Immune system

recognize specific pathogens more efficiently. Adaptive

(or acquired) immunity creates immunological memory
after an initial response to a specific pathogen, leading to
an enhanced response to subsequent encounters with that
same pathogen. This process of acquired immunity is the
basis of vaccination.
Disorders of the immune system can result in
autoimmune diseases, inflammatory diseases and
cancer.[2] Immunodeficiency occurs when the immune
system is less active than normal, resulting in recurring
and life-threatening infections. In humans, immunodefi-
ciency can either be the result of a genetic disease such as
severe combined immunodeficiency, acquired conditions
such as HIV/AIDS, or the use of immunosuppressive
medication. In contrast, autoimmunity results from a
hyperactive immune system attacking normal tissues as
if they were foreign organisms. Common autoimmune
diseases include Hashimoto’s thyroiditis, rheumatoid
arthritis, diabetes mellitus type 1, and systemic lupus
A scanning electron microscope image of a single neutrophil (yel- erythematosus. Immunology covers the study of all
low), engulfing anthrax bacteria (orange) aspects of the immune system.

The immune system is a host defense system compris-

ing many biological structures and processes within an
organism that protects against disease. To function prop- 1 History of immunology
erly, an immune system must detect a wide variety of
agents, known as pathogens, from viruses to parasitic For more details on this topic, see History of immunol-
worms, and distinguish them from the organism’s own ogy.
healthy tissue. In many species, the immune system can
be classified into subsystems, such as the innate immune Immunology is a science that examines the structure
system versus the adaptive immune system, or humoral and function of the immune system. It originates from
immunity versus cell-mediated immunity. In humans, medicine and early studies on the causes of immunity
the blood–brain barrier, blood–cerebrospinal fluid bar- to disease. The earliest known reference to immunity
rier, and similar fluid–brain barriers separate the periph- was during the plague of Athens in 430 BC. Thucydides
eral immune system from the neuroimmune system which noted that people who had recovered from a previous
protects the brain. bout of the disease could nurse the sick without con-
Pathogens can rapidly evolve and adapt, and thereby tracting the illness a second time.[3] In the 18th century,
avoid detection and neutralization by the immune sys- Pierre-Louis Moreau de Maupertuis made experiments
tem; however, multiple defense mechanisms have also with scorpion venom and observed that certain dogs and
evolved to recognize and neutralize pathogens. Even mice were immune to this venom.[4] This and other ob-
simple unicellular organisms such as bacteria possess a servations of acquired immunity were later exploited by
rudimentary immune system, in the form of enzymes Louis Pasteur in his development of vaccination and his
that protect against bacteriophage infections. Other ba- proposed germ theory of disease.[5] Pasteur’s theory was
sic immune mechanisms evolved in ancient eukaryotes in direct opposition to contemporary theories of disease,
and remain in their modern descendants, such as such as the miasma theory. It was not until Robert Koch's
plants and invertebrates. These mechanisms include 1891 proofs, for which he was awarded a Nobel Prize in
phagocytosis, antimicrobial peptides called defensins, 1905, that microorganisms were confirmed as the cause
and the complement system. Jawed vertebrates, in- of infectious disease.[6] Viruses were confirmed as human
cluding humans, have even more sophisticated defense pathogens in 1901, with the discovery of the yellow fever
mechanisms,[1] including the ability to adapt over time to virus by Walter Reed.[7]

1
2 3 INNATE IMMUNE SYSTEM

Immunology made a great advance towards the end of the Innate immune defenses are non-specific, meaning these
19th century, through rapid developments, in the study systems respond to pathogens in a generic way.[14] This
of humoral immunity and cellular immunity.[8] Particu- system does not confer long-lasting immunity against a
larly important was the work of Paul Ehrlich, who pro- pathogen. The innate immune system is the dominant
posed the side-chain theory to explain the specificity of system of host defense in most organisms.[10]
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 3.1 Surface barriers
awarded to the founder of cellular immunology, Elie
Metchnikoff.[9] Several barriers protect organisms from infection, includ-
ing mechanical, chemical, and biological barriers. The
waxy cuticle of many leaves, the exoskeleton of insects,
the shells and membranes of externally deposited eggs,
2 Layered defense and skin are examples of mechanical barriers that are
the first line of defense against infection.[14] However,
The immune system protects organisms from infection as organisms cannot be completely sealed from their en-
with layered defenses of increasing specificity. In sim- vironments, other systems act to protect body openings
ple terms, physical barriers prevent pathogens such as such as the lungs, intestines, and the genitourinary tract.
bacteria and viruses from entering the organism. If a In the lungs, coughing and sneezing mechanically eject
pathogen breaches these barriers, the innate immune sys- pathogens and other irritants from the respiratory tract.
tem provides an immediate, but non-specific response. The flushing action of tears and urine also mechanically
Innate immune systems are found in all plants and expels pathogens, while mucus secreted by the respira-
animals.[10] If pathogens successfully evade the innate re- tory and gastrointestinal tract serves to trap and entangle
sponse, vertebrates possess a second layer of protection, microorganisms.[17]
the adaptive immune system, which is activated by the Chemical barriers also protect against infection. The
innate response. Here, the immune system adapts its re- skin and respiratory tract secrete antimicrobial peptides
sponse during an infection to improve its recognition of such as the β-defensins.[18] Enzymes such as lysozyme
the pathogen. This improved response is then retained and phospholipase A2 in saliva, tears, and breast milk
after the pathogen has been eliminated, in the form of an are also antibacterials.[19][20] Vaginal secretions serve as a
immunological memory, and allows the adaptive immune chemical barrier following menarche, when they become
system to mount faster and stronger attacks each time this slightly acidic, while semen contains defensins and zinc
pathogen is encountered.[11][12] to kill pathogens.[21][22] In the stomach, gastric acid and
Both innate and adaptive immunity depend on the abil- proteases serve as powerful chemical defenses against in-
ity of the immune system to distinguish between self gested pathogens.
and non-self molecules. In immunology, self molecules Within the genitourinary and gastrointestinal tracts,
are those components of an organism’s body that can
commensal flora serve as biological barriers by compet-
be distinguished from foreign substances by the im- ing with pathogenic bacteria for food and space and, in
[13]
mune system. Conversely, non-self molecules are some cases, by changing the conditions in their envi-
those recognized as foreign molecules. One class of ronment, such as pH or available iron.[23] This reduces
non-self molecules are called antigens (short for antibody the probability that pathogens will reach sufficient num-
generators) and are defined as substances that bind to spe- bers to cause illness. However, since most antibiotics
cific immune receptors and elicit an immune response.[14] 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
3 Innate immune system infection).[24] There is good evidence that re-introduction
of probiotic flora, such as pure cultures of the lactobacilli
normally found in unpasteurized yogurt, helps restore a
For more details on this topic, see Innate immune system.
healthy balance of microbial populations in intestinal in-
fections in children and encouraging preliminary data in
Microorganisms or toxins that successfully enter an or- studies on bacterial gastroenteritis, inflammatory bowel
ganism encounter the cells and mechanisms of the in- diseases, urinary tract infection and post-surgical infec-
nate immune system. The innate response is usually tions.[25][26][27]
triggered when microbes are identified by pattern recog-
nition receptors, which recognize components that are
conserved among broad groups of microorganisms,[15] or 3.2 Inflammation
when damaged, injured or stressed cells send out alarm
signals, many of which (but not all) are recognized by For more details on this topic, see Inflammation.
the same receptors as those that recognize pathogens.[16]
3.4 Cellular barriers 3

