IMMUNOLOGY

History of immunology

Immunology is a science that examines the structure and function of the immune system. It originates from medicine
and early studies on the causes of immunity to disease. The earliest known mention of immunity was during the
plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease
could nurse the sick without contracting the illness a second time.[114] This observation of acquired immunity was
later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease.[115]
Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not
until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were
confirmed as the cause of infectious disease.[116] Viruses were confirmed as human pathogens in 1901, with the
discovery of the yellow fever virus by Walter Reed.[117]

Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of
humoral immunity and cellular immunity.[118] Particularly important was the work of Paul Ehrlich, who proposed the
side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of
humoral immunity were recognized by the award of a Nobel Prize in 1908, which was jointly awarded to the
founder of cellular immunology, Elie Metchnikoff.[119]

Phagocytosis is the cellular process of Phagocytes and Protists of engulfing solid particles by the cell membrane to
form an internal phagosome, which is a food vacuole, or pteroid. Phagocytosis is a specific form of endocytosis
involving the vesicular internalization of solid particles, such as bacteria, and is therefore distinct from other forms
of endocytosis such as pinocytosis, the vesicular internalization of various liquids. Phagocytosis is involved in the
acquisition of nutrients for some cells, and in the immune system it is a major mechanism used to remove pathogens
and cell debris. Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be
phagocytosed.

The process is only homologous to eating at the level of single-celled organisms; in multicellular animals, the
process has been adapted to eliminate debris and pathogens, as opposed to taking in fuel for cellular processes,
except in the case of the Trichoplax.

Phagocytosis in mammalian immune cells is activated by attachment to Pathogen-associated molecular patterns

(PAMPS), which leads to NF-κB activation. Opsonins such as C3b and antibodies can act as attachment sites and aid
phagocytosis of pathogens.[1]

Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome of ingested material is
then fused with the lysosome, leading to degradation

Degradation can be oxygen-dependent or oxygen-independent.

 Oxygen-dependent degradation depends on NADPH and the production of reactive oxygen species.
Hydrogen peroxide and myeloperoxidase activate a halogenating system which leads to the destruction of
bacteria.
 Oxygen-independent degradation depends on the release of granules, containing proteolytic enzymes such
as defensins, lysozyme and cationic proteins. Other antimicrobial peptides are present in these granules,
including lactoferrin which sequesters iron to provide unfavourable growth conditions for bacteria.
It is possible for cells other than dedicated phagocytes (such as dendritic cells) to engage in phagocytosis.[2]

In Apoptosis

Following apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages in a process
called Efferocytosis. One of the features of an apoptotic cell is the presentation of a variety of intracellular
molecules on the cell surface, such as Calreticulin, Phosphatidylserine (From the inner layer of the plasma
membrane), Annexin A1 and oxidised LDL. These molecules are recognised by receptors on the cell surface of the
macrophage such as the Phosphatidylserine Receptor, or by soluble (free floating) receptors such as
Thrombospondin 1, which then themselves bind to other receptors on the macrophage such as CD36 and Alpha-V
Beta-3 Integrin.

In protists

Trophozoites of Entamoeba histolytica with ingested erythrocytes

In many protists, phagocytosis is used as a means of feeding, providing part or all of their nourishment. This is
called phagotrophic nutrition, as distinguished from osmotrophic nutrition, which takes place by absorption.

 In some, such as amoeba, phagocytosis takes place by surrounding the target object with pseudopods, as in
animal phagocytes. In humans, Entamoeba histolytica can phagocytose red blood cells.[3] This process is
known as "erythrophagocystosis", and is considered the only reliable way to distinguish Entamoeba
histolytica from noninvasive species such as Entamoeba dispar.[4]

 Ciliates also engage in phagocytosis.[5] In ciliates there is a specialized groove or chamber in the cell where
phagocytosis takes place, called the cytostome or mouth.

The resulting phagosome may be merged with lysosomes containing digestive enzymes, forming a phagolysosome.
The food particles will then be digested, and the released nutrients are diffused or transported into the cytosol for use
in other metabolic processes.

Mixotrophy can involve phagotrophic nutrition and phototrophic nutrition.[6]

External links

An immune system is a collection of biological processes within an organism that protects against disease by
identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic
worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function
properly. Detection is complicated as pathogens can evolve rapidly, producing adaptations that avoid the immune
system and allow the pathogens to successfully infect their hosts.

