules contain a variety of toxic substances that kill or inhibit growth of bacteria and
fungi. Similar to macrophages, neutrophils attack pathogens by activating a respiratory
burst. The main products of the neutrophil respiratory burst are strong oxidizing agents
including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the
most abundant type of phagocyte, normally representing 50 to 60% of the total
circulating leukocytes, and are usually the first cells to arrive at the site of an infection.[3]
The bone marrow of a normal healthy adult produces more than 100 billion neutrophils
per day, and more than 10 times that many per day during acute inflammation.[3]
[edit] Dendritic cells
Dendritic cells (DC) are phagocytic cells present in tissues that are in contact with the
external environment, mainly the skin (where they are often called Langerhans cells), and
the inner mucosal lining of the nose, lungs, stomach and intestines.[1] They are named for
their resemblance to neuronal dendrites, but dendritic cells are not connected to the
nervous system. Dendritic cells are very important in the process of antigen presentation,
and serve as a link between the innate and adaptive immune systems.

An eosinophil

[edit] Basophils and eosinophils

Main articles: Basophil granulocyte and Eosinophil granulocyte
Basophils and eosinophils are cells related to the neutrophil (see above). When activated
by a pathogen encounter, basophils releasing histamine are important in defense against

parasites, and play a role in allergic reactions (such as asthma).[2] Upon activation,
eosinophils secrete a range of highly toxic proteins and free radicals that are highly
effective in killing bacteria and parasites, but are also responsible for tissue damage
occurring during allergic reactions. Activation and toxin release by eosinophils is
therefore tightly regulated to prevent any inappropriate tissue destruction.[3]

[edit] Natural killer cells

Main article: Natural killer cell
Natural killer cells, or NK cells, are a component of the innate immune system. NK cells
attack host cells that have been infected by microbes, but do not directly attack invading
microbes. For example, NK cells attack and destroy tumor cells, and virus-infected cells,
through a process known as "missing-self." This term describes cells with low levels of a
cell-surface marker called MHC I (major histocompatibility complex) - a situation that
can arise in viral infections of host cells.[4] They were named "natural killer" because of
the initial notion that they do not require activation in order to kill cells that are "missing
self."

[edit] T cells
Main article: gamma/delta T cells
Like other 'unconventional' T cell subsets bearing invariant T cell receptors (TCRs), such
as CD1d-restricted Natural Killer T cells, T cells exhibit characteristics that place them
at the border between innate and adaptive immunity. On one hand, T cells may be
considered a component of adaptive immunity in that they rearrange TCR genes to
produce junctional diversity and develop a memory phenotype. However, the various
subsets may also be considered part of the innate immune system where a restricted TCR
or NK receptors may be used as a pattern recognition receptor. For example, according to
this paradigm, large numbers of V9/V2 T cells respond within hours to common
molecules produced by microbes, and highly restricted intraepithelial V1 T cells will
respond to stressed epithelial cells.

[edit] Pathogen-specificity
The parts of the innate immune system have different specificity for different pathogens.
Pathogen

Intracellular
and
cytoplasmic

Main examples [5]

influenza
mumps
measles

Phagocytosis [5] complement[5] NK cells[5]

yes

no

yes

virus

Intracellular
bacteria

Extracellular
bacteria

Intracellular
protozoa

rhinovirus

Listeria
monocytogenes
yes (specifically
Legionella
neutrophils, no for no
Mycobacterium
rickettsia)