Inflammation is one of the first responses of the im-

mune system to infection.[28] The symptoms of in-
flammation are redness, swelling, heat, and pain,
which are caused by increased blood flow into tis-
sue. 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).[29][30] Common cytokines in-
clude interleukins that are responsible for communica-
tion between white blood cells; chemokines that pro-
mote chemotaxis; and interferons that have anti-viral ef-
fects, such as shutting down protein synthesis in the host
cell.[31] Growth factors and cytotoxic factors may also
be released. These cytokines and other chemicals re-
cruit immune cells to the site of infection and promote
healing of any damaged tissue following the removal of
pathogens.[32]

3.3 Complement system

For more details on this topic, see Complement system. A scanning electron microscope image of normal circulating hu-
man blood. One can see red blood cells, several knobby white
blood cells including lymphocytes, a monocyte, a neutrophil, and
The complement system is a biochemical cascade that at- many small disc-shaped platelets.
tacks the surfaces of foreign cells. It contains over 20
different proteins and is named for its ability to “com-
plement” the killing of pathogens by antibodies. Com-
the phagocytes (macrophages, neutrophils, and dendritic
plement is the major humoral component of the innate
cells), innate lymphoid cells, mast cells, eosinophils,
immune response.[33][34] Many species have complement
basophils, and natural killer cells. These cells iden-
systems, including non-mammals like plants, fish, and
tify and eliminate pathogens, either by attacking larger
some invertebrates.[35]
pathogens through contact or by engulfing and then
In humans, this response is activated by complement killing microorganisms.[35] Innate cells are also important
binding to antibodies that have attached to these microbes mediators in lymphoid organ development and the acti-
or the binding of complement proteins to carbohydrates vation of the adaptive immune system.[38]
on the surfaces of microbes. This recognition signal trig-
Phagocytosis is an important feature of cellular innate im-
gers a rapid killing response.[36] The speed of the re-
munity performed by cells called 'phagocytes' that engulf,
sponse is a result of signal amplification that occurs fol-
or eat, pathogens or particles. Phagocytes generally patrol
lowing sequential proteolytic activation of complement
the body searching for pathogens, but can be called to spe-
molecules, which are also proteases. After complement
cific locations by cytokines.[14] Once a pathogen has been
proteins initially bind to the microbe, they activate their
engulfed by a phagocyte, it becomes trapped in an intra-
protease activity, which in turn activates other comple-
cellular vesicle called a phagosome, which subsequently
ment proteases, and so on. This produces a catalytic cas-
fuses with another vesicle called a lysosome to form a
cade that amplifies the initial signal by controlled positive
phagolysosome. The pathogen is killed by the activity of
feedback.[37] The cascade results in the production of
digestive enzymes or following a respiratory burst that re-
peptides that attract immune cells, increase vascular per-
leases free radicals into the phagolysosome.[39][40] Phago-
meability, and opsonize (coat) the surface of a pathogen,
cytosis evolved as a means of acquiring nutrients, but this
marking it for destruction. This deposition of comple-
role was extended in phagocytes to include engulfment
ment can also kill cells directly by disrupting their plasma
of pathogens as a defense mechanism.[41] Phagocytosis
membrane.[33]
probably represents the oldest form of host defense, as
phagocytes have been identified in both vertebrate and
invertebrate animals.[42]
3.4 Cellular barriers
Neutrophils and macrophages are phagocytes that travel
Leukocytes (white blood cells) act like independent, throughout the body in pursuit of invading pathogens.[43]
single-celled organisms and are the second arm of the Neutrophils are normally found in the bloodstream and
innate immune system.[14] The innate leukocytes include are the most abundant type of phagocyte, normally repre-
4 4 ADAPTIVE IMMUNE SYSTEM

