Immunity (medical)

In biology, immunity is the balanced state of having adequate biological defenses to fight
infection, disease, or other unwanted biological invasion, while having adequate tolerance to
avoid allergy, and autoimmune diseases.

Innate and adaptive immunity

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Scheme of a Fc receptor

It is the capability of the body to resist harmful microorganisms or viruses from entering it.
Immunity involves both specific and nonspecific components. The nonspecific components act
either as barriers or as eliminators of wide range of pathogens irrespective of antigenic
specificity. Other components of the immune system adapt themselves to each new disease
encountered and are able to generate pathogen-specific immunity.
The basic premise for the division of the immune system into innate and adaptive components
comes down to the innate system being composed of primitive bone marrow cells that are
programmed to recognise foreign substances and react, versus the adaptive system being
composed of more advanced lymphatic cells that are programmed to recognise self substances
and don't react. The reaction to foreign substances is etymologically described as inflammation,
meaning to set on fire, while the non-reaction to self substances is etymologically described as
immunity, meaning to exempt. The interaction of these two components of the immune system
creates a dynamic biological environment where "Health" can be seen as an active physical state
where what is self is immunologically spared, and what is foreign is inflammatorily and

immunologically eliminated. Extending this concept, "Disease" then can arise when what is
foriegn cannot be eliminated, or what is self is not spared.
Innate immunity, or nonspecific immunity, is the natural resistances with which a person is born.
It provides resistances through several physical, chemical and cellular approaches. Microbes first
encounter the epithelial layers, physical barriers that line skin and mucous membranes.
Subsequent general defences include secreted chemical signals (cytokines), antimicrobial
substances, fever, and phagocytic activity associated with the inflammatory responses. The
phagocytes express cell surface receptors that can bind and respond to common molecular
patterns expressed on the surface of invading microbes. Through these approaches, innate
immunity can prevent the colonization, entry and spread of microbes.
Adaptive immunity is often sub-divided into two major types depending on how the immunity
was introduced. 'Naturally acquired immunity' occurs through contact with a disease causing
agent, when the contact was not deliberate, whereas 'artificially acquired immunity' develops
only through deliberate actions such as vaccination. Both naturally and artificially acquired
immunity can be further subdivided depending on whether immunity is induced in the host or
passively transferred from an immune host. 'Passive immunity' is acquired through transfer of
antibodies or activated T-cells from an immune host, and is short livedusually lasting only a
few monthswhereas 'active immunity' is induced in the host itself by antigen and lasts much
longer, sometimes lifelong. The diagram below summarizes these divisions of immunity.

A further subdivision of adaptive immunity is characterized by the cells involved; humoral

immunity is the aspect of immunity that is mediated by secreted antibodies, whereas the
protection provided by cell mediated immunity involves T-lymphocytes alone. Humoral
immunity is active when the organism generates its own antibodies, and passive when antibodies
are transferred between individuals. Similarly, cell mediated immunity is active when the
organisms own T-cells are stimulated and passive when T cells come from another organism.

History of theories of immunity

A representation of the cholera epidemic of the nineteenth century.

The concept of immunity has intrigued mankind for thousands of years. The prehistoric view of
disease was that it was caused by supernatural forces, and that illness was a form of theurgic
punishment for "bad deeds" or "evil thoughts" visited upon the soul by the gods or by ones
enemies.[1] Between the time of Hippocrates and the 19th century, when the foundations of the
scientific methods were laid, diseases were attributed to an alteration or imbalance in one of the
four humors (blood, phlegm, yellow bile or black bile).[2] Also popular during this time before
learning that communicable diseases came from germs/microbes was the miasma theory, which
held that diseases such as cholera or the Black Plague were caused by a miasma, a noxious form
of "bad air".[1] If someone were exposed to the miasma in a swamp, in evening air, or breathing
air in a sickroom or hospital ward, they could get a disease.
The modern word "immunity" derives from the Latin immunis, meaning exemption from military
service, tax payments or other public services.[3] The first written descriptions of the concept of
immunity may have been made by the Athenian Thucydides who, in 430 BC, described that
when the plague hit Athens: "the sick and the dying were tended by the pitying care of those who
had recovered, because they knew the course of the disease and were themselves free from
apprehensions. For no one was ever attacked a second time, or not with a fatal result".[3] The term
"immunes", is also found in the epic poem "Pharsalia" written around 60 B.C. by the poet
Marcus Annaeus Lucanus to describe a North African tribes resistance to snake venom.[2]
The first clinical description of immunity which arose from a specific disease causing organism
is probably Kitab fi al-jadari wa-al-hasbah ('A Treatise on Smallpox and Measles', translated
1848[4]) written by the Islamic physician Al-Razi in the 9th century. In the treatise, Al Razi
describes the clinical presentation of smallpox and measles and goes on to indicate that that
exposure to these specific agents confers lasting immunity (although he does not use this term).[2]
The first scientist who developed full theory of immunity was Ilya Mechnikov after he revealed
phagocytosis in 1882. With Louis Pasteurs germ theory of disease, the fledgling science of

immunology began to explain how bacteria caused disease, and how, following infection, the
human body gained the ability to resist further infections.[3]

Louis Pasteur in his laboratory, 1885.

The birth of active immunotherapy may have begun with Mithridates VI of Pontus.[5] To induce
active immunity for snake venom, he recommended using a method similar to modern toxoid
serum therapy, by drinking the blood of animals which fed on venomous snakes.[5] According to
Jean de Maleissye, Mithridates assumed that animals feeding on venomous snakes acquired
some detoxifying property in their bodies, and their blood must contain attenuated or
transformed components of the snake venom. The action of those components might be
strengthening the body to resist against the venom instead of exerting toxic effect. Mithridates
reasoned that, by drinking the blood of these animals, he could acquire the similar resistance to
the snake venom as the animals feeding on the snakes.[5] Similarly, he sought to harden himself
against poison, and took daily sub-lethal to build tolerance. Mithridates is also said to have
fashioned a 'universal antidote' to protect him from all earthly poisons.[2] For nearly 2000 years,
poisons were thought to be the proximate cause of disease, and a complicated mixture of
ingredients, called Mithridate, was used to cure poisoning during the Renaissance.[2] An updated
version of this cure, Theriacum Andromachi, was used well into the 19th century.[6] In 1888
Emile Roux and Alexandre Yersin isolated diphtheria toxin, and following the 1890 discovery by
Behring and Kitasato of antitoxin based immunity to diphtheria and tetanus, the antitoxin became
the first major success of modern therapeutic Immunology.[2]
In Europe, the induction of active immunity emerged in an attempt to contain smallpox.
Immunization, however, had existed in various forms for at least a thousand years.[3] The earliest
use of immunization is unknown, however, around 1000 A.D. the Chinese began practicing a
form of immunization by drying and inhaling powders derived from the crusts of smallpox
lesions.[3] Around the fifteenth century in India, the Ottoman Empire, and east Africa, the practice
of inoculation (poking the skin with powdered material derived from smallpox crusts) became

quite common.[3] This practice was first introduced into the west in 1721 by Lady Mary Wortley
Montagu.[3] In 1798, Edward Jenner introduced the far safer method of deliberate infection with
cowpox virus, (smallpox vaccine), which caused a mild infection that also induced immunity to
smallpox. By 1800 the procedure was referred to as vaccination. To avoid confusion, smallpox
inoculation was increasingly referred to as variolation, and it became common practice to use
this term without regard for chronology. The success and general acceptance of Jenner's
procedure would later drive the general nature of vaccination developed by Pasteur and others
towards the end of the 19th century.[2] In 1891, Pasteur widened the definition of vaccine in
honour of Jenner and it then became essential to qualify the term, by referring to polio vaccine,
measles vaccine etc.

Passive immunity
Main article: Passive immunity

Passive immunity is the transfer of active immunity, in the form of readymade antibodies, from
one individual to another. Passive immunity can occur naturally, when maternal antibodies are
transferred to the fetus through the placenta, and can also be induced artificially, when high
levels of human (or horse) antibodies specific for a pathogen or toxin are transferred to nonimmune individuals. Passive immunization is used when there is a high risk of infection and
insufficient time for the body to develop its own immune response, or to reduce the symptoms of
ongoing or immunosuppressive diseases.[7] Passive immunity provides immediate protection, but
the body does not develop memory, therefore the patient is at risk of being infected by the same
pathogen later.[8]
Naturally acquired passive immunity

Maternal passive immunity is a type of naturally acquired passive immunity, and refers to
antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal
antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental
cells. This occurs around the third month of gestation.[9] IgG is the only antibody isotype that can
pass through the placenta.[9] Passive immunity is also provided through the transfer of IgA
antibodies found in breast milk that are transferred to the gut of the infant, protecting against
bacterial infections, until the newborn can synthesize its own antibodies.[8]

One of the first bottles of diphtheria antitoxin produced (Dated 1895).

Artificially acquired passive immunity
See also: Temporarily induced immunity

Artificially acquired passive immunity is a short-term immunization induced by the transfer of

antibodies, which can be administered in several forms; as human or animal blood plasma, as
pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form
of monoclonal antibodies (MAb). Passive transfer is used prophylactically in the case of
immunodeficiency diseases, such as hypogammaglobulinemia.[10] It is also used in the treatment
of several types of acute infection, and to treat poisoning.[7] Immunity derived from passive
immunization lasts for only a short period of time, and there is also a potential risk for
hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human
origin.[8]
The artificial induction of passive immunity has been used for over a century to treat infectious
disease, and prior to the advent of antibiotics, was often the only specific treatment for certain
infections. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe
respiratory diseases until the 1930s, even after sulfonamide lot antibiotics were introduced.[10]
Passive transfer of cell-mediated immunity

Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of

"sensitized" or activated T-cells from one individual into another. It is rarely used in humans
because it requires histocompatible (matched) donors, which are often difficult to find. In
unmatched donors this type of transfer carries severe risks of graft versus host disease.[7] It has,
however, been used to treat certain diseases including some types of cancer and
immunodeficiency. This type of transfer differs from a bone marrow transplant, in which
(undifferentiated) hematopoietic stem cells are transferred.

Active immunity

The time course of an immune response. Due to the formation of immunological

memory, reinfection at later time points leads to a rapid increase in antibody
production and effector T cell activity. These later infections can be mild or even
unapparent.

When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop, and
the primary immune response results. Throughout the lifetime of an animal these memory cells
will "remember" each specific pathogen encountered, and are able to mount a strong secondary
response, if the pathogen is detected again. The primary and secondary responses were first
described in 1921 by English immunologist Alexander Glenny[11] although the mechanism
involved was not discovered until later.This type of immunity is both active and adaptive
because the body's immune system prepares itself for future challenges. Active immunity often
involves both the cell-mediated and humoral aspects of immunity as well as input from the
innate immune system.
Naturally acquired active immunity
For more details on this topic, see Immune system.