To survive this challenge, multiple mechanisms evolved that recognize and neutralize pathogens. Even simple
unicellular organisms such as bacteria possess enzyme systems that protect against viral infections. Other basic
immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants, fish,
reptiles, and insects. These mechanisms include antimicrobial peptides called defensins, phagocytosis, and the
complement system. Vertebrates such as humans have even more sophisticated defense mechanisms.[1] The immune
systems of vertebrates consist of many types of proteins, cells, organs, and tissues, which interact in an elaborate and
dynamic network. As part of this more complex immune response, the human immune system adapts over time to
recognise specific pathogens more efficiently. This adaptation process is referred to as "adaptive immunity" or
"acquired immunity" and creates immunological memory. Immunological memory created from a primary response
to a specific pathogen, provides an enhanced response to secondary encounters with that same, specific pathogen.
This process of acquired immunity is the basis of vaccination.

Disorders in the immune system can result in disease. Immunodeficiency diseases occur when the immune system is
less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the
result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an
infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In
contrast, autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were
foreign organisms. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus type 1 and lupus
erythematosus. Immunology covers the study of all aspects of the immune system which has significant relevance to
human health and diseases. Further investigation in this field is expected to play a serious role in promotion of
health and treatment of diseases.

Layered defense

The immune system protects organisms from infection with layered defenses of increasing specificity. Most simply,
physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches
these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems
are found in all plants and animals.[2] However, if pathogens successfully evade the innate response, vertebrates
possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the
immune system adapts its response during an infection to improve its recognition of the pathogen. This improved
response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and
allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. [3]

Components of the immune system

Innate immune system Adaptive immune system

Response is non-specific Pathogen and antigen specific response

 Exposure leads to immediate maximal response Lag time between exposure and maximal response

Cell-mediated and humoral components Cell-mediated and humoral components

No immunological memory Exposure leads to immunological memory

Found in nearly all forms of life Found only in jawed vertebrates

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-
self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished
from foreign substances by the immune system.[4] Conversely, non-self molecules are those recognized as foreign
molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as
substances that bind to specific immune receptors and elicit an immune response.[5]

Surface barriers

Several barriers protect organisms from infection, including mechanical, chemical and biological barriers. The waxy
cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin
are examples of the mechanical barriers that are the first line of defense against infection.[5] However, as organisms
cannot be completely sealed against their environments, other systems act to protect body openings such as the
lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and
other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens,
while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.[6]

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as
the β-defensins.[7] Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also
antibacterials.[8][9] Vaginal secretions serve as a chemical barrier following menarche, when they become slightly
acidic, while semen contains defensins and zinc to kill pathogens.[10][11] In the stomach, gastric acid and proteases
serve as powerful chemical defenses against ingested pathogens.

Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with
pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as
pH or available iron.[12] This reduces the probability that pathogens will be able to reach sufficient numbers to cause
illness. However, since most antibiotics non-specifically target bacteria and do not affect fungi, oral antibiotics can
lead to an “overgrowth” of fungi and cause conditions such as a vaginal candidiasis (a yeast infection).[13] There is
good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in
unpasteurized yoghurt, helps restore a healthy balance of microbial populations in intestinal infections in children
and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases, urinary tract
infection and post-surgical infections.[14][15][16]

Innate

Microorganisms or toxins that successfully enter an organism will encounter the cells and mechanisms of the innate
immune system. The innate response is usually triggered when microbes are identified by pattern recognition
receptors, which recognize components that are conserved among broad groups of microorganisms, [17] or when
damaged, injured or stressed cells send out alarm signals, many of which (but not all) are recognized by the same
receptors as those that recognize pathogens.[18] Innate immune defenses are non-specific, meaning these systems
respond to pathogens in a generic way.[5] This system does not confer long-lasting immunity against a pathogen. The
innate immune system is the dominant system of host defense in most organisms. [2]

Humoral and chemical barriers

Inflammation

Inflammation is one of the first responses of the immune system to infection.[19] The symptoms of inflammation are
redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by
eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that
produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain
white blood cells (leukocytes).[20][21] Common cytokines include interleukins that are responsible for communication
between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as
shutting down protein synthesis in the host cell.[22] Growth factors and cytotoxic factors may also be released. These
cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged
tissue following the removal of pathogens. [23]

Complement system

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20
different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement
is the major humoral component of the innate immune response.[24][25] Many species have complement systems,
including non-mammals like plants, fish, and some invertebrates.[26]