senting 50% to 60% of the total circulating leukocytes.[44] 4 Adaptive immune system
During the acute phase of inflammation, particularly as a
result of bacterial infection, neutrophils migrate toward For more details on this topic, see Adaptive immune
the site of inflammation in a process called chemotaxis, system.
and are usually the first cells to arrive at the scene of in-
fection. Macrophages are versatile cells that reside within
tissues and: (i) produce a wide array of chemicals includ- The adaptive immune system evolved in early vertebrates
ing enzymes, complement proteins, and cytokines, while and allows for a stronger immune response as well as
they can also (ii) act as scavengers that rid the body of immunological memory, where each pathogen is “re-
worn-out cells and other debris, and as antigen-presenting membered” by a signature antigen.[51] The adaptive im-
cells that activate the adaptive immune system.[45] mune response is antigen-specific and requires the recog-
nition of specific “non-self” antigens during a process
Dendritic cells (DC) are phagocytes in tissues that are called antigen presentation. Antigen specificity allows
in contact with the external environment; therefore, they for the generation of responses that are tailored to spe-
are located mainly in the skin, nose, lungs, stomach, and cific pathogens or pathogen-infected cells. The ability to
intestines.[46] They are named for their resemblance to mount these tailored responses is maintained in the body
neuronal dendrites, as both have many spine-like projec- by “memory cells”. Should a pathogen infect the body
tions, but dendritic cells are in no way connected to the more than once, these specific memory cells are used to
nervous system. Dendritic cells serve as a link between quickly eliminate it.
the bodily tissues and the innate and adaptive immune
systems, as they present antigens to T cells, one of the
key cell types of the adaptive immune system.[46] 4.1 Lymphocytes
Mast cells reside in connective tissues and mucous
membranes, and regulate the inflammatory response.[47] The cells of the adaptive immune system are special types
They are most often associated with allergy and of leukocytes, called lymphocytes. B cells and T cells
anaphylaxis.[44] Basophils and eosinophils are related to are the major types of lymphocytes and are derived from
neutrophils. They secrete chemical mediators that are in- hematopoietic stem cells in the bone marrow.[35] B cells
volved in defending against parasites and play a role in are involved in the humoral immune response, whereas T
allergic reactions, such as asthma.[48] Natural killer (NK cells are involved in cell-mediated immune response.
cells) cells are leukocytes that attack and destroy tumor Both B cells and T cells carry receptor molecules that
cells, or cells that have been infected by viruses.[49] 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
3.5 Natural killer cells a major histocompatibility complex (MHC) molecule.
There are two major subtypes of T cells: the killer T cell
Main article: Natural killer cell and the helper T cell. In addition there are regulatory T
cells which have a role in modulating immune response.
Natural killer cells, or NK cells, are a component of the Killer T cells only recognize antigens coupled to Class I
innate immune system which does not directly attack in- MHC molecules, while helper T cells and regulatory T
vading microbes. Rather, NK cells destroy compromised cells only recognize antigens coupled to Class II MHC
host cells, such as tumor cells or virus-infected cells, rec- molecules. These two mechanisms of antigen presenta-
ognizing such cells by a condition known as “missing tion reflect the different roles of the two types of T cell.
self.” This term describes cells with low levels of a cell- A third, minor subtype are the γδ T cells that recognize
surface marker called MHC I (major histocompatibility intact antigens that are not bound to MHC receptors.[52]
complex) – a situation that can arise in viral infections of In contrast, the B cell antigen-specific receptor is an
host cells.[35] They were named “natural killer” because antibody molecule on the B cell surface, and recognizes
of the initial notion that they do not require activation in whole pathogens without any need for antigen processing.
order to kill cells that are “missing self.” For many years Each lineage of B cell expresses a different antibody, so
it was unclear how NK cells recognize tumor cells and in- the complete set of B cell antigen receptors represent all
fected cells. It is now known that the MHC makeup on the the antibodies that the body can manufacture.[35]
surface of those cells is altered and the NK cells become
activated through recognition of “missing self”. Normal
body cells are not recognized and attacked by NK cells 4.1.1 Killer T cells
because they express intact self MHC antigens. Those
MHC antigens are recognized by killer cell immunoglob- Killer T cells are a sub-group of T cells that kill cells
ulin receptors (KIR) which essentially put the brakes on that are infected with viruses (and other pathogens), or
NK cells.[50] are otherwise damaged or dysfunctional.[53] As with B
4.1 Lymphocytes 5