Naturally acquired active immunity occurs when a person is exposed to a live pathogen, and
develops a primary immune response, which leads to immunological memory.[7] This type of
immunity is "natural" because it is not induced by deliberate exposure. Many disorders of
immune system function can affect the formation of active immunity such as immunodeficiency
(both acquired and congenital forms) and immunosuppression.
Artificially acquired active immunity
Main articles: artificial induction of immunity and vaccination

Artificially acquired active immunity can be induced by a vaccine, a substance that contains
antigen. A vaccine stimulates a primary response against the antigen without causing symptoms
of the disease.[7] The term vaccination was coined by Richard Dunning, a colleague of Edward

Jenner, and adapted by Louis Pasteur for his pioneering work in vaccination. The method Pasteur
used entailed treating the infectious agents for those diseases so they lost the ability to cause
serious disease. Pasteur adopted the name vaccine as a generic term in honor of Jenner's
discovery, which Pasteur's work built upon.

Poster from before the 1979 eradication of smallpox, promoting vaccination.

In 1807, the Bavarians became the first group to require that their military recruits be vaccinated
against smallpox, as the spread of smallpox was linked to combat.[12] Subsequently the practice
of vaccination would increase with the spread of war.
There are four types of traditional vaccines:[13]

Inactivated vaccines are composed of micro-organisms that have been killed

with chemicals and/or heat and are no longer infectious. Examples are
vaccines against flu, cholera, plague, and hepatitis A. Most vaccines of this
type are likely to require booster shots.

Live, attenuated vaccines are composed of micro-organisms that have been

cultivated under conditions which disable their ability to induce disease.
These responses are more durable and do not generally require booster
shots. Examples include yellow fever, measles, rubella, and mumps.

Toxoids are inactivated toxic compounds from micro-organisms in cases

where these (rather than the micro-organism itself) cause illness, used prior
to an encounter with the toxin of the micro-organism. Examples of toxoidbased vaccines include tetanus and diphtheria.

Subunit vaccines are composed of small fragments of disease causing

organisms. A characteristic example is the subunit vaccine against Hepatitis
B virus.

Most vaccines are given by hypodermic or intramuscular injection as they are not absorbed
reliably through the gut. Live attenuated polio and some typhoid and cholera vaccines are given
orally in order to produce immunity based in the bowel.
Immune system

The immune system is a system of many biological structures and processes within an organism
that protects against disease. To function properly, an immune system must detect a wide variety
of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the
organism's own healthy tissue. In many species, the immune system can be classified into
subsystems, such as the innate immune system versus the adaptive immune system, or humoral
immunity versus cell-mediated immunity. In humans, the bloodbrain barrier, blood
cerebrospinal fluid barrier, and similar fluidbrain barriers separate the peripheral immune
system from the neuroimmune system which protects the brain.
Pathogens can rapidly evolve and adapt, and thereby avoid detection and neutralization by the
immune system; however, multiple defense mechanisms have also evolved to recognize and
neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary
immune system, in the form of enzymes that protect against bacteriophage infections. Other
basic immune mechanisms evolved in ancient eukaryotes and remain in their modern
descendants, such as plants and insects. These mechanisms include phagocytosis, antimicrobial
peptides called defensins, and the complement system. Jawed vertebrates, including humans,
have even more sophisticated defense mechanisms,[1] including the ability to adapt over time to
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, immunodeficiency 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 erythematosus. Immunology covers the study of all aspects
of the immune system.

History of immunology
Immunology is a science that examines the structure and function of the immune system. It
originates from medicine and early studies on the causes of immunity to disease. The earliest
known reference to 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.[3] In the 18th century, Pierre-Louis Moreau de Maupertuis
made experiments with scorpion venom and observed that certain dogs and mice were immune
to this venom.[4] This and other observations of acquired immunity were later exploited by Louis
Pasteur in his development of vaccination and his proposed germ theory of disease.[5] 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.[6] Viruses were confirmed
as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.[7]
Immunology made a great advance towards the end of the 19th century, through rapid
developments, in the study of humoral immunity and cellular immunity.[8] 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.[9]

Layered defense
The immune system protects organisms from infection with layered defenses of increasing
specificity. In simple terms, 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.[10] If pathogens successfully evade the innate response, vertebrates possess a second
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.[11]
Components of the immune system
Innate immune system
Response is non-specific

Adaptive immune system

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.[12]
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.[13]

Innate immune system

Microorganisms or toxins that successfully enter an organism 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,[14] 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.[15] Innate immune defenses are non-specific, meaning these systems
respond to pathogens in a generic way.[13] 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.[10]
The innate immune system, also known as the nonspecific immune system or in-born
immunity system,[1] is an important subsystem of the overall immune system that comprises the
cells and mechanisms that defend the host from infection by other organisms. The cells of the
innate system recognize and respond to pathogens in a generic way, but, unlike the adaptive
immune system, the system does not confer long-lasting or protective immunity to the host.[2]
Innate immune systems provide immediate defense against infection, and are found in all classes
of plant and animal life.
The innate immune system is an evolutionarily older defense strategy, and is the dominant
immune system found in plants, fungi, insects, and primitive multicellular organisms.[3]
The major functions of the vertebrate innate immune system include:

Recruiting immune cells to sites of infection, through the production of chemical factors,
including specialized chemical mediators, called cytokines

Activation of the complement cascade to identify bacteria, activate cells, and promote
clearance of antibody complexes or dead cells

Identification and removal of foreign substances present in organs, tissues, the blood and
lymph, by specialised white blood cells

Activation of the adaptive immune system through a process known as antigen

presentation

Acting as a physical and chemical barrier to infectious agents.

Anatomical barriers
Anatomical barrier

Additional defense mechanisms

Skin

Sweat, desquamation, flushing,[4] organic acids[4]

Gastrointestinal tract

Peristalsis, gastric acid, bile acids, digestive enzyme,

flushing, thiocyanate,[4] defensins,[4] gut flora[4]

Respiratory airways and lungs Mucociliary elevator, surfactant,[4] defensins[4]

Nasopharynx

Mucus, saliva, lysozyme[4]

Eyes

Tears[4]

Anatomical barriers include physical, chemical and biological barriers. The epithelial surfaces
form a physical barrier that is impermeable to most infectious agents, acting as the first line of
defense against invading organisms.[4] Desquamation of skin epithelium also helps remove
bacteria and other infectious agents that have adhered to the epithelial surfaces. Lack of blood
vessels and inability of the epidermis to retain moisture, presence of sebaceous glands in the
dermis provides an environment unsuitable for the survival of microbes.[4] In the gastrointestinal
and respiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious
agents.[4] Also, mucus traps infectious agents.[4] The gut flora can prevent the colonization of
pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for
nutrients or attachment to cell surfaces.[4] The flushing action of tears and saliva helps prevent
infection of the eyes and mouth.[4]

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.[5]
The process of acute inflammation is initiated by cells already present in all tissues, mainly
resident macrophages, dendritic cells, histiocytes, Kupffer cells, and mastocytes. These cells
present receptors contained on the surface or within the cell, named pattern recognition
receptors (PRRs), which recognize molecules that are broadly shared by pathogens but
distinguishable from host molecules, collectively referred to as pathogen-associated molecular
patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo
activation (one of their PRRs recognizes a PAMP) and release inflammatory mediators
responsible for the clinical signs of inflammation.
Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes,
and prostaglandins) sensitize pain receptors, cause local vasodilation of the blood vessels, and
attract phagocytes, especially neutrophils.[5] Neutrophils then trigger other parts of the immune
system by releasing factors that summon additional leukocytes and lymphocytes. Cytokines
produced by macrophages and other cells of the innate immune system mediate the inflammatory
response. These cytokines include TNF, HMGB1, and IL-1.[6]
The inflammatory response is characterized by the following symptoms:

redness of the skin, due to locally increased blood circulation;

heat, either increased local temperature, such as a warm feeling around a

localized infection, or a systemic fever;

swelling of affected tissues, such as the upper throat during the common cold
or joints affected by rheumatoid arthritis;

increased production of mucus, which can cause symptoms like a runny nose
or a productive cough;

pain, either local pain, such as painful joints or a sore throat, or affecting the
whole body, such as body aches; and

possible dysfunction of the organs or tissues involved.

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

form holes in the plasma membrane of the pathogen, resulting in cytolysis of

the pathogen cell, causing the death of the pathogen

rid the body of neutralised antigen-antibody complexes.

Elements of the complement cascade can be found in many non-mammalian species including
plants, birds, fish, and some species of invertebrates.[7]

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-shape platelets.

All white blood cells (WBCs) are known as leukocytes. Leukocytes differ from other cells of the
body in that they are not tightly associated with a particular organ or tissue; thus, their function is
similar to that of independent, single-cell organisms. Leukocytes are able to move freely and
interact with and capture cellular debris, foreign particles, and 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 multipotent hematopoietic stem cells present in the bone marrow.[2]

The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and the
phagocytic cells include macrophages, neutrophils, and dendritic cells, and function within the
immune system by identifying and eliminating pathogens that might cause infection.[3]
Mast cells
Main article: Mast cell

Mast cells are a type of innate immune cell that reside in connective tissue and in the mucous
membranes. They are intimately associated with wound healing and defense against pathogens,
but are also often associated with allergy and anaphylaxis.[5] 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.[5]
Phagocytes
Main article: Phagocyte

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or
'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.[3] The lysosome contains enzymes
and acids that kill and digest the particle or organism. In general, phagocytes 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 by programmed cell death (also called apoptosis) or by
cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal
from the affected site.[2] 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

Macrophages
Main article: Macrophages

Macrophages, from the Greek, meaning "large eaters," are large phagocytic leukocytes, which
are able to move outside of the vascular system by migrating across the walls 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.[3] 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 summon other cells to the site of infection.[3]
Neutrophils
Main article: 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
50-60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an
infection.[5] 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.[5]
Dendritic cells
Main article: Dendritic cell

Dendritic cells (DCs) 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.[2] 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
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, histamine-releasing basophils are important in the defense against parasites
and play a role in allergic reactions, such as asthma.[3] Upon activation, eosinophils secrete a
range of highly toxic proteins and free radicals that are highly effective in killing parasites, but
may also damage tissue during an allergic reaction. Activation and release of toxins by
eosinophils are, therefore, tightly regulated to prevent any inappropriate tissue destruction.[5]
Natural killer cells
Main article: Natural killer cell

Natural killer cells (NK cells) are a component of the innate immune system that does not
directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as
tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self."
This term describes cells with abnormally low levels of a cell-surface marker called MHC I
(major histocompatibility complex) - a situation that can arise in viral infections of host cells.[8]
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." For many years, it was unclear how NK cell
recognize tumor cells and infected cells. It is now known that the MHC makeup on the 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 because they express intact self
MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors
(KIR) that, in essence, put the brakes on NK cells. The NK-92 cell line does not express KIR and
is developed for tumor therapy.[9][10][11][12]
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.