In humans, this response is activated by complement binding to antibodies that have attached to these microbes or
the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a
rapid killing response.[27] The speed of the response is a result of signal amplification that occurs following
sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins
initially bind to the microbe, they activate their protease activity, which in turn activates other complement
proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive
feedback.[28] The cascade results in the production of peptides that attract immune cells, increase vascular
permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of
complement can also kill cells directly by disrupting their plasma membrane.[24]

Cellular barriers
A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several
knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate
immune system.[5] The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells),
mast cells, eosinophils, basophils, and natural killer cells. These cells identify and eliminate pathogens, either by
attacking larger pathogens through contact or by engulfing and then killing microorganisms.[26] Innate cells are also
important mediators in the activation of the adaptive immune system.[3]

Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf,
or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to
specific locations by cytokines.[5] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an
intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a
phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that
releases free radicals into the phagolysosome.[29][30] Phagocytosis evolved as a means of acquiring nutrients, but this
role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.[31] Phagocytosis
probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and
invertebrate animals.[32]

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. [33]
Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally
representing 50% to 60% of the total circulating leukocytes. [34] During the acute phase of inflammation, particularly
as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis,
and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within
tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such
as interleukin 1.[35] Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as
antigen-presenting cells that activate the adaptive immune system.[3]

Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are
located mainly in the skin, nose, lungs, stomach, and intestines.[36] They are named for their resemblance to neuronal
dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous
system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as
they present antigen to T cells, one of the key cell types of the adaptive immune system.[36]

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.[37] They are
most often associated with allergy and anaphylaxis.[34] Basophils and eosinophils are related to neutrophils. They
secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such
as asthma.[38] Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been
infected by viruses.[39]

Adaptive

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as
immunological memory, where each pathogen is "remembered" by a signature antigen. [40] The adaptive immune
response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called
antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific
pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by
"memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly
eliminate it.

Lymphocytes

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are
the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.[26] B cells are
involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.

Association of a T cell with MHC class I or MHC class II, and antigen (in red)

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a “non-self”
target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented
in combination with a “self” receptor called a major histocompatibility complex (MHC) molecule. There are two
major subtypes of T cells: the killer T cell and the helper T cell. Killer T cells only recognize antigens coupled to
Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These
two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype
are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. [41]

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole
pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the
complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.

[26]
Killer T cells

Killer T cells directly attack other cells carrying foreign or abnormal antigens on their surfaces. [42]

Killer T cell are a sub-group of T cells that kill cells infected with viruses (and other pathogens), or are otherwise
damaged or dysfunctional.[43] As with B cells, each type of T cell recognises a different antigen. Killer T cells are
activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor
of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T
cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an
activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's
plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease)
induces the target cell to undergo apoptosis.[44] T cell killing of host cells is particularly important in preventing the
replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen
activation signal, or additional activation signals provided by "helper" T cells (see below).[44]

Helper T cells

Function of T helper cells: Antigen presenting cells (APCs) present antigen on their Class II MHC molecules
(MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The
activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that
stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B
cells and macrophages succeeds a proliferation of T helper cells.

Helper T cells regulate both the innate and adaptive immune responses and help determine which types of immune
responses the body will make to a particular pathogen. [45][46] These cells have no cytotoxic activity and do not kill
infected cells or clear pathogens directly. They instead control the immune response by directing other cells to
perform these tasks.

Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The
MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T
cell (e.g. Lck) that are responsible for T cell's activation. Helper T cells have a weaker association with the
MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T
cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by
engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement
with an antigen-presenting cell.[47] The activation of a resting helper T cell causes it to release cytokines that
influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal
function of macrophages and the activity of killer T cells.[5] In addition, helper T cell activation causes an
upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which
provide extra stimulatory signals typically required to activate antibody-producing B cells. [48]

γδ T cells

γδ T cells possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the
characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T
cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-
restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity.[49] On one
hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity
and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune
system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers
of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted
Vδ1+ T cells in epithelia will respond to stressed epithelial cells.[50]
An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to
recognize its matching antigen. [42]

B lymphocytes and antibodies

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. [51] This
antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then
displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen
attracts a matching helper T cell, which releases lymphokines and activates the B cell.[52] As the activated B cell then
begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen.
These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for
destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize
challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to
infect cells.[53]

Alternative adaptive immune system

Although the classical molecules of the adaptive immune system (e.g. antibodies and T cell receptors) exist only in
jawed vertebrates, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates,
such as the lamprey and hagfish. These animals possess a large array of molecules called variable lymphocyte
receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one
or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with
the same degree of specificity.[54]

Immunological memory

When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived
memory cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen
encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs
during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system
for future challenges. Immunological memory can either be in the form of passive short-term memory or active
long-term memory.