cells, each type of T cell recognizes a different antigen. vated by engagement of a single MHC:antigen molecule.
Killer T cells are activated when their T cell receptor Helper T cell activation also requires longer duration of
(TCR) binds to this specific antigen in a complex with the engagement with an antigen-presenting cell.[57] The acti-
MHC Class I receptor of another cell. Recognition of this vation of a resting helper T cell causes it to release cy-
MHC:antigen complex is aided by a co-receptor on the T tokines that influence the activity of many cell types. Cy-
cell, called CD8. The T cell then travels throughout the tokine signals produced by helper T cells enhance the
body in search of cells where the MHC I receptors bear microbicidal function of macrophages and the activity
this antigen. When an activated T cell contacts such cells, of killer T cells.[14] In addition, helper T cell activation
it releases cytotoxins, such as perforin, which form pores causes an upregulation of molecules expressed on the T
in the target cell’s plasma membrane, allowing ions, wa- cell’s surface, such as CD40 ligand (also called CD154),
ter and toxins to enter. The entry of another toxin called which provide extra stimulatory signals typically required
granulysin (a protease) induces the target cell to undergo to activate antibody-producing B cells.[58]
apoptosis.[54] T cell killing of host cells is particularly im-
portant in preventing the replication of viruses. T cell ac-
tivation is tightly controlled and generally requires a very
strong MHC/antigen activation signal, or additional acti- 4.1.3 Gamma delta T cells
vation signals provided by “helper” T cells (see below).[54]
Gamma delta T cells (γδ T cells) possess an alternative
4.1.2 Helper T cells T cell receptor (TCR) as opposed to CD4+ and CD8+
(αβ) T cells and share the characteristics of helper T cells,
cytotoxic T cells and NK cells. The conditions that pro-
duce responses from γδ T cells are not fully understood.
Like other 'unconventional' T cell subsets bearing invari-
ant TCRs, such as CD1d-restricted Natural Killer T cells,
γδ T cells straddle the border between innate and adaptive
immunity.[59] On one hand, γδ T cells are a component of
adaptive immunity as they rearrange TCR genes to pro-
duce 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 re-
ceptors. For example, large numbers of human Vγ9/Vδ2
Function of T helper cells: Antigen-presenting cells (APCs) T cells respond within hours to common molecules pro-
present antigen on their Class II MHC molecules (MHC2). Helper duced by microbes, and highly restricted Vδ1+ T cells in
T cells recognize these, with the help of their expression of CD4 epithelia respond to stressed epithelial cells.[52]
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 im-

mune responses and help determine which immune re-
sponses the body makes to a particular pathogen.[55][56]
These cells have no cytotoxic activity and do not kill in-
fected cells or clear pathogens directly. They instead con-
trol the immune response by directing other cells to per-
form these tasks.
Helper T cells express T cell receptors (TCR) that rec-
ognize antigen bound to Class II MHC molecules. The
MHC:antigen complex is also recognized by the helper
cell’s CD4 co-receptor, which recruits molecules inside
the T cell (e.g., Lck) that are responsible for the T cell’s
activation. Helper T cells have a weaker association with
the MHC:antigen complex than observed for killer T An antibody is made up of two heavy chains and two light chains.
cells, meaning many receptors (around 200–300) on the The unique variable region allows an antibody to recognize its
matching antigen.[60]
helper T cell must be bound by an MHC:antigen in order
to activate the helper cell, while killer T cells can be acti-
6 4 ADAPTIVE IMMUNE SYSTEM

4.1.4 B lymphocytes and antibodies of passive protection are provided by the mother. Dur-
ing pregnancy, a particular type of antibody, called IgG,
A B cell identifies pathogens when antibodies on its is transported from mother to baby directly across the
surface bind to a specific foreign antigen.[61] This anti- placenta, so human babies have high levels of antibodies
gen/antibody complex is taken up by the B cell and pro- even at birth, with the same range of antigen specificities
cessed by proteolysis into peptides. The B cell then as their mother.[65] Breast milk or colostrum also contains
displays these antigenic peptides on its surface MHC antibodies that are transferred to the gut of the infant and
class II molecules. This combination of MHC and anti- protect against bacterial infections until the newborn can
gen attracts a matching helper T cell, which releases synthesize its own antibodies.[66] This is passive immu-
lymphokines and activates the B cell.[62] As the activated nity because the fetus does not actually make any mem-
B cell then begins to divide, its offspring (plasma cells) ory cells or antibodies—it only borrows them. This pas-
secrete millions of copies of the antibody that recognizes sive immunity is usually short-term, lasting from a few
this antigen. These antibodies circulate in blood plasma days up to several months. In medicine, protective pas-
and lymph, bind to pathogens expressing the antigen and sive immunity can also be transferred artificially from one
mark them for destruction by complement activation or individual to another via antibody-rich serum.[67]
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.[63]

4.1.5 Alternative adaptive immune system

Evolution of the adaptive immune system occurred in an

ancestor of the jawed vertebrates. Many of the clas-
sical molecules of the adaptive immune system (e.g.,
immunoglobulins and T cell receptors) exist only in jawed
vertebrates. However, a distinct lymphocyte-derived
molecule has been discovered in primitive jawless ver- The time-course of an immune response begins with the initial
tebrates, such as the lamprey and hagfish. These ani- pathogen encounter, (or initial vaccination) and leads to the for-
mals possess a large array of molecules called Variable mation and maintenance of active immunological memory.
lymphocyte receptors (VLRs) that, like the antigen re-
ceptors of jawed vertebrates, are produced from only a
small number (one or two) of genes. These molecules are
4.2.2 Active memory and immunization
believed to bind pathogenic antigens in a similar way to
antibodies, and with the same degree of specificity.[64]
Long-term active memory is acquired following infection
by activation of B and T cells. Active immunity can also
4.2 Immunological memory be generated artificially, through vaccination. The prin-
ciple behind vaccination (also called immunization) is to
For more details on this topic, see Immunity (medical). introduce an antigen from a pathogen in order to stimu-
late the immune system and develop specific immunity
against that particular pathogen without causing disease
When B cells and T cells are activated and begin to repli- associated with that organism.[14] This deliberate induc-
cate, some of their offspring become long-lived memory tion of an immune response is successful because it ex-
cells. Throughout the lifetime of an animal, these mem- ploits the natural specificity of the immune system, as
ory cells remember each specific pathogen encountered well as its inducibility. With infectious disease remaining
and can mount a strong response if the pathogen is de- one of the leading causes of death in the human popula-
tected again. This is “adaptive” because it occurs during tion, vaccination represents the most effective manipula-
the lifetime of an individual as an adaptation to infection tion of the immune system mankind has developed.[35][68]
with that pathogen and prepares the immune system for
future challenges. Immunological memory can be in the Most viral vaccines are based on live attenuated viruses,
form of either passive short-term memory or active long- while many bacterial vaccines are based on acellular com-
term memory. ponents of micro-organisms, including harmless toxin
components.[14] Since many antigens derived from acel-
lular vaccines do not strongly induce the adaptive re-
4.2.1 Passive memory sponse, most bacterial vaccines are provided with ad-
ditional adjuvants that activate the antigen-presenting
Newborn infants have no prior exposure to microbes and cells of the innate immune system and maximize
are particularly vulnerable to infection. Several layers immunogenicity.[69]
5.3 Hypersensitivity 7