Other vertebrate mechanisms

The coagulation system overlaps with the immune system. Some products of the coagulation
system can contribute to the non-specific defenses by their ability to increase vascular
permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products
of the coagulation system are directly antimicrobial. For example, beta-lysine, a protein
produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by
acting as a cationic detergent.[4] Many acute-phase proteins of inflammation are involved in the
coagulation system.
Also increased levels of lactoferrin and transferrin inhibit bacterial growth by binding iron, an
essential nutrient for bacteria.[4]

Neural regulation of innate immunity

The innate immune response to infectious and sterile injury is modulated by neural circuits that
control cytokine production period. The Inflammatory Reflex is a prototypical neural circuit that
controls cytokine production in spleen.[13] Action potentials transmitted via the vagus nerve to
spleen mediate the release of acetylcholine, the neurotransmitter that inhibits cytokine release by
interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokineproducing cells.[14] The motor arc of the inflammatory reflex is termed the cholinergic antiinflammatory pathway.

Pathogen-specificity
The parts of the innate immune system have different specificity for different pathogens.
Pathogen
Intracellular
and
cytoplasmic
virus

Main examples[15]

Phagocytosis[15]
yes

influenza

mumps

compleme
nt[15]
no

NK
cells[15]
Yes

Intracellular
bacteria

Extracellular
bacteria

Intracellular
protozoa

Extracellular
protozoa

Extracellular
fungi

measles

rhinovirus

Listeria
monocytogenes

Legionella

Mycobacterium

Rickettsia

Staphylococcus

Streptococcus

Neisseria

Salmonella typhi

Plasmodium
malariae

Leishmania
donovani

Entamoeba
histolytica

Giardia lamblia

Candida

Histoplasma

Cryptococcus

yes (specifically
neutrophils, no for no
rickettsia)

yes (no for

rickettsia)

yes

yes

no

no

no

No

yes

yes

No

no

yes

No

Innate immune evasion

Cells of the innate immune system, in effect, prevent free growth of bacteria within the body;
however, many pathogens have evolved mechanisms allowing them to evade the innate immune
system.[16][17]
Evasion strategies that circumvent the innate immune system include intracellular replication,
such as in Mycobacterium tuberculosis, or a protective capsule that prevents lysis by
complement and by phagocytes, as in salmonella.[18] Bacteroides species are normally mutualistic
bacteria, making up a substantial portion of the mammalian gastrointestinal flora.[19] 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.[20]
Evasion of the innate immune system by virus.

Type I interferons (IFN), secreted mainly by dendritic cells,[21] play the central role in antiviral
host defense and creation of an effective antiviral state in a cell.[22] Viral components are
recognized by different receptors: Toll-like receptors are located in the endosomal membrane and
recognize double-stranded RNA (dsRNA), MDA5 and RIG-I receptors are located in the
cytoplasm and recognize long dsRNA and phosphate-containing dsRNA respectively.[23] The
viral recognition by MDA5 and RIG-I receptors in the cytoplasm induces a conformational
change between the caspase-recruitment domain (CARD) and the CARD-containing adaptor
MAVS. In parallel, the viral recognition by toll-like receptors in the endocytic compartments
induces the activation of the adaptor protein TRIF. These two pathways converge in the
recruitment and activation of the IKK/TBK-1 complex, inducing phosphorylation and homoand hetero-dimerization of transcription factors IRF3 and IRF7. These molecules are translocated
in the nucleus, where they induce IFN production with the presence of C-Jun (a particular
transcription factor) and activating transcription factor 2. IFN then binds to the IFN receptors,
inducing expression of hundreds of interferon-stimulated genes. This leads to production of
proteins with antiviral properties, such as protein kinase R, which inhibits viral protein synthesis,
or the 2,5-oligoadenylate synthetase family, which degrades viral RNA. These molecules
establish an antiviral state in the cell.[22]

Some viruses are able to evade this immune system by producing molecules that interfere with
the IFN production pathway. For example, the Influenza A virus produces NS1 protein, which
can bind to single-stranded and double-stranded RNA, thus inhibiting type I IFN production.
Influenza A virus also blocks protein kinase R activation and the establishment of the antiviral
state.[24] The dengue virus also inhibits type I IFN production by blocking IRF-3
phosophorylation using NS2B3 protease complex.[25]

Innate immunity in other species

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.[26]
Restriction endonucleases and the restriction modification system exist exclusively in
prokaryotes.
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.[27]
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.[28] 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.[27]
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.
Proteolytic cascades

In invertebrates, pattern recognition proteins (PRPs) trigger proteolytic cascades that degrade
proteins and control many of the mechanisms of the innate immune system of invertebrates
including hemolymph coagulation and melanization. Proteolytic cascades are important
components of the invertebrate immune system because they are turned on more rapidly than
other innate immune reactions because they do not rely on gene changes. Proteolytic cascades

have been found to function the same in both vertebrate and invertebrates, even though different
proteins are used throughout the cascades.[29]
Clotting mechanisms

In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like
fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are
various different proteins and mechanisms that are involved in invertebrate clotting. In
crustaceans, transglutaminase from blood cells and mobile plasma proteins make up the clotting
system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein.
On the other hand, in the horseshoe crab species clotting system, components of proteolytic
cascades are stored as inactive forms in granules of hemocytes, which are released when foreign
molecules, like lipopolysaccharides enter.[29]
Host defense in plants

Members of every class of pathogen that 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.[30] (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.[30]
Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants
use pattern-recognition receptors to recognize conserved microbial signatures. This recognition
triggers an immune response. The first plant receptors of conserved microbial signatures were
identified in rice (XA21, 1995)[31][32] and in Arabidopsis (FLS2, 2000).[33] Plants also carry
immune receptors that recognize highly variable pathogen effectors. These include the NBSLRR class of proteins. 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.[34]
"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 Toll-like
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.
[35]
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.[36] 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.[37] The jasmonic acid response, is stimulated in leaves damaged by
insects, and involves the production of methyl jasmonate.[30]

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 mechanical barriers that are
the first line of defense against infection.[13] However, as organisms cannot be completely sealed
from 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.[16]
Chemical barriers also protect against infection. The skin and respiratory tract secrete
antimicrobial peptides such as the -defensins.[17] Enzymes such as lysozyme and phospholipase
A2 in saliva, tears, and breast milk are also antibacterials.[18][19] Vaginal secretions serve as a
chemical barrier following menarche, when they become slightly acidic, while semen contains
defensins and zinc to kill pathogens.[20][21] 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.[22] This reduces the probability that
pathogens will reach sufficient numbers to cause illness. However, since most antibiotics nonspecifically 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).[23] 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 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.
[24][25][26]

Inflammation
For more details on this topic, see Inflammation.

Inflammation is one of the first responses of the immune system to infection.[27] The symptoms of
inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow
into 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).[28][29] 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.[30] 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.[31]
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.[32][33] Many species have complement systems, including non-mammals like plants,
fish, and some invertebrates.[34]
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.[35] 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.[36] 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.[32]

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.[13] 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.[34] Innate cells are also
important mediators in the activation of the adaptive immune system.[11]
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.[13] 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.[37][38] Phagocytosis evolved as
a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of
pathogens as a defense mechanism.[39] Phagocytosis probably represents the oldest form of host
defense, as phagocytes have been identified in both vertebrate and invertebrate animals.[40]
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of
invading pathogens.[41] 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.[42] 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.[43] 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.[11]
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.[44] 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 antigens
to T cells, one of the key cell types of the adaptive immune system.[44]
Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory
response.[45] They are most often associated with allergy and anaphylaxis.[42] 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.[46] Natural killer
(NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been
infected by viruses.[47]
Natural killer cells
Main article: Natural killer cell

Natural killer cells, or NK cells, are a component of the innate immune system which does not
directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as
tumor cells or virus-infected cells, recognizing such cells by a condition 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.[34] 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." For many years it was unclear how NK cells recognize
tumor cells and infected cells. It is now known that the MHC makeup on the 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 because they express intact self MHC
antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR)
which essentially put the brakes on NK cells.[48]
Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune
system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive
immune response. NK cells provide rapid responses to viral-infected cells, acting at around 3
days after infection, and respond to tumor formation. Typically, immune cells detect major
histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine

release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to
recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster
immune reaction. They were named "natural killers" because of the initial notion that they do not
require activation to kill cells that are missing "self" markers of MHC class 1.[1] This role is
especially important because harmful cells that are missing MHC I markers cannot be detected
and destroyed by other immune cells, such as T lymphocyte cells.
NK cells (belonging to the group of innate lymphoid cells) are defined as large granular
lymphocytes (LGL) and constitute the third kind of cells differentiated from the common
lymphoid progenitor-generating B and T lymphocytes.[2] NK cells are known to differentiate and
mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus, where they then enter into
the circulation.[3] NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and
by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting
IFN. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T
marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the
surface markers CD16 (FcRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. The
NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference
being expressed in both humans, several strains of mice (including BALB/c mice) and in three
common monkey species.[4][5]
In addition to the knowledge that natural killer cells are effectors of innate immunity, recent
research has uncovered information on both activating and inhibitory NK cell receptors which
play important function roles including self tolerance and sustaining NK cell activity. NK cells
also play a role in adaptive immune response,[6] numerous experiments have worked to
demonstrate their ability to readily adjust to the immediate environment and formulate antigenspecific immunological memory, fundamental for responding to secondary infections with the
same antigen. The role of NK cells in both the innate and adaptive immune responses is
becoming increasingly important in research using NK cell activity and potential cancer
therapies.

NK cell receptors

The HLA ligand for KIR

NK cell receptors can also be differentiated based on function. NK Cells are not a subset of the T
lymphocyte family. Natural cytotoxicity receptors directly induce apoptosis after binding to Fas
ligand that directly indicate infection of a cell. The MHC-dependent receptors (described above)
use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is
determined by the balance of inhibitory and activating receptor stimulation. For example, if the
inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited; similarly,
if the activating signal is dominant, then NK cell activation will result.[7]

Protein structure of NKG2D

NK cell receptor types (with inhibitory, as well as some activating members) are differentiated
by structure, with a few examples to follow:

Protein structure of NKp44

Activating receptors

Ly49 (homodimers), relatively ancient, C-type lectin family receptors, are of

multigenic presence in mice, while humans have only one pseudogenic Ly49,
the receptor for classical (polymorphic) MHC I molecules.

NCR (natural cytotoxicity receptors), upon stimulation, mediate NK killing

and release of IFN.

CD94 : NKG2 (heterodimers), a C-type lectin family receptor, is conserved in

both rodents and primates and identifies nonclassical (also nonpolymorphic)
MHC I molecules such as HLA-E. Expression of HLA-E at the cell surface is
dependent on the presence of nonamer peptide epitope derived from the
signal sequence of classical MHC class I molecules, which is generated by the
sequential action of signal peptide peptidase and the proteasome. Though
indirect, this is a way to survey the levels of classical (polymorphic) HLA
molecules.

CD16 (FcIIIA) plays a role in antibody-dependent cell-mediated

cytotoxicity; in particular, they bind IgG.

Inhibitory receptors

Killer-cell immunoglobulin-like receptors (KIRs) belong to a multigene family

of more recently evolved Ig-like extracellular domain receptors; they are
present in nonhuman primates, and are the main receptors for both classical
MHC I (HLA-A, HLA-B, HLA-C) and nonclassical Mamu-G (HLA-G) in primates.
Some KIRs are specific for certain HLA subtypes. Most KIRs are inhibitory and
dominant. Regular cells express MHC class 1, so are recognised by KIR
receptors and NK cell killing is inhibited. [3]

ILT or LIR (leukocyte inhibitory receptors) are recently discovered

members of the Ig receptor family.