Passive memory

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of
passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is
transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at
birth, with the same range of antigen specificities as their mother.[55] Breast milk also contains antibodies that are
transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own
antibodies.[56] This is passive immunity because the fetus does not actually make any memory cells or antibodies--it
only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In
medicine, protective passive immunity can also be transferred artificially from one individual to another via
antibody-rich serum.[57]

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

Active memory and immunization

Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also
be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to
introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity
against that particular pathogen without causing disease associated with that organism. [5] This deliberate induction of
an immune response is successful because it exploits the natural specificity of the immune system, as well as its
inducibility. With infectious disease remaining one of the leading causes of death in the human population,
vaccination represents the most effective manipulation of the immune system mankind has developed. [58][26]

Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular
components of micro-organisms, including harmless toxin components.[5] Since many antigens derived from
acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional
adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.[59]

Disorders of human immunity

The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation.
Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity,
and hypersensitivities.

Immunodeficiencies

Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of
the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses
beginning to decline at around 50 years of age due to immunosenescence.[60][61] In developed countries, obesity,
alcoholism, and drug use are common causes of poor immune function.[61] However, malnutrition is the most
common cause of immunodeficiency in developing countries.[61] Diets lacking sufficient protein are associated with
impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and
cytokine production. Deficiency of single nutrients such as iron; copper; zinc; selenium; vitamins A, C, E, and B6;
and folic acid (vitamin B9) also reduces immune responses.[61] Additionally, the loss of the thymus at an early age
through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to
infection.[62]

Immunodeficiencies can also be inherited or 'acquired'.[5] Chronic granulomatous disease, where phagocytes have a
reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and
some types of cancer cause acquired immunodeficiency.[63][64]

Autoimmunity

Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune
disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the
body. Under normal circumstances, many T cells and antibodies react with “self” peptides. [65] One of the functions of
specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens
produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.[51]

Hypersensitivity

Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes
(Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I
hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from
mild discomfort to death. Type I hypersensitivity is mediated by IgE released from mast cells and basophils.[66] Type
II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction.
This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.[66]
Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in
various tissues trigger Type III hypersensitivity reactions. [66] Type IV hypersensitivity (also known as cell-mediated
or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are
involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These
reactions are mediated by T cells, monocytes, and macrophages.[66]

Other mechanisms

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not
generate lymphocytes or an antibody-based humoral response.[1] Many species, however, utilize mechanisms that
appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the most
structurally-simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification
system to protect themselves from viral pathogens, called bacteriophages.[67] Prokaryotes also possess acquired
immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have
come into contact with in the past, which allows them to block virus replication through a form of RNA interference.
[68][69]

Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with
pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune
response found in all animals and plants, and represent the main form of invertebrate systemic immunity.[1] The
complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the
RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune
response to viruses.[70]

Unlike animals, plants lack phagocytic cells, and most plant immune responses involve systemic chemical signals
that are sent through a plant.[71] When a part of a plant becomes infected, the plant produces a localized
hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the
disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants
that renders the entire plant resistant to a particular infectious agent.[71] RNA silencing mechanisms are particularly
important in this systemic response as they can block virus replication. [72]

Tumor immunology

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the
macrophages (smaller white cells) will inject toxins that kill the tumor cell. Immunotherapy for the treatment of
cancer is an active area of medical research.[73]

Another important role of the immune system is to identify and eliminate tumors. The transformed cells of tumors
express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their
presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several
sources;[74] some are derived from oncogenic viruses like human papillomavirus, which causes cervical cancer,[75]
while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor
cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells
(e.g. melanocytes) into tumors called melanomas.[76][77] A third possible source of tumor antigens are proteins
normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules
called oncogenes.[74][78][79]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes
with the assistance of helper T cells.[77][80] Tumor antigens are presented on MHC class I molecules in a similar way
to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. [81] NK cells also kill tumorous
cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal;
this is a common phenomenon with tumors.[82] Sometimes antibodies are generated against tumor cells allowing for
their destruction by the complement system.[78]

Clearly, some tumors evade the immune system and go on to become cancers. [83] Tumor cells often have a reduced
number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. [81] Some tumor cells
also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which
suppresses the activity of macrophages and lymphocytes.[84] In addition, immunological tolerance may develop
against tumor antigens, so the immune system no longer attacks the tumor cells. [83]

Paradoxically, macrophages can promote tumor growth [85] when tumor cells send out cytokines that attract
macrophages which then generate cytokines and growth factors that nurture tumor development. In addition, a
combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease
production of a protein that blocks metastasis and thereby assists spread of cancer cells.