5 Disorders of human immunity 5.3 Hypersensitivity

For more details on this topic, see Hypersensitivity.

The immune system is a remarkably effective structure
that incorporates specificity, inducibility and adaptation.
Failures of host defense do occur, however, and fall into Hypersensitivity is an immune response that damages the
three broad categories: immunodeficiencies, autoimmu- body’s own tissues. They are divided into four classes
nity, and hypersensitivities. (Type I – IV) based on the mechanisms involved and the
time course of the hypersensitive reaction. Type I hy-
persensitivity is an immediate or anaphylactic reaction,
often associated with allergy. Symptoms can range from
mild discomfort to death. Type I hypersensitivity is me-
5.1 Immunodeficiencies diated by IgE, which triggers degranulation of mast cells
and basophils when cross-linked by antigen.[76] Type II
hypersensitivity occurs when antibodies bind to antigens
For more details on this topic, see Immunodeficiency.
on the patient’s own cells, marking them for destruc-
tion. This is also called antibody-dependent (or cyto-
Immunodeficiencies occur when one or more of the com- toxic) hypersensitivity, and is mediated by IgG and IgM
ponents of the immune system are inactive. The ability antibodies.[76] Immune complexes (aggregations of anti-
of the immune system to respond to pathogens is dimin- gens, complement proteins, and IgG and IgM antibodies)
ished in both the young and the elderly, with immune re- deposited in various tissues trigger Type III hypersensi-
sponses beginning to decline at around 50 years of age tivity reactions.[76] Type IV hypersensitivity (also known
due to immunosenescence.[70][71] In developed countries, as cell-mediated or delayed type hypersensitivity) usually
obesity, alcoholism, and drug use are common causes of takes between two and three days to develop. Type IV re-
poor immune function.[71] However, malnutrition is the actions are involved in many autoimmune and infectious
most common cause of immunodeficiency in developing diseases, but may also involve contact dermatitis (poison
countries.[71] Diets lacking sufficient protein are asso- ivy). These reactions are mediated by T cells, monocytes,
ciated with impaired cell-mediated immunity, comple- and macrophages.[76]
ment activity, phagocyte function, IgA antibody concen-
trations, and cytokine production. Additionally, the loss
of the thymus at an early age through genetic mutation or
surgical removal results in severe immunodeficiency and 6 Other mechanisms and evolution
a high susceptibility to infection.[72]
Immunodeficiencies can also be inherited or For more details on this topic, see Innate immune system
'acquired'.[14] Chronic granulomatous disease, where § Other forms of innate immunity.
phagocytes have a reduced ability to destroy pathogens,
is an example of an inherited, or congenital, immunode- It is likely that a multicomponent, adaptive immune sys-
ficiency. AIDS and some types of cancer cause acquired tem arose with the first vertebrates, as invertebrates do
immunodeficiency.[73][74] 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 struc-
turally most simple forms of life, with bacteria using a
5.2 Autoimmunity unique defense mechanism, called the restriction modifi-
cation system to protect themselves from viral pathogens,
For more details on this topic, see Autoimmunity. called bacteriophages.[77] Prokaryotes also possess ac-
quired immunity, through a system that uses CRISPR se-
Overactive immune responses comprise the other end of quences to retain fragments of the genomes of phage that
immune dysfunction, particularly the autoimmune dis- they have come into contact with in the past, which al-
orders. Here, the immune system fails to properly dis- lows them to block virus replication through a form of
tinguish between self and non-self, and attacks part of RNA interference.[78][79] Offensive elements of the im-
the body. Under normal circumstances, many T cells mune systems are also present in unicellular eukaryotes,
and antibodies react with “self” peptides.[75] One of the but studies of their roles in defense are few.[80]
functions of specialized cells (located in the thymus and Pattern recognition receptors are proteins used by nearly
bone marrow) is to present young lymphocytes with self all organisms to identify molecules associated with
antigens produced throughout the body and to elimi- pathogens. Antimicrobial peptides called defensins are
nate those cells that recognize self-antigens, preventing an evolutionarily conserved component of the innate im-
autoimmunity.[61] mune response found in all animals and plants, and repre-
8 8 PHYSIOLOGICAL REGULATION