Ly49 (homodimers) have both activating and inhibitory isoforms. They are
highly polymorphic on the population level; though they are structurally
unrelated to KIRs, they are the functional homologues of KIRs in mice,
including the expression pattern. Ly49s are receptor for classical
(polymorphic) MHC I molecules.

Function
Cytolytic granule mediated cell apoptosis

NK cells are cytotoxic; small granules in their cytoplasm contain proteins such as perforin and
proteases known as granzymes. Upon release in close proximity to a cell slated for killing,
perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through
which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic
cell lysis. The distinction between apoptosis and cell lysis is important in immunology: lysing a
virus-infected cell could potentially only release the virions, whereas apoptosis leads to
destruction of the virus inside. -defensins, antimicrobial molecules, are also secreted by NK
cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of
neutrophils.[3]
Antibody-dependent cell-mediated cytotoxicity

Infected cells are routinely opsonized with antibodies for detection by immune cells. Antibodies
that bind to antigens can be recognised by FcRIII (CD16) receptors expressed on NK cells,
resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. This is a
major killing mechanism of some monoclonal antibodies like rituximab (Rituxan), ofatumumab
(Azzera), and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor
cell killing can be measured with a specific test that uses NK-92 that has been transfected with a
high-affinity FcR. Results are compared to the "wild type" NK-92 that does not express the FcR.
[8]

Cytokine-induced NK and CTL activation

Cytokines play a crucial role in NK cell activation. As these are stress molecules released by
cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens in
the affected area. Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and
CCL5. NK cells are activated in response to interferons or macrophage-derived cytokines. They
serve to contain viral infections while the adaptive immune response generates antigen-specific
cytotoxic T cells that can clear the infection. NK cells work to control viral infections by
secreting IFN and TNF. IFN activates macrophages for phagocytosis and lysis, and TNF
acts to promote direct NK tumor cell killing. Patients deficient in NK cells prove to be highly
susceptible to early phases of herpes virus infection.
Missing 'self' hypothesis

Schematic diagram indicating the complementary activities of cytotoxic T cells and

NK cells

For NK cells to defend the body against viruses and other pathogens, they require mechanisms
that enable the determination of whether a cell is infected or not. The exact mechanisms remain
the subject of current investigation, but recognition of an "altered self" state is thought to be
involved. To control their cytotoxic activity, NK cells possess two types of surface receptors:
activating receptors and inhibitory receptors, including killer-cell immunoglobulin-like receptors.
Most of these receptors are not unique to NK cells and can be present in some T cell subsets, as
well.
These inhibitory receptors recognize MHC class I alleles, which could explain why NK cells
preferentially kill cells that possess low levels of MHC class I molecules. This mode of NK cell

target interaction is known as "missing-self recognition", a term coined by Klas Krre and coworkers in the late 90s. MHC class I molecules are the main mechanism by which cells display
viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in
both intracellular microbes and tumors: the chronic down-regulation of MHC I molecules, which
makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK
cells apparently evolved as an evolutionary response to this adaptation (the loss of the MHC
eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function). [9]
Tumor cell surveillance

Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate
immunity, i.e. able to react immediately with no prior exposure to the pathogen. In both mice and
humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the
death of tumor cells (NKs act as cytolytic effector lymphocytes), even in the absence of surface
adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success
particularly because T cells are unable to recognize pathogens in the absence of surface antigens.
[1]
Tumor cell detection results in activation of NK cells and consequent cytokine production and
release.
If tumor cells do not cause inflammation, they will also be regarded as self and will not induce a
T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor
(TNF), IFN, and interleukin (IL-10). TNF and IL-10 act as proinflammatory and
immunosuppressors, respectively. The activation of NK cells and subsequent production of
cytolytic effector cells impacts macrophages, dendritic cells, and neutrophils, which
subsequently enables antigen-specific T and B cell responses. Instead of acting via antigenspecific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including
NKG2D, NKp44, NKp46, NKp30, and DNAM.[7] NKG2D is a disulfide-linked homodimer
which recognizes a number of ligands, including ULBP and MICA, which are typically
expressed on tumor cells.
NK cells, along with macrophages and several other cell types, express the Fc receptor (FcR)
molecule (FC-gamma-RIII = CD16), an activating biochemical receptor that binds the Fc portion
of antibodies. This allows NK cells to target cells against which a humoral response has been
mobilized and to lyse cells through ADCC. This response depends on the affinity of the Fc
receptor expressed on NK cells, which can have high, intermediate, and low affinity for the Fc
portion of the antibody or IgG. This affinity is determined by the nucleotide status in position
158 of the gene, which can code phenylalanine (F allele) or valine (V allele). Individuals with
high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been
shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158
V/V allele had a better antitumor response. Only 1525% of the population expressed the 158
V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a
"pure" NK cell line) has been transfected with the gene for the high-affinity FcR.

Adaptive features of NK cells"memory-like" and memory NK cells

The ability to generate memory cells following a primary infection and the consequent rapid
immune activation and response to succeeding infections by the same antigen is fundamental to
the role T and B cells play in the adaptive immune response. For many years, NK cells have been
considered to be a part of the innate immune system. However, recently increasing evidence
suggests that NK cells can display several features that are usually attributed to adaptive immune
cells (e.g. T cell responses) such as expansion and contraction of subsets, increased longevity and
a form of immunological memory, characterized by a more potent response upon secondary
challenge with the same antigen.[10][11] These exciting new data have been generated in a diverse
set of experimental systems. In mice the majority of research was carried out with murine
cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. In humans most
studies focused on the expansion of an NK cell subset carrying the activating receptor NKG2C.
This expansion was observed primarily in response to Human Cytomegalovirus (HCMV) but
other infections, e.g. Hantavirus, have been reported to trigger expansion of NKG2C+ NK cells
as well.
NK cell function in pregnancy

As the majority of pregnancies involve two parents who are not tissue-matched, successful
pregnancy requires the mother's immune system to be suppressed. NK cells are thought to be an
important cell type in this process.[12] These cells are known as "uterine NK cells" (uNK cells)
and they differ from peripheral NK cells. They are in the CD56bright NK cell subset, potent at
cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56bright
NK cells, with a slightly different receptor profile.[12] These uNK cells are the most abundant
leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but
from where they originate remains controversial.[13]
These NK cells have the ability to elicit cell cytotoxicity in vitro, but at a lower level than
peripheral NK cells, despite containing perforin.[14] Lack of cytotoxicity in vivo may be due to the
presence of ligands for their inhibitory receptors. Trophoblast cells downregulate HLA-A and
HLA-B to defend against cytotoxic T cell-mediated death. This would normally trigger NK cells
by missing self recognition; however, these cells survive. The selective retention of HLA-E
(which is a ligand for NK cell inhibitory receptor NKG2A) and HLA-G (which is a ligand for
NK cell inhibitory receptor KIR2DL4) by the trophoblast is thought to defend it against NK cellmediated death.[12]
Uterine NK cells have shown no significant difference in women with recurrent miscarriage
compared with controls. However, higher peripheral NK cell percentages occur in women with
recurrent miscarriages than in control groups.[15]
NK cells secrete a high level of cytokines which help mediate their function. Some important
cytokines they secrete include TNF-, IL-10, IFN-, and TGF-, among others.[12] For example,

IFN- dilates and thins the walls of maternal spiral arteries to enhance blood flow to the
implantation site.[16]
NK cell evasion by tumor cells

By shedding decoy NKG2D soluble ligands, tumor cells may avoid immune responses. These
soluble NKG2D ligands bind to NK cell NKG2D receptors, activating a false NK response and
consequently creating competition for the receptor site.[1] This method of evasion occurs in
prostate cancer. In addition, prostate cancer tumors can evade CD8 cell recognition due to their
ability to downregulate expression of MHC class 1 molecules. This example of immune evasion
actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can
consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive
immune response).[17]

History
In early experiments on cell-mediated cytotoxicity against tumor target cells, both in cancer
patients and animal models, investigators consistently observed what was termed a "natural"
reactivity; that is, a certain population of cells seemed to be able to lyse tumor cells without
having been previously sensitized to them. As these discoveries were inconsistent with the
established model at the time, many initially considered these observations to be artifacts.[18]
However, by 1973, 'natural killing' activity was established across a wide variety of species, and
the existence of a separate lineage of cells possessing this ability was postulated.
The discovery that a unique type of lymphocyte was responsible for natural or spontaneous
cytotoxicity was made in the early 1970s by doctoral student Rolf Kiessling and postdoctoral
fellow Hugh Pross, in the mouse,[19] and by Hugh Pross and doctoral student Mikael Jondal in the
human.[20][21] The mouse and human work was carried out under the supervision of professors Eva
Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm. Kiesslings
research involved the well-characterized ability of T lymphocytes to lyse tumor cells against
which they had been previously immunized. Pross and Jondal were studying cell-mediated
cytotoxicity in normal human blood and the effect of the removal of various receptor-bearing
cells on this cytotoxicity. Later that same year, Ronald Herberman published similar data with
respect to the unique nature of the mouse effector cell.[22] The human data were confirmed, for
the most part, by West et al.[23] using similar techniques and the same erythroleukemic target cell
line, K562. K562 is highly sensitive to lysis by human NK cells and, over the decades, the K562
51
chromium-release assay has become the most commonly used assay to detect human NK
functional activity.[24] Its almost universal use has meant that experimental data can be compared
easily by different laboratories around the world.
Using discontinuous density centrifugation, and later monoclonal antibodies, natural killing
ability was mapped to the subset of large, granular lymphocytes known today as NK cells. The
demonstration that density gradient-isolated large granular lymphocytes were responsible for

human NK activity, made by Timonen and Saksela in 1980,[25] was the first time that NK cells
had been visualized microscopically, and was a major breakthrough in the field.

New findings
Anticancer therapy

Since NK cells recognize target cells when they express nonself HLA antigens (but not self),
autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead,
investigators are working on using allogeneic cells from peripheral blood, which requires that all
T cells be removed before infusion into the patients to remove the risk of graft versus host
disease, which can be fatal. This can be achieved using an immunomagnetic column
(CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of
lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few
weeks and the yield is donor-dependent. A simpler way to obtain high numbers of pure NK cells
is to expand NK-92 cells whose cells continuously grow in culture and can be expanded to
clinical grade numbers in bags or bioreactors.[26] Clinical studies have shown it to be well
tolerated and some antitumor responses have been seen in patients with lung cancer, melanoma,
and lymphoma.[27][28]
Infusions of T cells engineered to express a chimeric antigen receptor that recognizes an antigen
molecule on leukemia cells could induce remissions in patients with advanced leukemia.
Logistical challenges are present for expanding T cells and investigators are working on applying
the same technology to peripheral blood NK cells and NK-92.
In a study at Boston Children's Hospital, in coordination with Dana-Farber Cancer Institute,
whereby immunocompromised mice had contracted lymphomas from EBV infection, an NKactivating receptor called NKG2D was fused with a stimulatory Fc portion of the EBV antibody.
The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the
recipients. In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved
capable of reducing tumor growth and prolonging survival of the recipients.
Innate resistance to HIV

Recent research suggests specific KIR-MHC class 1 gene interactions might control innate
genetic resistance to certain viral infections, including HIV and its consequent development of
AIDS.[3] Certain HLA allotypes have been found to determine the progression of HIV to AIDS;
an example is the HLA-B57 and HLA-B27 alleles, which have been found to delay progression
from HIV to AIDS. This is evident because patients expressing these HLA alleles are observed to
have lower viral loads and a more gradual decline in CD4+ T cells numbers. Despite considerable
research and data collected measuring the genetic correlation of HLA alleles and KIR allotypes,
a firm conclusion has not yet been drawn as to what combination provides decreased HIV and
AIDS susceptibility.