Rickettsia

Staphylococcus
Streptococcus
Neisseria
yes

Salmonella typhi

Plasmodium
malariae

Leishmania
donovani

Entamoeba
histolytica

Extracellular
protozoa

Extracellular
fungi

Giardia lamblia

Candida
Histoplasma

Cryptococcus

yes (no for

rickettsia)

yes

no

no

no

no

yes

yes

no

no

yes

no

[edit] Innate immune evasion

Cells of the innate immune system effectively prevent free growth of bacteria within the
body; however, many pathogens have evolved mechanisms allowing them to evade the
innate immune system.[6][7]
Evasion strategies that circumvent the innate immune system include intracellular
replication, such as in Salmonella, or a protective capsule that prevents lysis by
complement and by phagocytes, as in Mycobacterium tuberculosis.[8] Bacteroides species
are normally commensal bacteria, making up a substantial portion of the mammalian
gastrointestinal flora.[9] Some species (B. fragilis, for example) are opportunistic
pathogens, causing infections of the peritoneal cavity. These species evade the immune
system through inhibition of phagocytosis by affecting the receptors that phagocytes use
to engulf bacteria or by mimicking host cells so that the immune system does not
recognize them as foreign. Staphylococcus aureus inhibits the ability of the phagocyte to

respond to chemokine signals. Other organisms such as M. tuberculosis, Streptococcus

pyogenes and Bacillus anthracis utilize mechanisms that directly kill the phagocyte.
Bacteria and fungi may also form complex biofilms, providing protection from the cells
and proteins of the immune system; recent studies indicate that such biofilms are present
in many successful infections, including the chronic Pseudomonas aeruginosa and
Burkholderia cenocepacia infections characteristic of cystic fibrosis.[10]

[edit] Other forms of innate immunity

[edit] Host defense in prokaryotes
Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism,
called the restriction modification system to protect themselves from pathogens, such as
bacteriophages. In this system, bacteria produce enzymes, called restriction
endonucleases, that attack and destroy specific regions of the viral DNA of invading
bacteriophages. Methylation of the host's own DNA marks it as "self" and prevents it
from being attacked by endonucleases.[11] Restriction endonucleases and the restriction
modification system exist exclusively in prokaryotes.

[edit] Host defense in invertebrates

Invertebrates do not possess lymphocytes or an antibody-based humoral immune system,
and it is likely that a multicomponent, adaptive immune system arose with the first
vertebrates.[12] Nevertheless, invertebrates possess mechanisms that appear to be
precursors of these aspects of vertebrate immunity. Pattern recognition receptors are
proteins used by nearly all organisms to identify molecules associated with microbial
pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists
in all coelomates (animals with a body-cavity), including humans.[13] The complement
system, as discussed above, is a biochemical cascade of the immune system that helps
clear pathogens from an organism, and exists in most forms of life. Some invertebrates,
including various insects, crabs, and worms utilize a modified form of the complement
response known as the prophenoloxidase (proPO) system.[12]
Antimicrobial peptides are an evolutionarily conserved component of the innate immune
response found among all classes of life and represent the main form of invertebrate
systemic immunity. Several species of insect produce antimicrobial peptides known as
defensins and cecropins.

[edit] Host defense in plants

Members of every class of pathogen which infect humans also infect plants. Although the
exact pathogenic species vary with the infected species, bacteria, fungi, viruses,
nematodes and insects can all cause plant disease. As with animals, plants attacked by
insects or other pathogens use a set of complex metabolic responses that lead to the

formation of defensive chemical compounds that fight infection or make the plant less
attractive to insects and other herbivores.[14] (see: plant defense against herbivory).
Like invertebrates, plants neither generate antibody or T-cell responses nor possess
mobile cells that detect and attack pathogens. In addition, in case of infection, parts of
some plants are treated as disposable and replaceable, in ways that very few animals are
able to do. Walling off or discarding a part of a plant helps stop spread of an infection.[14]
Most plant immune responses involve systemic chemical signals sent throughout a plant.
Plants use pattern-recognition receptors to identify pathogens and to start a basal
response, which produces chemical signals that aid in warding off infection. When a part
of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible
interaction triggered by specific elicitors, the plant produces a localized hypersensitive
response (HR), in which cells at the site of infection undergo rapid programmed cell
death to prevent the spread of the disease to other parts of the plant. HR has some
similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic
activity of VPE, a cysteine protease that regulates cell disassembly during cell death.[15]
"Resistance" (R) proteins, encoded by R genes, are widely present in plants and detect
pathogens. These proteins contain domains similar to the NOD Like Receptors and Tolllike receptors utilized in animal innate immunity. Systemic acquired resistance (SAR) is a
type of defensive response that renders the entire plant resistant to a broad spectrum of
infectious agents. SAR involves the production of chemical messengers, such as salicylic
acid or jasmonic acid. Some of these travel through the plant and signal other cells to
produce defensive compounds to protect uninfected parts, e.g., leaves. Salicylic acid
itself, although indispensable for expression of SAR, is not the translocated signal
responsible for the systemic response. Recent evidence indicates a role for jasmonates in
transmission of the signal to distal portions of the plant. RNA silencing mechanisms are
also important in the plant systemic response, as they can block virus replication.[16] The
jasmonic acid response, is stimulated in leaves damaged by insects, and involves the
production of methyl jasmonate.[14]