sent the main form of invertebrate systemic immunity.[1] certain skin cells (e.g. melanocytes) into tumors called
The complement system and phagocytic cells are also melanomas.[88][89] A third possible source of tumor anti-
used by most forms of invertebrate life. Ribonucleases gens are proteins normally important for regulating cell
and the RNA interference pathway are conserved across growth and survival, that commonly mutate into cancer
all eukaryotes, and are thought to play a role in the im- inducing molecules called oncogenes.[86][90][91]
mune response to viruses.[81] The main response of the immune system to tumors is to
Unlike animals, plants lack phagocytic cells, but many destroy the abnormal cells using killer T cells, sometimes
plant immune responses involve systemic chemical sig- with the assistance of helper T cells.[89][92] Tumor anti-
nals that are sent through a plant.[82] Individual plant cells gens are presented on MHC class I molecules in a similar
respond to molecules associated with pathogens known way to viral antigens. This allows killer T cells to recog-
as Pathogen-associated molecular patterns or PAMPs.[83] nize the tumor cell as abnormal.[93] NK cells also kill tu-
When a part of a plant becomes infected, the plant pro- morous cells in a similar way, especially if the tumor cells
duces a localized hypersensitive response, whereby cells have fewer MHC class I molecules on their surface than
at the site of infection undergo rapid apoptosis to pre- normal; this is a common phenomenon with tumors.[94]
vent the spread of the disease to other parts of the plant. Sometimes antibodies are generated against tumor cells
Systemic acquired resistance (SAR) is a type of defen- allowing for their destruction by the complement sys-
sive response used by plants that renders the entire plant tem.[90]
resistant to a particular infectious agent.[82] RNA silenc-
Clearly, some tumors evade the immune system and go on
ing mechanisms are particularly important in this sys-
to become cancers.[95] Tumor cells often have a reduced
temic response as they can block virus replication.[84]
number of MHC class I molecules on their surface, thus
avoiding detection by killer T cells.[93] Some tumor cells
also release products that inhibit the immune response;
7 Tumor immunology for example by secreting the cytokine TGF-β, which sup-
presses the activity of macrophages and lymphocytes.[96]
Further information: Cancer immunology In addition, immunological tolerance may develop against
Another important role of the immune system is to tumor antigens, so the immune system no longer attacks
the tumor cells.[95]
Paradoxically, macrophages can promote tumor growth
[97]
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 pro-
duced by macrophages induces tumor cells to decrease
production of a protein that blocks metastasis and thereby
assists spread of cancer cells.

8 Physiological regulation
Hormones can act as immunomodulators, altering the
Macrophages have identified a cancer cell (the large, spiky mass). sensitivity of the immune system. For example, female
Upon fusing with the cancer cell, the macrophages (smaller white sex hormones are known immunostimulators of both
cells) inject toxins that kill the tumor cell. Immunotherapy for the adaptive[98] and innate immune responses.[99] Some au-
treatment of cancer is an active area of medical research.[85] toimmune diseases such as lupus erythematosus strike
women preferentially, and their onset often coincides
identify and eliminate tumors. This is called immune with puberty. By contrast, male sex hormones such as
surveillance. The transformed cells of tumors express testosterone seem to be immunosuppressive.[100] Other
antigens that are not found on normal cells. To the im- hormones appear to regulate the immune system as well,
mune system, these antigens appear foreign, and their most notably prolactin, growth hormone and vitamin
presence causes immune cells to attack the transformed D.[101][102]
tumor cells. The antigens expressed by tumors have sev-
eral sources;[86] some are derived from oncogenic viruses
like human papillomavirus, which causes cervical can- 8.1 Vitamin D
cer,[87] while others are the organism’s own proteins that
occur at low levels in normal cells but reach high lev- When a T-cell encounters a foreign pathogen, it extends a
els in tumor cells. One example is an enzyme called vitamin D receptor. This is essentially a signaling device
tyrosinase that, when expressed at high levels, transforms that allows the T-cell to bind to the active form of vitamin
8.3 Nutrition and diet 9