NK cells can impose immune pressure on HIV, which had previously been described only for T
cells and antibodies.[29] HIV mutates to avoid NK cell activity.[29]

Adaptive immune system

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.[49] The adaptive immune response is antigen-specific and requires the
recognition of specific "non-self" antigens during a process called antigen presentation. Antigen
specificity allows for the generation of responses that are tailored to specific pathogens or
pathogen-infected cells. The ability to mount these tailored responses is maintained in the body
by "memory cells". Should a pathogen infect the body more than once, these specific memory
cells are used to quickly eliminate it.

Adaptive immune system

From Wikipedia, the free encyclopedia

A scanning electron microscope (SEM) image of a single human lymphocyte

The adaptive immune system, also known as the acquired immune system or, more rarely, as
the specific immune system, is a subsystem of the overall immune system that is composed of
highly specialized, systemic cells and processes that eliminate or prevent pathogen growth. The
adaptive immune system is one of the two main immunity strategies found in vertebrates (the
other being the innate immune system). Adaptive immunity creates immunological memory after
an initial response to a specific pathogen, and leads to an enhanced response to subsequent
encounters with that pathogen. This process of acquired immunity is the basis of vaccination.
Like the innate system, the adaptive system includes both humoral immunity components and
cell-mediated immunity components.
Unlike the innate immune system, the adaptive immune system is highly specific to a particular
pathogen. Adaptive immunity can also provide long-lasting protection: for example; someone

who recovers from measles is now protected against measles for their lifetime but in other cases
it does not provide lifetime protection: for example; chickenpox. The adaptive system response
destroys invading pathogens and any toxic molecules they produce. Sometimes the adaptive
system is unable to distinguish foreign molecules, the effects of this may be hayfever, asthma or
any other allergies. Antigens are any substances that elicit the adaptive immune response. The
cells that carry out the adaptive immune response are white blood cells known as lymphocytes.
Two main broad classesantibody responses and cell mediated immune responseare also
carried by two different lymphocytes (B cells and T cells). In antibody responses, B cells are
activated to secrete antibodies, which are proteins also known as immunoglobulins. Antibodies
travel through the bloodstream and bind to the foreign antigen causing it to inactivate, which
does not allow the antigen to bind to the host.[1]
In acquired immunity, pathogen-specific receptors are "acquired" during the lifetime of the
organism (whereas in innate immunity pathogen-specific receptors are already encoded in the
germline). The acquired response is called "adaptive" because it prepares the body's immune
system for future challenges (though it can actually also be maladaptive when it results in
autoimmunity).[n 1]
The system is highly adaptable because of somatic hypermutation (a process of accelerated
somatic mutations), and V(D)J recombination (an irreversible genetic recombination of antigen
receptor gene segments). This mechanism allows a small number of genes to generate a vast
number of different antigen receptors, which are then uniquely expressed on each individual
lymphocyte. Since the gene rearrangement leads to an irreversible change in the DNA of each
cell, all progeny (offspring) of that cell inherit genes that encode the same receptor specificity,
including the memory B cells and memory T cells that are the keys to long-lived specific
immunity.
A theoretical framework explaining the workings of the acquired immune system is provided by
immune network theory. This theory, which builds on established concepts of clonal selection, is
being applied in the search for an HIV vaccine.

Functions
Acquired immunity is triggered in vertebrates when a pathogen evades the innate immune
system and (1) generates a threshold level of antigen and (2) generates "stranger" or "danger"
signals activating dendritic cells.[2]
The major functions of the acquired immune system include:

Recognition of specific "non-self" antigens in the presence of "self", during

the process of antigen presentation.

Generation of responses that are tailored to maximally eliminate specific

pathogens or pathogen-infected cells.

Development of immunological memory, in which pathogens are

"remembered" through memory B cells and memory T cells.

Lymphocytes
Main article: Lymphocyte

The cells of the acquired immune system are T and B lymphocytes; lymphocytes are a subset of
leukocyte. B cells and T cells are the major types of lymphocytes. The human body has about 2
trillion lymphocytes, constituting 2040% of white blood cells (WBCs); their total mass is about
the same as the brain or liver. The peripheral blood contains 2% of circulating lymphocytes; the
rest move within the tissues and lymphatic system.[1]
B cells and T cells are derived from the same multipotent hematopoietic stem cells, and are
morphologically indistinguishable from one another until after they are activated. B cells play a
large role in the humoral immune response, whereas T cells are intimately involved in cellmediated immune responses. In all vertebrates except Agnatha, B cells and T cells are produced
by stem cells in the bone marrow.[3]
T progenitors migrate from the bone marrow to the thymus where they are called thymocytes and
where they develop into T cells. In humans, approximately 12% of the lymphocyte pool
recirculates each hour to optimize the opportunities for antigen-specific lymphocytes to find their
specific antigen within the secondary lymphoid tissues.[4]
In an adult animal, the peripheral lymphoid organs contain a mixture of B and T cells in at least
three stages of differentiation:

naive B and naive T cells (cells that have not matured), left the bone marrow
or thymus, have entered the lymphatic system, but have yet to encounter
their cognate antigen,

effector cells that have been activated by their cognate antigen, and are
actively involved in eliminating a pathogen.

memory cells the long-lived survivors of past infections.

Antigen presentation
Main article: Antigen presentation

Acquired immunity relies on the capacity of immune cells to distinguish between the body's own
cells and unwanted invaders. The host's cells express "self" antigens. These antigens are different
from those on the surface of bacteria or on the surface of virus-infected host cells ("non-self" or
"foreign" antigens). The acquired immune response is triggered by recognizing foreign antigen in
the cellular context of a danger-activated dendritic cell.
With the exception of non-nucleated cells (including erythrocytes), all cells are capable of
presenting antigen through the function of major histocompatibility complex (MHC) molecules.

[3]

Some cells are specially equipped to present antigen, and to prime naive T cells. Dendritic
cells and B-cells (and to a lesser extent macrophages) are equipped with special "co-stimulatory"
ligands recognized by co-stimulatory receptors on T cells, and are termed professional antigenpresenting cells (APC).
Several T cells subgroups can be activated by professional APCs, and each type of T cell is
specially equipped to deal with each unique toxin or bacterial and viral pathogen. The type of T
cell activated, and the type of response generated, depends, in part, on the context in which the
APC first encountered the antigen.[2]
Exogenous antigens

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or

"helper" CD4+ cells.

Dendritic cells engulf exogenous pathogens, such as bacteria, parasites or toxins in the tissues
and then migrate, via chemotactic signals, to the T cell-enriched lymph nodes. During migration,
dendritic cells undergo a process of maturation in which they lose most of their ability to engulf
other pathogens and develop an ability to communicate with T-cells. The dendritic cell uses
enzymes to chop the pathogen into smaller pieces, called antigens. In the lymph node, the
dendritic cell displays these "non-self" antigens on its surface by coupling them to a "self"receptor called the major histocompatibility complex, or MHC (also known in humans as human
leukocyte antigen (HLA)). This MHC:antigen complex is recognized by T-cells passing through
the lymph node. Exogenous antigens are usually displayed on MHC class II molecules, which
activate CD4+T helper cells.[2]
Endogenous antigens

Endogenous antigens are produced by intracellular bacteria and viruses replicating within a host
cell.The host cell uses enzymes to digest virally associated proteins, and displays these pieces on
its surface to T-cells by coupling them to MHC. Endogenous antigens are typically displayed on
MHC class I molecules, and activate CD8+ cytotoxic T-cells. With the exception of nonnucleated cells (including erythrocytes), MHC class I is expressed by all host cells.[2]

T lymphocytes
Main article: T cell

CD8+ T lymphocytes and cytotoxicity

Main article: Cytotoxic T cell

Cytotoxic T cells (also known as TC, killer T cell, or cytotoxic T-lymphocyte (CTL)) are a subgroup of T cells that induce the death of cells that are infected with viruses (and other
pathogens), or are otherwise damaged or dysfunctional.[2]
Naive cytotoxic T cells are activated when their T-cell receptor (TCR) strongly interacts with a
peptide-bound MHC class I molecule. This affinity depends on the type and orientation of the
antigen/MHC complex, and is what keeps the CTL and infected cell bound together.[2] Once
activated, the CTL undergoes a process called clonal selection, in which it gains functions and
divides rapidly to produce an army of armed effector cells. Activated CTL then travels
throughout the body searching for cells that bear that unique MHC Class I + peptide.
When exposed to these infected or dysfunctional somatic cells, effector CTL release perforin and
granulysin: cytotoxins that form pores in the target cell's plasma membrane, allowing ions and
water to flow into the infected cell, and causing it to burst or lyse. CTL release granzyme, a
serine protease that enters cells via pores to induce apoptosis (cell death). To limit extensive
tissue damage during an infection, CTL activation is tightly controlled and in general requires a
very strong MHC/antigen activation signal, or additional activation signals provided by "helper"
T-cells (see below).[2]
On resolution of the infection, most effector cells die and phagocytes clear them awaybut a
few of these cells remain as memory cells.[3] On a later encounter with the same antigen, these
memory cells quickly differentiate into effector cells, dramatically shortening the time required
to mount an effective response.