Physiological regulation

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex
hormones are known immunostimulators of both adaptive[86] and innate immune responses.[87] Some autoimmune
diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By
contrast, male sex hormones such as testosterone seem to be immunosuppressive.[88] Other hormones appear to
regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.[89][90] It is conjectured
that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in
aging individuals.[91] Conversely, some hormones are regulated by the immune system, notably thyroid hormone
activity.[92]

The immune system is enhanced by sleep and rest,[93] and is impaired by stress.[94]

Diet may affect the immune system; for example, fresh fruits, vegetables, and foods rich in certain fatty acids may
foster a healthy immune system. [95] Likewise, fetal undernourishment can cause a lifelong impairment of the immune
system.[96] In traditional medicine, some herbs are believed to stimulate the immune system, such as echinacea,
licorice, ginseng, astragalus, sage, garlic, elderberry, shiitake and lingzhi mushrooms, and hyssop, as well as honey.
Studies have suggested that such herbs can indeed stimulate the immune system, [97] although their mode of action is
complex and difficult to characterize.

Manipulation in medicine

The immunosuppressive drug dexamethasone

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and
transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system
(see immunization). Immunosuppressive drugs are used to control autoimmune disorders or inflammation when
excessive tissue damage occurs, and to prevent transplant rejection after an organ transplant.[26][98]

Anti-inflammatory drugs are often used to control the effects of inflammation. The glucocorticoids are the most
powerful of these drugs; however, these drugs can have many undesirable side effects (e.g., central obesity,
hyperglycemia, osteoporosis) and their use must be tightly controlled.[99] Therefore, lower doses of anti-
inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate
or azathioprine. Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells.
However, the killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes
toxic side effects.[98] Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals
correctly by inhibiting signal transduction pathways.[100]

Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered
repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are
typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with
an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to
predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic
antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based
drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented
in epitope regions than hydrophobic amino acids;[101] however, more recent developments rely on machine learning
techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.[102] A
publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be
recognizable by B cells.[103] The emerging field of bioinformatics-based studies of immunogenicity is referred to as
immunoinformatics.[104]

Manipulation by pathogens

The success of any pathogen is dependent on its ability to elude host immune responses. Therefore, pathogens have
developed several methods that allow them to successfully infect a host, while evading detection or destruction by
the immune system.[105] Bacteria often overcome physical barriers by secreting enzymes that digest the barrier — for
example, by using a type II secretion system.[106] Alternatively, using a type III secretion system, they may insert a
hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These
proteins are often used to shut down host defenses.[107]

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their
host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it
is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular
pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria
(Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis,
live inside a protective capsule that prevents lysis by complement.[108] Many pathogens secrete compounds that
diminish or misdirect the host's immune response.[105] Some bacteria form biofilms to protect themselves from the
cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic
Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.[109] Other
bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include
Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).[110]

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to
rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping
essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the
proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These
frequent changes in antigens may explain the failures of vaccines directed at this virus.[111] The parasite
Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it
to stay one step ahead of the antibody response.[112] Masking antigens with host molecules is another common
strategy for avoiding detection by the immune system. In HIV, the envelope that covers the viron is formed from the
outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify
them as "non-self" structures.[113]

The ancestral roots of B cells

In an October 2006 issue of Nature Immunology, certain B cells of primitive vertebrates (like fish and amphibians)
were shown to be capable of phagocytosis, a function usually associated with cells of the innate immune system.
The authors postulate that these phagocytic B-cells represent the ancestral history shared between macrophages and
lymphocytes. B-cells may have evolved from macrophage-like cells during the formation of the adaptive immune
system[9].

B cells in humans (and other vertebrates) are nevertheless able to endocytose antibody-fixed pathogens, and it is
through this route that MHC Class II presentation by B cells is possible, allowing Th2 help and stimulation of B cell
proliferation. This is purely for the benefit of MHC Class II presentation, not as a significant method of reducing the
pathogen load.