[edit] See also

Apoptosis

[edit] References
1. ^ a b c d Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and
Peter Walters (2002). Molecular Biology of the Cell; Fourth Edition. New York and
London: Garland Science. ISBN 0-8153-3218-1.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2.
2. ^ a b c d e f Janeway, Charles; Paul Travers, Mark Walport, and Mark Shlomchik (2001).
Immunobiology; Fifth Edition. New York and London: Garland Science. ISBN 0-8153-

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.

4101-6. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?
call=bv.View..ShowTOC&rid=imm.TOC&depth=10..
^ a b c d e f g Stvrtinov, Viera; Jn Jakubovsk and Ivan Huln (1995). Inflammation and
Fever from Pathophysiology: Principles of Disease. Computing Centre, Slovak Academy
of Sciences: Academic Electronic Press. http://nic.sav.sk/logos/books/scientific.
^ a b Janeway CA, Jr. et al (2005). Immunobiology. (6th ed. ed.). Garland Science. ISBN
0-443-07310-4.
^ a b c d Unless else specified in boxes, then ref is: Lippincott's Illustrated Reviews:
Immunology. Paperback: 384 pages. Publisher: Lippincott Williams & Wilkins; (July 1,
2007). Language: English. ISBN-10: 0781795435. ISBN-13: 978-0781795432. Page 172
^ Kennedy, Alan. "Immune Evasion by bacteria".
http://alan.kennedy.name/crohns/primer/imunevad.htm.
^ Finlay B, McFadden G (2006). "Anti-immunology: evasion of the host immune system
by bacterial and viral pathogens". Cell 124 (4): 76782. doi:10.1016/j.cell.2006.01.034.
PMID 16497587.
^ Finlay B, Falkow S (1997). "Common themes in microbial pathogenicity revisited".
Microbiol Mol Biol Rev 61 (2): 13669. PMID 9184008.
http://mmbr.asm.org/cgi/reprint/61/2/136.pdf.
^ Dorland WAN (editor) (2003). Dorland's Illustrated Medical Dictionary (30th ed.).
W.B. Saunders. ISBN 0-7216-0146-4.
^ Kobayashi H (2005). "Airway biofilms: implications for pathogenesis and therapy of
respiratory tract infections". Treat Respir Med 4 (4): 24153. doi:10.2165/00151829200504040-00003. PMID 16086598.
^ Restriction Enzymes Access Excellence Classic Collection Background Paper.
^ a b Beck, Gregory and Habicht, Gail S. Immunity and the Invertebrates Scientific
American. November 1996:60-66.
^ Imler JL, Hoffmann JA. (2001) Toll receptors in innate immunity. Trends Cell Biol.
Jul;11(7):304-11. Review. PMID 11413042
^ a b c Schneider, David (2005) Plant immune responses Stanford University Department
of Microbiology and Immunology.
^ Rojo, E. et al. (2004). "VPEgamma exhibits a caspase-like activity that contributes to
defense against pathogens.". Curr Biol. 14 (21): 18971906.
doi:10.1016/j.cub.2004.09.056. PMID 15530390.
^ Baulcombe D (2004). "RNA silencing in plants". Nature 431 (7006): 35663.
doi:10.1038/nature02874. PMID 15372043.