Helper T-cells
Main article: T helper cell

The T lymphocyte activation pathway. T cells contribute to immune defenses in two

major ways: some direct and regulate immune responses; others directly attack
infected or cancerous cells.[5]

CD4+ lymphocytes, also called "helper" or "regulatory" T cells, are immune response mediators,
and play an important role in establishing and maximizing the capabilities of the acquired
immune response.[2] These cells have no cytotoxic or phagocytic activity; and cannot kill infected
cells or clear pathogens, but, in essence "manage" 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 activation of a naive helper T-cell causes it to release cytokines, which influences
the activity of many cell types, including the APC (Antigen-Presenting Cell) that activated it.
Helper T-cells require a much milder activation stimulus than cytotoxic T cells. Helper T cells
can provide extra signals that "help" activate cytotoxic cells.[3]
Th1 and Th2: helper T cell responses

Classically, two types of effector CD4+ T helper cell responses can be induced by a professional
APC, designated Th1 and Th2, each designed to eliminate different types of pathogens. The
factors that dictate whether an infection triggers a Th1 or Th2 type response are not fully

understood, but the response generated does play an important role in the clearance of different
pathogens.[2] The Th1 response is characterized by the production of Interferon-gamma, which
activates the bactericidal activities of macrophages, and induces B cells to make opsonizing
(coating) and complement-fixing antibodies, and leads to cell-mediated immunity.[2] The Th2
response is characterized by the release of Interleukin 5, which induces eosinophils in the
clearance of parasites.[6] Th2 also produce Interleukin 4, which facilitates B cell isotype
switching.[2] In general, Th1 responses are more effective against intracellular pathogens (viruses
and bacteria that are inside host cells), whereas Th2 responses are more effective against
extracellular bacteria, parasites including helminths and toxins.[2] Like cytotoxic T cells, most of
the CD4+ helper cells die on resolution of infection, with a few remaining as CD4+ memory
cells.
Increasingly, there is strong evidence from mouse and human-based scientific studies of a
broader diversity in CD4+ effector T helper cell subsets. Regulatory T (Treg) cells, have been
identified as important negative regulators of adaptive immunity as they limit and suppresses the
immune system to control aberrant immune responses to self-antigens; an important mechanism
in controlling the development of autoimmune diseases.[3] Follicular helper T (Tfh) cells are
another distinct population of effector CD4+ T cells that develop from naive T cells post-antigen
activation. Tfh cells are specialized in helping B cell humoral immunity as they are uniquely
capable of migrating to follicular B cells in secondary lymphoid organs and provide them
positive paracrine signals to enable the generation and recall production of high-quality affintymatured antibodies. Similar to Tregs, Tfh cells also play a role in immunological tolerance as an
abnormal expansion of Tfh cell numbers can lead to unrestricted autoreactive antibody
production causing severe systemic autoimmune disorders.[7]
The relevance of CD4+ T helper cells is highlighted during an HIV infection. HIV is able to
subvert the immune system by specifically attacking the CD4+ T cells, precisely the cells that
could drive the clearance of the virus, but also the cells that drive immunity against all other
pathogens encountered during an organism's lifetime.[3]
Gamma delta T cells
Main article: Gamma delta T cell

Gamma delta T cells ( T cells) possess an alternative T cell receptor (TCR) as opposed to
CD4+ and CD8+ T cells and share characteristics of helper T cells, cytotoxic T cells and
natural killer cells. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as
CD1d-restricted natural killer T cells, T cells exhibit characteristics that place them at the
border between innate and acquired immunity. On one hand, T cells may be considered a
component of acquired immunity in that they rearrange TCR genes via V(D)J recombination,
which also produces junctional diversity, and develop a memory phenotype. On the other hand,
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 respond to
stressed epithelial cells.

B lymphocytes and antibody production

Main articles: B cell and Humoral immunity

The B lymphocyte activation pathway. B cells function to protect the host by

producing antibodies that identify and neutralize foreign objects like bacteria and
viruses.[5]

B Cells are the major cells involved in the creation of antibodies that circulate in blood plasma
and lymph, known as humoral immunity. Antibodies (also known as immunoglobulin, Ig), are
large Y-shaped proteins used by the immune system to identify and neutralize foreign objects. In
mammals, there are five types of antibody: IgA, IgD, IgE, IgG, and IgM, differing in biological
properties; each has evolved to handle different kinds of antigens. Upon activation, B cells
produce antibodies, each of which recognizing a unique antigen, and neutralizing specific
pathogens.[2]
Like the T cell, B cells express a unique B cell receptor (BCR), in this case, an immobilized
antibody molecule. All the BCR of any one clone of B cells recognizes and binds to only one
particular antigen. A critical difference between B cells and T cells is how each cell "sees" an
antigen. T cells recognize their cognate antigen in a processed form as a peptide in the context

of an MHC molecule,[2] whereas B cells recognize antigens in their native form.[2] Once a B cell
encounters its cognate (or specific) antigen (and receives additional signals from a helper T cell
(predominately Th2 type)), it further differentiates into an effector cell, known as a plasma cell.[2]
Plasma cells are short-lived cells (23 days) that secrete antibodies. These antibodies bind to
antigens, making them easier targets for phagocytes, and trigger the complement cascade.[2]
About 10% of plasma cells survive to become long-lived antigen-specific memory B cells.[2]
Already primed to produce specific antibodies, these cells can be called upon to respond quickly
if the same pathogen re-infects the host, while the host experiences few, if any, symptoms.

Alternative acquired immune system

Main article: Adaptive immunity in jawless vertebrates

Although the classical molecules of the acquired 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 for short) 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.[8]

Immunological memory
For more details on this topic, see Immunity (medical).

When B cells and T cells are activated some become memory B cells and some memory T cells.
Throughout the lifetime of an animal these memory cells form a database of effective B and T
lymphocytes. Upon interaction with a previously encountered antigen, the appropriate memory
cells are selected and activated. In this manner, the second and subsequent exposures to an
antigen produce a stronger and faster immune response. This is "adaptive" because the body's
immune system prepares itself for future challenges, but is "maladaptive" of course if the
receptors are autoimmune. Immunological memory can be in the form of either passive shortterm memory or active long-term memory.
Passive memory

Passive memory is usually short-term, lasting between a few days and several months. Newborn
infants have had no prior exposure to microbes and are particularly vulnerable to infection.
Several layers of passive protection are provided by the mother. In utero, maternal IgG is
transported directly across the placenta, so that, at birth, human babies have high levels of
antibodies, with the same range of antigen specificities as their mother.[2] Breast milk contains
antibodies (mainly IgA) that are transferred to the gut of the infant, protecting against bacterial
infections, until the newborn can synthesize its own antibodies.[2]

This is passive immunity because the fetus does not actually make any memory cells or
antibodies: It only borrows them. Short-term passive immunity can also be transferred artificially
from one individual to another via antibody-rich serum.
Active memory

In general, active immunity is long-term and can be acquired by infection followed by B cells
and T cells activation, or artificially acquired by vaccines, in a process called immunization.
Immunization

Historically, infectious disease has been the leading cause of death in the human population.
Over the last century, two important factors have been developed to combat their spread:
sanitation and immunization.[3] Immunization (commonly referred to as vaccination) is the
deliberate induction of an immune response, and represents the single most effective
manipulation of the immune system that scientists have developed.[3] Immunizations are
successful because they utilize the immune system's natural specificity as well as its inducibility.
The principle behind immunization is to introduce an antigen, derived from a disease-causing
organism, that stimulates the immune system to develop protective immunity against that
organism, but that does not itself cause the pathogenic effects of that organism. An antigen (short
for antibody generator), is defined as any substance that binds to a specific antibody and elicits
an adaptive immune response.[1]
Most viral vaccines are based on live attenuated viruses, whereas many bacterial vaccines are
based on acellular components of microorganisms, including harmless toxin components.[1]
Many antigens derived from acellular vaccines do not strongly induce an acquired response, and
most bacterial vaccines require the addition of adjuvants that activate the antigen-presenting cells
of the innate immune system to enhance immunogenicity.[3]

Immunological diversity

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. [5]

Most large molecules, including virtually all proteins and many polysaccharides, can serve as
antigens.[2] The parts of an antigen that interact with an antibody molecule or a lymphocyte
receptor, are called epitopes, or antigenic determinants. Most antigens contain a variety of
epitopes and can stimulate the production of antibodies, specific T cell responses, or both.[2] A
very small proportion (less than 0.01%) of the total lymphocytes are able to bind to a particular
antigen, which suggests that only a few cells respond to each antigen.[3]
For the acquired response to "remember" and eliminate a large number of pathogens the immune
system must be able to distinguish between many different antigens,[1] and the receptors that
recognize antigens must be produced in a huge variety of configurations, in essence one receptor
(at least) for each different pathogen that might ever be encountered. Even in the absence of
antigen stimulation, a human can produce more than 1 trillion different antibody molecules.[3]
Millions of genes would be required to store the genetic information that produces these
receptors, but, the entire human genome contains fewer than 25,000 genes.[9]
Myriad receptors are produced through a process known as clonal selection.[1][2] According to the
clonal selection theory, at birth, an animal randomly generates a vast diversity of lymphocytes
(each bearing a unique antigen receptor) from information encoded in a small family of genes.
To generate each unique antigen receptor, these genes have undergone a process called V(D)J
recombination, or combinatorial diversification, in which one gene segment recombines with
other gene segments to form a single unique gene. This assembly process generates the enormous

diversity of receptors and antibodies, before the body ever encounters antigens, and enables the
immune system to respond to an almost unlimited diversity of antigens.[2] Throughout an animal's
lifetime, lymphocytes that can react against the antigens an animal actually encounters are
selected for actiondirected against anything that expresses that antigen.
Note that the innate and acquired portions of the immune system work together, not in spite of
each other. The acquired arm, B, and T cells couldn't function without the innate system' input. T
cells are useless without antigen-presenting cells to activate them, and B cells are crippled
without T cell help. On the other hand, the innate system would likely be overrun with pathogens
without the specialized action of the acquired immune response.

Acquired immunity during pregnancy

The cornerstone of the immune system is the recognition of "self" versus "non-self". Therefore,
the mechanisms that protect the human fetus (which is considered "non-self") from attack by the
immune system, are particularly interesting. Although no comprehensive explanation has
emerged to explain this mysterious, and often repeated, lack of rejection, two classical reasons
may explain how the fetus is tolerated. The first is that the fetus occupies a portion of the body
protected by a non-immunological barrier, the uterus, which the immune system does not
routinely patrol.[2] The second is that the fetus itself may promote local immunosuppression in
the mother, perhaps by a process of active nutrient depletion.[2] A more modern explanation for
this induction of tolerance is that specific glycoproteins expressed in the uterus during pregnancy
suppress the uterine immune response (see eu-FEDS).
During pregnancy in viviparous mammals (all mammals except Monotremes), endogenous
retroviruses (ERVs) are activated and produced in high quantities during the implantation of the
embryo. They are currently known to possess immunosuppressive properties, suggesting a role in
protecting the embryo from its mother's immune system. Also, viral fusion proteins cause the
formation of the placental syncytium[10] to limit exchange of migratory cells between the
developing embryo and the body of the mother (something an epithelium can't do sufficiently, as
certain blood cells specialize to insert themselves between adjacent epithelial cells). The
immunodepressive action was the initial normal behavior of the virus, similar to HIV. The fusion
proteins were a way to spread the infection to other cells by simply merging them with the
infected one (HIV does this too). It is believed that the ancestors of modern viviparous mammals
evolved after an infection by this virus, enabling the fetus to survive the immune system of the
mother.[11]
The human genome project found several thousand ERVs classified into 24 families.[12]

Immune network theory

Main article: Immune network theory

A theoretical framework explaining the workings of the acquired immune system is provided by
immune network theory, based on interactions between idiotypes (unique molecular features of
one clonotype, i.e. the unique set of antigenic determinants of the variable portion of an
antibody) and 'anti-idiotypes' (antigen receptors that react with the idiotype as if it were a foreign
antigen). This theory, which builds on the existing clonal selection hypothesis and since 1974 has
been developed mainly by Niels Jerne and Geoffrey W. Hoffmann, is seen as being relevant to
the understanding of the HIV pathogenesis and the search for an HIV vaccine.
Stimulation of adaptive immunity