D, the steroid hormone calcitriol. T-cells have a symbi- and prolactin. These signals induce a pro-inflammatory
otic relationship with vitamin D. Not only does the T-cell state through the production of the pro-inflammatory
extend a vitamin D receptor, in essence asking to bind cytokines interleukin-1, interleukin-12, TNF-alpha and
to the steroid hormone version of vitamin D, calcitriol, IFN-gamma. These cytokines then stimulate immune
but the T-cell expresses the gene CYP27B1, which is the functions such as immune cells activation, proliferation,
gene responsible for converting the pre-hormone version and differentiation. It is during this time that undifferen-
of vitamin D, calcidiol into the steroid hormone version, tiated, or less differentiated, like naïve and central mem-
calcitriol. Only after binding to calcitriol can T-cells per- ory T cells, peak (i.e. during a time of a slowly evolving
form their intended function. Other immune system cells adaptive immune response). In addition to these effects,
that are known to express CYP27B1 and thus activate vi- the milieu of hormones produced at this time (leptin, pi-
tamin D calcidiol, are dendritic cells, keratinocytes and tuitary growth hormone, and prolactin) support the inter-
macrophages.[103][104] actions between APCs and T-cells, a shift of the T 1/T 2
cytokine balance towards one that supports T 1, an in-
It is conjectured that a progressive decline in hormone
levels with age is partially responsible for weakened crease in overall T cell proliferation, and naïve T cell
migration to lymph nodes. This milieu is also thought to
immune responses in aging individuals.[105] Conversely,
some hormones are regulated by the immune system, no- support the formation of long-lasting immune memory
tably thyroid hormone activity.[106] The age-related de- through the initiation of Th1 immune responses.[113]
cline in immune function is also related to decreasing vi- In contrast, during wake periods differentiated effector
tamin D levels in the elderly. As people age, two things cells, such as cytotoxic natural killer cells and CTLs (cy-
happen that negatively affect their vitamin D levels. First, totoxic T lymphocytes), peak in order to elicit an effective
they stay indoors more due to decreased activity levels. response against any intruding pathogens. As well during
This means that they get less sun and therefore produce awake active times, anti-inflammatory molecules, such as
less cholecalciferol via UVB radiation. Second, as a per- cortisol and catecholamines, peak. There are two theo-
son ages the skin becomes less adept at producing vitamin ries as to why the pro-inflammatory state is reserved for
D.[107] sleep time. First, inflammation would cause serious cog-
nitive and physical impairments if it were to occur dur-
ing wake times. Second, inflammation may occur during
8.2 Sleep and rest sleep times due to the presence of melatonin. Inflamma-
tion causes a great deal of oxidative stress and the pres-
The immune system is affected by sleep and rest, [108]
and ence of melatonin during sleep times could actively coun-
[113][114]
sleep deprivation is detrimental to immune function. [109] teract free radical production during this time.
Complex feedback loops involving cytokines, such as
interleukin-1 and tumor necrosis factor-α produced in re-
sponse to infection, appear to also play a role in the regu-
lation of non-rapid eye movement (REM) sleep.[110] Thus
the immune response to infection may result in changes to 8.3 Nutrition and diet
the sleep cycle, including an increase in slow-wave sleep
relative to REM sleep.[111] Overnutrition is associated with diseases such as diabetes
When suffering from sleep deprivation, active immuniza- and obesity, which are known to affect immune function.
tions may have a diminished effect and may result in More moderate malnutrition, as well as certain specific
lower antibody production, and a lower immune response, trace mineral and nutrient deficiencies, can also compro-
[115]
than would be noted in a well-rested individual. Addi- mise the immune response.
tionally, proteins such as NFIL3, which have been shown Foods rich in certain fatty acids may foster a healthy im-
to be closely intertwined with both T-cell differentiation mune system.[116] Likewise, fetal undernourishment can
and our circadian rhythms, can be affected through the cause a lifelong impairment of the immune system.[117]
disturbance of natural light and dark cycles through in-
stances of sleep deprivation, shift work, etc. As a result,
these disruptions can lead to an increase in chronic condi-
tions such as heart disease, chronic pain, and asthma.[112]
In addition to the negative consequences of sleep depri- 9 Manipulation in medicine
vation, sleep and the intertwined circadian system have
been shown to have strong regulatory effects on im-
munological functions affecting both the innate and the The immune response can be manipulated to suppress un-
adaptive immunity. First, during the early slow-wave- wanted responses resulting from autoimmunity, allergy,
sleep stage, a sudden drop in blood levels of cortisol, and transplant rejection, and to stimulate protective re-
epinephrine, and norepinephrine induce increased blood sponses against pathogens that largely elude the immune
levels of the hormones leptin, pituitary growth hormone, system (see immunization) or cancer.
10 11 PREDICTING IMMUNOGENICITY

present time. The end of the 19th century and the begin-
ning of the 20th century saw a battle between “cellular”
and “humoral” theories of immunity. According to the
cellular theory of immunity, represented in particular by
Elie Metchnikoff, it was cells – more precisely, phago-
cytes – that were responsible for immune responses. In
contrast, the humoral theory of immunity, held, among
others, by Robert Koch and Emil von Behring, stated
that the active immune agents were soluble components
(molecules) found in the organism’s “humors” rather than
its cells.[121][122][123]
In the mid-1950s, Frank Burnet, inspired by a sugges-
tion made by Niels Jerne,[124] formulated the clonal se-
lection theory (CST) of immunity.[125] On the basis of
The immunosuppressive drug dexamethasone
CST, Burnet developed a theory of how an immune re-
sponse is triggered according to the self/nonself distinc-
tion: “self” constituents (constituents of the body) do
9.1 Immunosuppression not trigger destructive immune responses, while “non-
self” entities (pathogens, an allograft) trigger a destruc-
Immunosuppressive drugs are used to control autoim- tive immune response.[126] The theory was later modified
mune disorders or inflammation when excessive tissue to reflect new discoveries regarding histocompatibility
damage occurs, and to prevent transplant rejection after or the complex “two-signal” activation of T cells.[127]
an organ transplant.[35][118] The self/nonself theory of immunity and the self/nonself
vocabulary have been criticized,[123][128][129] but remain
Anti-inflammatory drugs are often used to control the
very influential.[130][131]
effects of inflammation. Glucocorticoids are the most
powerful of these drugs; however, these drugs can have More recently, several theoretical frameworks have
many undesirable side effects, such as central obe- been suggested in immunology, including "autopoietic"
sity, hyperglycemia, osteoporosis, and their use must be views,[132] “cognitive immune” views,[133] the "danger
tightly controlled.[119] Lower doses of anti-inflammatory model" (or “danger theory”,[128] and the “discon-
drugs are often used in conjunction with cytotoxic tinuity” theory.[134][135] The danger model, sug-
or immunosuppressive drugs such as methotrexate or gested by Polly Matzinger and colleagues, has
azathioprine. Cytotoxic drugs inhibit the immune re- been very influential, arousing many comments and
sponse by killing dividing cells such as activated T discussions.[136][137][138][139]
cells. However, the killing is indiscriminate and other
constantly dividing cells and their organs are affected,
which causes toxic side effects.[118] Immunosuppressive 11 Predicting immunogenicity
drugs such as cyclosporin prevent T cells from respond-
ing to signals correctly by inhibiting signal transduction
Larger drugs (>500 Da) can provoke a neutralizing im-
pathways.[120]
mune response, particularly if the drugs are adminis-
tered repeatedly, or in larger doses. This limits the ef-
9.2 Immunostimulation fectiveness of drugs based on larger peptides and pro-
teins (which are typically larger than 6000 Da). In
Main articles: Immunotherapy and Vaccination some cases, the drug itself is not immunogenic, but
may be co-administered with an immunogenic com-
pound, as is sometimes the case for Taxol. Computa-
Cancer immunotherapy covers the medical ways to stim- tional methods have been developed to predict the im-
ulate the immune system to attack cancer tumours. munogenicity of peptides and proteins, which are particu-
larly useful in designing therapeutic antibodies, assessing
likely virulence of mutations in viral coat particles, and
10 Theoretical approaches to the validation of proposed peptide-based drug treatments.
Early techniques relied mainly on the observation that
immune system hydrophilic amino acids are overrepresented in epitope
regions than hydrophobic amino acids;[140] however,
Immunology is strongly experimental in everyday prac- more recent developments rely on machine learning tech-
tice but is also characterized by an ongoing theoretical niques using databases of existing known epitopes, usu-
attitude. Many theories have been suggested in immunol- ally on well-studied virus proteins, as a training set.[141]
ogy from the end of the nineteenth century up to the A publicly accessible database has been established for
 11