Origin of the word B cell

The abbreviation "B" in B cell originally came from Bursa of Fabricius, an organ in birds in which avian B cells
mature.[10] When it was discovered that in most mammals immature B cells are formed in bone marrow, the word B
cell continued to be used, although other blood cells also originate from pluripotent stem cells in the bone marrow.
The fact that bone and bursa both start with the letter 'B' is a coincidence.

B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-mediated
immune response, which is governed by T cells). The principal functions of B cells are to make antibodies against
antigens, perform the role of Antigen Presenting Cells (APCs) and eventually develop into memory B cells after
activation by antigen interaction. B cells are an essential component of the adaptive immune system.

Development of B cells

Immature B cells are produced in the bone marrow of most mammals. Rabbits are an exception; their B cells
develop in the appendix-sacculus rotundus. After reaching the IgM+ immature stage in the bone marrow, these
immature B cells migrate to the spleen, where they are called transitional B cells, and some of these cells
differentiate into mature B lymphocytes.[1]

B cell development occurs through several stages, each stage representing a change in the genome content at the
antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H) chains, and the genes
specifying them are found in the 'V' (Variable) region and the 'C' (Constant) region. In the heavy-chain 'V' region
there are three segments; V, D and J, which recombine randomly, in a process called VDJ recombination, to produce
a unique variable domain in the immunoglobulin of each individual B cell. Similar rearrangements occur for light-
chain 'V' region except there are only two segments involved; V and J. The list below describes the process of
immunoglobulin formation at the different stages of B cell development.

IL-7
Stage Heavy chain Light chain Ig CD19?
receptor?

Progenitor B
germline germline - No No
cells

Early Pro-B undergoes D-J

germline - No No
cells rearrangement

Late Pro-B undergoes V-DJ

germline - No Yes[2]
cells rearrangement

Large Pre-B
is VDJ rearranged germline IgM in cytoplasm Yes[3] Yes
cells
Small Pre-B undergoes V-J
is VDJ rearranged IgM in cytoplasm Yes Yes
cells rearrangement

Immature B
is VDJ rearranged VJ rearranged IgM on surface Yes Yes
cells

IgM and IgD on

Mature B cells is VDJ rearranged VJ rearranged Yes Yes
surface

When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis, here called
clonal deletion.[4] If it recognizes self-antigen during the maturation process, the B cell will become suppressed
(known as anergy) or undergo apoptosis (also termed negative selection). B cells are continuously produced in the
bone marrow. When B cell receptors on the surface of the cell matches the detected antigens present in the body; the
B cell proliferates and secretes a free form of those receptors (antibodies) with identical binding sites as the ones on
the original cell surface. After activation, the cell proliferates and B memory cells would form to recognise the same
antigen. This information would then be used as a part of the adaptive immune system for a more efficient and more
powerful immune response for all previously encountered antigens.

B cell membrane receptors evolve and change throughout the B cell life span. [5] TACI, BCMA and BAFF-R are
present on both immature B cells and mature B cells. All of these 3 receptors may be inhibited by Belimumab. CD20
is expressed on all stages of B cell development except the first and last; it is present from pre-pre B cells through
memory cells, but not on either pro-B cells or plasma cells. [6]

Functions

The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic
system performing the role of immune surveillance. They do not produce antibodies until they become fully
activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will
bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows
the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell
activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can
further differentiate into one of the two types of B cells listed below (plasma B cells and memory B cells). The B
cell may either become one of these cell types directly or it may undergo an intermediate differentiation step, the
germinal center reaction, where the B cell will hypermutate the variable region of its immunoglobulin gene
("somatic hypermutation") and possibly undergo class switching.

Clonality

B cells exist as clones. All B cells derive from a particular cell, and thus, the antibodies their differentiated progenies
(see below) produce can recognize and/or bind the same components (epitope) of a given antigen. Such clonality has
important consequences, as immunogenic memory relies on it. The great diversity in immune response comes about
because there are up to 109 clones with specificities for recognizing different antigens. A single B cell or a clone of
cells with shared specificity upon encountering its specific antigen divides to produce many B cells. Most of such B
cells differentiate into plasma cells that secrete antibodies into blood that bind the same epitope that elicited
proliferation in the first place. A small minority survives as memory cells that can recognize only the same epitope.
However, with each cycle, the number of surviving memory cells increases. The increase is accompanied by affinity
maturation which induces the survival of B cells that bind to the particular antigen with high affinity. This
subsequent amplification with improved specificity of immune response is known as secondary immune response. B
cells that encounter antigen for the first time are known as naive B cells.
B cell types