One of the most interesting developments in biomedical science during the past few decades has
been elucidation of mechanisms mediating innate immunity. One set of innate immune
mechanisms is humoral, such as complement activation. Another set comprises pattern
recognition receptors such as Toll-like receptors, which induce the production of interferons and
other cytokines increasing resistance of cells such as monocytes to infections.[13] Cytokines
produced during innate immune responses are among the activators of adaptive immune
responses.[13] Antibodies exert additive or synergistic effects with mechanisms of innate
immunity. Unstable HbS clusters Band-3, a major integral red cell protein;[14] antibodies
recognize these clusters and accelerate their removal by phagocytic cells. Clustered Band 3
proteins with attached antibodies activate complement, and complement C3 fragments are
opsonins recognized by the CR1 complement receptor on phagocytic cells.[15]
A population study has shown that the protective effect of the sickle-cell trait against falciparum
malaria involves the augmentation of adaptive as well as innate immune responses to the malaria
parasite, illustrating the expected transition from innate to adaptive immunity.[16]
Repeated malaria infections strengthen adaptive immunity and broaden its effects against
parasites expressing different surface antigens. By school age most children have developed
efficacious adaptive immunity against malaria. These observations raise questions about
mechanisms that favor the survival of most children in Africa while allowing some to develop
potentially lethal infections.
In malaria, as in other infections,[13] innate immune responses lead into, and stimulate, adaptive
immune responses. The genetic control of innate and adaptive immunity is now a large and
flourishing discipline.
Humoral and cell-mediated immune responses limit malaria parasite multiplication, and many
cytokines contribute to the pathogenesis of malaria as well as to the resolution of infections.[17]

Evolution
The adaptive immune system, which has been best-studied in mammals, originated in a jawed
fish approximately 500 million years ago. Most of the molecules, cells, tissues, and associated

mechanisms of this system of defense are found in cartilaginous fishes.[18] Lymphocyte receptors,
Ig and TCR, are found in all jawed vertebrates. The most ancient Ig class, IgM, is membranebound and then secreted upon stimulation of cartilaginous fish B cells. Another isotype, shark
IgW, is related to mammalian IgD. TCRs, both / and /, are found in all animals from
gnathostomes to mammals. The organization of gene segments that undergo gene rearrangement
differs in cartilaginous fishes, which have a cluster form as compared to the translocon form in
bony fish to mammals. Like TCR and Ig, the MHC is found only in jawed vertebrates. Genes
involved in antigen processing and presentation, as well as the class I and class II genes, are
closely linked within the MHC of almost all studied species.
Lymphoid cells can be identified in some pre-vertebrate deuterostomes (i.e., sea urchins).[19]
These bind antigen with pattern recognition receptors (PRRs) of the innate immune system. In
jawless fishes, two subsets of lymphocytes use variable lymphocyte receptors (VLRs) for antigen
binding.[20] Diversity is generated by a cytosine deaminase-mediated rearrangement of LRRbased DNA segments.[21] There is no evidence for the recombination-activating genes (RAGs)
that rearrange Ig and TCR gene segments in jawed vertebrates.
The evolution of the AIS, based on Ig, TCR, and MHC molecules, is thought to have arisen from
two major evolutionary events: the transfer of the RAG transposon (possibly of viral origin) and
two whole genome duplications.[18] Though the molecules of the AIS are well-conserved, they are
also rapidly evolving. Yet, a comparative approach finds that many features are quite uniform
across taxa. All the major features of the AIS arose early and quickly. Jawless fishes have a
different AIS that relies on gene rearrangement to generate diversity but has little else in common
with the jawed vertebrate AIS. The innate immune system, which has an important role in AIS
activation, is the most important defense system of invertebrates and plants.
Gamma delta T cells ( T cells), represent a small subset of T cells that possess a distinct T-cell
receptor (TCR) on their surface. Most T cells are (alpha beta) T cells with TCR composed of
two glycoprotein chains called (alpha) and (beta) TCR chains. In contrast, gamma delta ()
T cells have a TCR that is made up of one (gamma) chain and one (delta) chain. This group
of T cells is usually much less common than T cells, but are at their highest abundance in the
gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).[1]
The antigenic molecules that activate gamma delta T cells are still largely unknown. However,
T cells are peculiar in that they do not seem to require antigen processing and majorhistocompatibility-complex (MHC) presentation of peptide epitopes, although some recognize
MHC class Ib molecules. Furthermore, T cells are believed to have a prominent role in
recognition of lipid antigens. They are of an invariant nature and may be triggered by alarm
signals, such as heat shock proteins (HSP).

There also exists a -T-cell sub-population within the epidermal compartment of the skin of
mice. Originally referred to as Thy-1+ dendritic epidermal cells (Thy1+DEC),[2] these cells are
more commonly known as dendritic epidermal T cells (DETC). DETCs arise during fetal
development and express an invariant and canonical V3 V1 T-cell receptor [using Garman
nomenclature].[3]

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.[34] B cells are involved in the humoral immune response, whereas T
cells are involved in cell-mediated immune response.
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. In addition there are regulatory T cells which have a role in
modulating immune response. Killer T cells only recognize antigens coupled to Class I MHC
molecules, while helper T cells and regulatory 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.[50]
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.[34]
Killer T cells

Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other
pathogens), or are otherwise damaged or dysfunctional.[51] As with B cells, each type of T cell
recognizes 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.[52] 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).[52]
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
immune responses the body makes to a particular pathogen.[53][54] These cells have no cytotoxic
activity and do not kill infected cells or clear pathogens directly. They instead control the
immune response by directing other cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC
molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor,
which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell's
activation. Helper T cells have a weaker association with the MHC:antigen complex than
observed for killer T cells, meaning many receptors (around 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.[55] 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.[13] 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.[56]
Gamma delta T cells

Gamma delta 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.[57] 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 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. [58]
B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.[59]
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.[60] 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.[61]
Alternative adaptive immune system

Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many
of the classical 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 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.[62]
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 become
long-lived memory cells. Throughout the lifetime of an animal, these memory cells 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 be in the form of either passive short-term memory or active longterm memory.
Passive memory

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection.
Several layers of passive protection are provided by the mother. During pregnancy, a particular
type of antibody, called IgG, is transported from mother to baby directly across the placenta, so
human babies have high levels of antibodies even at birth, with the same range of antigen
specificities as their mother.[63] Breast milk or colostrum also contains antibodies that are
transferred to the gut of the infant and protect against bacterial infections until the newborn can
synthesize its own antibodies.[64] This is passive immunity because the fetus does not actually
make any memory cells or antibodiesit 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.[65]

The time-course of an immune response begins with the initial pathogen encounter,
(or initial vaccination) and leads to the formation and maintenance of active
immunological memory.
Active memory and immunization

Long-term active memory is acquired following infection by activation of B and T cells. Active
immunity can also be generated artificially, through vaccination. The principle behind
vaccination (also called immunization) is to introduce an antigen from a pathogen in order to
stimulate the immune system and develop specific immunity against that particular pathogen
without causing disease associated with that organism.[13] 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.[34][66]
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.[13] 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 antigenpresenting cells of the innate immune system and maximize immunogenicity.[67]

Disorders of human immunity

The immune system is a remarkably effective structure that incorporates specificity, inducibility
and adaptation. Failures of host defense do occur, however, and fall into three broad categories:
immunodeficiencies, autoimmunity, and hypersensitivities.
Immunodeficiencies
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.[68][69] In developed countries, obesity, alcoholism, and drug use are
common causes of poor immune function.[69] However, malnutrition is the most common cause
of immunodeficiency in developing countries.[69] Diets lacking sufficient protein are associated
with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody
concentrations, and cytokine production. 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.[70]
Immunodeficiencies can also be inherited or 'acquired'.[13] 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.[71][72]
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.[73] 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.[59]
Autoimmune diseases arise from an abnormal immune response of the body against substances
and tissues normally present in the body (autoimmunity). This may be restricted to certain organs
(e.g. in autoimmune thyroiditis) or involve a particular tissue in different places (e.g.
Goodpasture's disease which may affect the basement membrane in both the lung and the
kidney).
The treatment of autoimmune diseases is typically with immunosuppressionmedication that
decreases the immune response.
A large number of autoimmune diseases are recognized. A major understanding of the underlying
pathophysiology of autoimmune diseases has been the application of genome wide association
scans that have identified a striking degree of genetic sharing among the autoimmune diseases.[1]

Definition
For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky's
postulates (first formulated by Ernst Witebsky and colleagues in 1957 and modified in 1994):[2][3]

Direct evidence from transfer of disease-causing antibody or disease-causing

T lymphocyte white blood cells

Indirect evidence based on reproduction of the autoimmune disease in

experimental animals

Circumstantial evidence from clinical clues

Genetic evidence suggesting "clustering" with other autoimmune diseases

Effects
Autoimmune diseases have a wide variety of different effects. They do tend to have one of three
characteristic pathological effects which characterize them as autoimmune diseases:[4]
1. Damage to or destruction of tissues
2. Altered organ growth
3. Altered organ function

It has been estimated that autoimmune diseases are among the leading causes of death among
women in the United States in all age groups up to 65 years.[5]
A substantial minority of the population suffers from these diseases, which are often chronic,
debilitating, and life-threatening.[citation needed]
There are more than 80 illnesses caused by autoimmunity.[6]

Pathophysiology
There are many theories as to how an autoimmune disease state arises. Some common ones are
listed below.
Cryptic determinants/molecular sequestration

Although it is possible for a potential auto antigen to be geographically sequestered in an

immune privileged site within the body (e.g. the eye), mechanisms exist to express even these
antigens in a tolerogenic fashion to the immune system. However, it is impossible to induce
tolerance (immune unresponsiveness) to all aspects of an autoantigen. This is because under
normal physiologic conditions some regions of a self-antigen are not expressed at a sufficient
level to induce tolerance. These poorly displayed areas of an antigen are called "cryptic
determinants." The immune system maintains a high-affinity repertoire to the cryptic self
because the presentation of these determinants was insufficient to induce strong tolerance.[7]

Molecular mimicry

The concept of molecular mimicry describes a situation in which a foreign antigen can initiate an
immune response in which a T or B cell component cross-recognizes self. The cross reactive
immune response is responsible for the autoimmune disease state.[8] Cross-reactive immune
responses to self were first described for antibodies.
Altered glycan theory

According to this theory the effector function of the immune response is mediated by the glycans
(polysaccharides) displayed by the cells and humoral components of the immune system.
Individuals with autoimmunity have alterations in their glycosylation profile such that a
proinflammatory immune response is favored. It is further hypothesized that individual
autoimmune diseases will have unique glycan signatures.[9]

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, which triggers degranulation of mast cells and basophils
when cross-linked by antigen.[74] Type II hypersensitivity occurs when antibodies bind to
antigens on the patient's own cells, marking them for destruction. This is also called antibodydependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.[74]
Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM
antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.[74] 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.[74]
Hypersensitivity (also called hypersensitivity reaction or intolerance) is a set of undesirable
reactions produced by the normal immune system, including allergies and autoimmunity. These
reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions
require a pre-sensitized (immune) state of the host. They are classified in four groups after the
proposal of P. G. H. Gell and Robin Coombs in 1963.[1]

Coombs and Gell classification

Comparison of hypersensitivity types

Typ
e

Alternative
names

Allergy
(immediate)

Often mentioned
disorders

Atopy

Anaphylaxis

Asthma

Mediators

IgE

Description
Fast response
which occurs
in minutes,
rather than
multiple hours
or days. Free
antigens cross
link the IgE on
mast cells
and basophils
which causes
a release of
vasoactive
biomolecules.