the cataloguing of epitopes from pathogens known to ing it to stay one step ahead of the antibody response.[151]
be recognizable by B cells.[142] The emerging field of Masking antigens with host molecules is another com-
bioinformatics-based studies of immunogenicity is re- mon strategy for avoiding detection by the immune sys-
ferred to as immunoinformatics.[143] Immunoproteomics tem. In HIV, the envelope that covers the virion is formed
is the study of large sets of proteins (proteomics) involved from the outermost membrane of the host cell; such “self-
in the immune response. cloaked” viruses make it difficult for the immune system
to identify them as “non-self” structures.[152]

12 Manipulation by pathogens
13 See also
The success of any pathogen depends on its ability to
elude host immune responses. Therefore, pathogens • Cataphylaxis
evolved several methods that allow them to successfully • Clonal selection
infect a host, while evading detection or destruction by
the immune system.[144] Bacteria often overcome physi- • Hapten
cal barriers by secreting enzymes that digest the barrier,
for example, by using a type II secretion system.[145] Al- • Human physiology
ternatively, using a type III secretion system, they may • Immune network theory
insert a hollow tube into the host cell, providing a di-
rect route for proteins to move from the pathogen to the • Immune system receptors
host. These proteins are often used to shut down host
defenses.[146] • Immunoproteomics

An evasion strategy used by several pathogens to avoid • Immunostimulator

the innate immune system is to hide within the cells of
• Original antigenic sin
their host (also called intracellular pathogenesis). Here,
a pathogen spends most of its life-cycle inside host • Plant disease resistance
cells, where it is shielded from direct contact with im-
mune cells, antibodies and complement. Some ex- • Polyclonal response
amples of intracellular pathogens include viruses, the
• Tumor antigens
food poisoning bacterium Salmonella and the eukaryotic
parasites that cause malaria (Plasmodium falciparum) • Vaccine-naive
and leishmaniasis (Leishmania spp.). Other bacteria,
such as Mycobacterium tuberculosis, live inside a pro- • Mucosal immunology
tective capsule that prevents lysis by complement.[147]
Many pathogens secrete compounds that diminish or
misdirect the host’s immune response.[144] Some bacte- 14 References
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16.2 Images 19

Pratyya Ghosh, FasulePelte, Cyberbot II, ChrisGualtieri, MadGuy7023, Tow, Ultra Venia, Stickiestpillow, BrightStarSky, Dexbot, Turkey-
boy1234567890, Viewmont Viking, ‫سیانف‬, Call me AK, Hesperia89, Cadillac000, BigBeak10101, Cjrop123, Cyzhou, Enock4seth,
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Soupvector, Amccann421, KasparBot, JJMC89, Jeffffff, McortNGHH, Charlotte135, Widgetdog, Qzd, InternetArchiveBot, Entranced98,
Peter SamFan, GreenC bot, MordeKyle, 20linb, Abyssinian1, Kaylynfra, Silvio Porcu5 and Anonymous: 1147

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cense: Public domain Contributors: Own work Original artist: Ed (Edgar181)
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SA-3.0 Contributors: User created but based on [1]. Original artist: DO11.10
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Contributors: ? Original artist: ?
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• File:Macs_killing_cancer_cell.jpg Source: https://upload.wikimedia.org/wikipedia/commons/5/56/Macs_killing_cancer_cell.jpg Li-
cense: Public domain Contributors: Image and description: Dr. Raowf Guirguis. National Cancer Institute Original artist: Susan Arnold
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• File:Neutrophil_with_anthrax_copy.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/f2/Neutrophil_with_anthrax_
copy.jpg License: CC BY 2.5 Contributors: (November 2005). "Neutrophil engulfing Bacillus anthracis". PLoS Pathogens 1 (3): Cover
page. DOI:10.1371. Retrieved on 2009-01-04. Original artist: Volker Brinkmann
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main Contributors: Image and description: National Cancer Institute Original artist: Bruce Wetzel (photographer). Harry Schaefer (pho-
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artist: →<ₐ ᵣₑ ₌'// ₒ ₒ . ᵢ ᵢ ₑ ᵢₐ.ₒᵣ / ᵢ ᵢ/U ₑᵣ:A ₐTₒ ' ᵢ ₑ₌'U ₑᵣ:A ₐTₒ '>A ₐ</ₐ><ₐ ᵣₑ ₌'// ₒ ₒ . ᵢ ᵢ ₑ ᵢₐ.ₒᵣ / ᵢ ᵢ/U ₑᵣ_ ₐ :A ₐTₒ ' ᵢ ₑ₌'U ₑᵣ ₐ :
A ₐTₒ '>Tₒ </ₐ>

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