A plasma cell
 Plasma B cells (also known as plasma cells) are large B cells that have been exposed to antigen and are
producing and secreting large amounts of antibodies, which assist in the destruction of microbes by binding
to them and making them easier targets for phagocytes and activation of the complement system. They are
sometimes referred to as antibody factories. An electron micrograph of these cells reveals large amounts of
rough endoplasmic reticulum, responsible for synthesizing the antibody, in the cell's cytoplasm. These are
short lived cells and undergo apoptosis when the inciting agent that induced immune response is
eliminated. This occurs because of cessation of continuous exposure to various colony stimulating factors
required for survival.

 Memory B cells are formed from activated B cells that are specific to the antigen encountered during the
primary immune response. These cells are able to live for a long time, and can respond quickly following a
second exposure to the same antigen.

 B-1 cells express IgM in greater quantities than IgG and its receptors show polyspecificity, meaning that
they have low affinities for many different antigens, but have a preference for other immunoglobulins, self
antigens and common bacterial polysaccharides. B-1 cells are present in low numbers in the lymph nodes
and spleen and are instead found predominantly in the peritoneal and pleural cavities.[7][8]

 B-2 cells are the conventional B cells most texts refer to.[citation needed]

 Marginal-zone B cells

 Follicular B Cells

Recognition of antigen by B cells

Mechanism of action.
T-cell dependent b-cell activation, showing TH2-cell (left) B-cell (right) and several interaction molecules

A critical difference between B cells and T cells is how each lymphocyte recognizes its antigen. B cells recognize
their cognate antigen in its native form. They recognize free (soluble) antigen in the blood or lymph using their BCR
or membrane bound-immunoglobulin. In contrast, T cells recognize their cognate antigen in a processed form, as a
peptide fragment presented by an antigen presenting cell's MHC molecule to the T cell receptor.

Activation of B cells

B cell recognition of antigen is not the only element necessary for B cell activation (a combination of clonal
proliferation and terminal differentiation into plasma cells). B cells that have not been exposed to antigen, also
known as Naïve B cells, can be activated in a T-cell dependent or independent manner.

T-cell dependent activation

Once a pathogen is ingested by an antigen-presenting cell such as a macrophage or dendritic cell, the pathogen's
proteins are then digested to peptides and attached to a class II MHC protein. This complex is then moved to the
outside of the cell membrane. The macrophage is now activated to deliver multiple signals to a specific T cell that
recognises the peptide presented. The T cell is then stimulated to produce autocrines (Refer to Autocrine signalling),
resulting in the proliferation and differentiation to effector and memory T cells. Helper T cells (i.e CD4+ T cells)
then activates specific B cells through a phenomenon known as an Immunological synapse. Activated B cells
subsequently produce antibodies which assist in inhibiting pathogens until phagocytes (i.e macrophages,
neutrophils) or the complement system for example clears the host of the pathogen(s).

Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With a T-
dependent antigen, the first signal comes from antigen cross linking the B cell receptor (BCR) and the second signal
comes from co-stimulation provided by a T cell. T dependent antigens contain proteins that are presented on B cell
Class II MHC to a special subtype of T cell called a Th2 cell. When a B cell processes and presents the same antigen
to the primed Th cell, the T cell secretes cytokines that activate the B cell. These cytokines trigger B cell proliferation
and differentiation into plasma cells. Isotype switching to IgG, IgA, and IgE and memory cell generation occur in
response to T-dependent antigens. This isotype switching is known as Class Switch Recombination (CSR). Once this
switch has occurred, that particular B-cell can no longer make the earlier isotypes, IgM or IgD.

T cell independent activation

Many antigens are T cell independent in that they can deliver both of the signals to the B cell. Mice without a
thymus (nude or athymic mice that do not produce any T cells) can respond to T independent antigens. Many
bacteria have repeating carbohydrate epitopes that stimulate B cells, by cross-linking the IgM antigen receptors in
the B-cell,responding with IgM synthesis in the absence of T cell help. There are two types of T-cell independent
activation; Type 1 T cell-independent (polyclonal) activation, and type 2 T cell-independent activation (in which
macrophages present several of the same antigen in a way that causes cross-linking of antibodies on the surface of B
cells).