Testing can be
done via skin
test for specific
IgE.[2]
II Cytotoxic,
antibodydependent

Autoimmune
hemolytic anemia
Rheumatic heart
disease

Thrombocytopenia

Erythroblastosis
fetalis

Goodpasture's
syndrome

Graves' disease
*see type V
explanation below

Myasthenia gravis
*see type V
explanation below

Antibody (IgM
IgM or IgG
or IgG) binds
to antigen on
(Complement) a target cell,
which is
MAC
actually a
host cell that
is perceived
by the
immune
system as
foreign,
leading to
cellular
destruction
via the MAC.

Testing includes
both the direct
and indirect

Coombs test.[3]

III

Immune
complex disease

IV Delayed-type
hypersensitivity,
[2][3]
cellmediated
immune
memory
response,
antibodyindependent

Serum sickness

Arthus reaction

Rheumatoid
arthritis

Post streptococcal
glomerulonephritis

Membranous
nephropathy

Lupus nephritis

Systemic lupus
erythematosus

Extrinsic allergic
alveolitis
(hypersensitivity
pneumonitis)

Contact dermatitis,
including Urushiolinduced contact
dermatitis (poison
ivy rash).

Mantoux test

Chronic transplant
rejection

Multiple sclerosis[5]

Antibody
(IgG) binds to
soluble
antigen,
forming a
circulating
immune
IgG
complex. This
is often
(Complement) deposited in
the vessel
Neutrophils
walls of the
joints and
kidney,
initiating a
local
inflammatory
reaction.[4]

T-cells

Helper T cells
(specifically
Th1 helper t
cells) are
activated by
an antigen
presenting
cell. When the
antigen is
presented
again in the
future, the
memory Th1
cells will
activate
macrophages
and cause an
inflammatory
response. This
ultimately can

lead to tissue
damage. [6]
Autoimmune
disease,
V receptor
mediated (see
below)

Graves' disease

IgM or IgG

Myasthenia gravis

(Complement)

Type V

This is an additional type that is sometimes (often in the UK) used as a distinction from Type 2.[7]
Instead of binding to cell surface s, the antibodies recognise and bind to the cell surface
receptors, which either prevents the intended ligand binding with the receptor or mimics the
effects of the ligand, thus impairing cell signaling.[citation needed]
Some clinical examples:

Graves' disease

Myasthenia gravis

The use of Type 5 is rare. These conditions are more frequently classified as Type 2, though
sometimes they are specifically segregated into their own subcategory of Type 2.[citation needed]

Other mechanisms and evolution

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 structurally most simple forms of life, with
bacteria using a unique defense mechanism, called the restriction modification system to protect
themselves from viral pathogens, called bacteriophages.[75] 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.[76][77] Offensive elements of the immune systems
are also present in unicellular eukaryotes, but studies of their roles in defense are few.[78]

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.[79]
Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic
chemical signals that are sent through a plant.[80] Individual plant cells respond to molecules
associated with pathogens known as Pathogen-associated molecular patterns or PAMPs.[81] 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.[80] RNA
silencing mechanisms are particularly important in this systemic response as they can block virus
replication.[82]

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) inject toxins that kill the
tumor cell. Immunotherapy for the treatment of cancer is an active area of medical
research.[83]

Another important role of the immune system is to identify and eliminate tumors. This is called
immune surveillance. 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;[84] some are derived from oncogenic viruses like human papillomavirus, which
causes cervical cancer,[85] 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.[86][87] 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.[84][88][89]
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.[87][90] 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.[91] 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.[92] Sometimes antibodies are generated against tumor cells allowing
for their destruction by the complement system.[88]
Clearly, some tumors evade the immune system and go on to become cancers.[93] Tumor cells
often have a reduced number of MHC class I molecules on their surface, thus avoiding detection
by killer T cells.[91] 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.[94] In addition, immunological tolerance may develop against tumor antigens, so the
immune system no longer attacks the tumor cells.[93]
Paradoxically, macrophages can promote tumor growth [95] when tumor cells send out cytokines
that attract macrophages, which then generate cytokines and growth factors that nurture tumor
development. In addition, a combination of hypoxia in the tumor and a cytokine produced by
macrophages induces tumor cells to decrease production of a protein that blocks metastasis and
thereby assists spread of cancer cells.

Physiological regulation
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For
example, female sex hormones are known immunostimulators of both adaptive[96] and innate
immune responses.[97] 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.[98] Other hormones appear to regulate the immune
system as well, most notably prolactin, growth hormone and vitamin D.[99][100]
When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially
a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid
hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell
extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin
D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for
converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version,

calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other
immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol,
are dendritic cells, keratinocytes and macrophages.[101][102]
It is conjectured that a progressive decline in hormone levels with age is partially responsible for
weakened immune responses in aging individuals.[103] Conversely, some hormones are regulated
by the immune system, notably thyroid hormone activity.[104] The age-related decline in immune
function is also related to decreasing vitamin D levels in the elderly. As people age, two things
happen that negatively affect their vitamin D levels. First, they stay indoors more due to
decreased activity levels. This means that they get less sun and therefore produce less
cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at
producing vitamin D.[105]
Sleep and Rest

The immune system is affected by sleep and rest,[106] and sleep deprivation is detrimental to
immune function.[107] Complex feedback loops involving cytokines, such as interleukin-1 and
tumor necrosis factor- produced in response to infection, appear to also play a role in the
regulation of non-rapid eye movement (REM) sleep.[108] Thus the immune response to infection
may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to
REM sleep.[109]
When suffering from sleep deprivation, active immunizations may have a diminished effect and
may result in lower antibody production, and a lower immune response, than would be noted in a
well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be
closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected
through the disturbance of natural light and dark cycles through instances of sleep deprivation,
shift work, etc. As a result, these disruptions can lead to an increase in chronic conditions such as
heart disease, chronic pain, and asthma.[110]
In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian
system have been shown to have strong regulatory effects on immunological functions affecting
both the innate and the adaptive immunity. First, during the early slow-wave-sleep stage, a
sudden drop in blood levels of cortisol, epinephrine, and norepinephrine induce increased blood
levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a
pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1,
interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions
such as immune cells activation, proliferation, and differentiation. It is during this time that
undifferentiated, or less differentiated, like nave and central memory T cells, peak (i.e. during a
time of a slowly evolving adaptive immune response). In addition to these effects, the milieu of
hormones produced at this time (leptin, pituitary growth hormone, and prolactin) support the
interactions between APCs and T-cells, a shift of the Th1/Th2 cytokine balance towards one that

supports Th1, an increase in overall Th cell proliferation, and nave T cell migration to lymph
nodes. This milieu is also thought to support the formation of long-lasting immune memory
through the initiation of Th1 immune responses.[111]
In contrast, during wake periods differentiated effector cells, such as cytotoxic natural killer cells
and CTLs (cytotoxic T lymphocytes), peak in order to elicit an effective response against any
intruding pathogens. As well during awake active times, anti-inflammatory molecules, such as
cortisol and catecholamines, peak. There are two theories as to why the pro-inflammatory state is
reserved for sleep time. First, inflammation would cause serious cognitive and physical
impairments if it were to occur during wake times. Second, inflammation may occur during sleep
times due to the presence of melatonin. Inflammation causes a great deal of oxidative stress and
the presence of melatonin during sleep times could actively counteract free radical production
during this time.[111][112]
Nutrition and diet

Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect
immune function. More moderate malnutrition, as well as certain specific trace mineral and
nutrient deficiencies, can also compromise the immune response.[113]
Foods rich in certain fatty acids may foster a healthy immune system.[114] Likewise, fetal
undernourishment can cause a lifelong impairment of the immune system.[115]

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) or cancer.
Immunosuppression

Immunosuppressive drugs are used to control autoimmune disorders or inflammation when

excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.[34]
[116]

Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids
are the most powerful of these drugs; however, these drugs can have many undesirable side
effects, such as central obesity, hyperglycemia, osteoporosis, and their use must be tightly
controlled.[117] 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.[116] Immunosuppressive drugs such as cyclosporin prevent T cells from
responding to signals correctly by inhibiting signal transduction pathways.[118]
Immunostimulation
Main articles: Immunotherapy and Vaccination

Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer
tumours.

Theoretical approaches to the immune system

Immunology is strongly experimental in everyday practice but is also characterized by an
ongoing theoretical attitude. Many theories have been suggested in immunology from the end of
the nineteenth century up to the present time. The end of the 19th century and the beginning 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, phagocytes 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 organisms
humors rather than its cells.[119][120][121]
In the mid-1950s, Frank Burnet, inspired by a suggestion made by Niels Jerne,[122] formulated the
clonal selection theory (CST) of immunity.[123] On the basis of CST, Burnet developed a theory of
how an immune response is triggered according to the self/nonself distinction: "self" constituents
(constituents of the body) do not trigger destructive immune responses, while "nonself" entities
(pathogens, an allograft) trigger a destructive immune response.[124] The theory was later
modified to reflect new discoveries regarding histocompatibility or the complex "two-signal"
activation of T cells.[125] The self/nonself theory of immunity and the self/nonself vocabulary
have been criticized,[121][126][127] but remain very influential.[128][129]
More recently, several theoretical frameworks have been suggested in immunology, including
"autopoietic" views,[130] "cognitive immune" views,[131] the "danger model" (or "danger theory",
[126]
and the "discontinuity" theory.[132][133] The danger model, suggested by Polly Matzinger and
colleagues, has been very influential, arousing many comments and discussions.[134][135][136][137]

Predicting immunogenicity
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;
[138]
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.[139] A publicly
accessible database has been established for the cataloguing of epitopes from pathogens known
to be recognizable by B cells.[140] The emerging field of bioinformatics-based studies of
immunogenicity is referred to as immunoinformatics.[141] Immunoproteomics is the study of large
sets of proteins (proteomics) involved in the immune response.

Manipulation by pathogens
The success of any pathogen depends on its ability to elude host immune responses. Therefore,
pathogens evolved several methods that allow them to successfully infect a host, while evading
detection or destruction by the immune system.[142] Bacteria often overcome physical barriers by
secreting enzymes that digest the barrier, for example, by using a type II secretion system.[143]
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.[144]
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.[145] Many
pathogens secrete compounds that diminish or misdirect the host's immune response.[142] 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.[146] 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).[147]

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.[148] 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.[149] Masking antigens with host molecules is another
common strategy for avoiding detection by the immune system. In HIV, the envelope that covers
the virion 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.[150]

See also