The
immune system is a system of 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.
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][3] 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[edit]
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.
[4] 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.
[5] 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.
[6] 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.
[7] Viruses were confirmed as human pathogens in 1901, with the discovery of the
yellow fever virus by
Walter Reed.
[8]
Immunology made a great advance towards the end of the 19th century, through rapid developments, in the study of
humoral immunity and
cellular immunity.
[9] 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.
[10]
Layered defense[edit]
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.
[11] 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.
[12]
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.
[13] 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.
[14]
Innate immune system[edit]
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,
[15] 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.
[16] Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way.
[14] 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.
[11]
Surface barriers[edit]
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.
[14] 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.
[17]
Chemical barriers also protect against infection. The skin and respiratory tract secrete
antimicrobial peptides such as the β-
defensins.
[18] Enzymes such as
lysozyme and
phospholipase A2 in
saliva, tears, and
breast milk are also
antibacterials.
[19][20] Vaginal secretions serve as a chemical barrier following
menarche, when they become slightly
acidic, while
semen contains defensins and
zinc to kill pathogens.
[21][22] 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.
[23] This reduces the probability that pathogens will 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).
[24] There is good evidence that re-introduction of
probiotic flora, such as pure cultures of the
lactobacilli normally found in unpasteurized
yogurt, helps restore a 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.
[25][26][27]
Inflammation[edit]
Inflammation is one of the first responses of the immune system to infection.
[28] 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).
[29][30] 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.
[31] 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.
[32]
Complement system[edit]
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.
[33][34] Many species have complement systems, including non-
mammals like plants, fish, and some
invertebrates.
[35]
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.
[36] 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.
[37] 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.
[33]
Cellular barriers[edit]
Leukocytes (
white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.
[14] 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.
[35] Innate cells are also important mediators in the activation of the
adaptive immune system.
[12]
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.
[14] 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.
[38][39] Phagocytosis evolved as a means of acquiring
nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.
[40] Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.
[41]
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.
[42] 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.
[43] 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.
[44] 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.
[12]
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.
[45] 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.
[45]
Mast cells reside in
connective tissues and
mucous membranes, and regulate the inflammatory response.
[46] They are most often associated with
allergy and
anaphylaxis.
[43] 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.
[47] Natural killer (
NK cells) cells are leukocytes that attack and destroy
tumor cells, or cells that have been infected by viruses.
[48]
Natural killer cells[edit]
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.
[35] 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.
[49]
Adaptive immune system[edit]
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.
[50] 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[edit]
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.
[35] 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. 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.
[51]
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.
[35]
Killer T cells[edit]
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.
[52] 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.
[53] 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).
[53]
Helper T cells[edit]
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.
[54][55] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.
Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's
CD4 co-receptor, which recruits molecules inside the T cell (e.g.,
Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.
[56] 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.
[14] 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.
[57]
Gamma delta T cells[edit]
Gamma delta 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.
[58] 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 respond to stressed epithelial cells.
[51]
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.
[59]
B lymphocytes and antibodies[edit]
A
B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.
[60] 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.
[61] 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.
[62]
Alternative adaptive immune system[edit]
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.
[63]
Immunological memory[edit]
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 long-term memory.
Passive memory[edit]
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.
[64] 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.
[65] 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.
[66]
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[edit]
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.
[14] 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.
[35][67]
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.
[14] 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.
[68]
Disorders of human immunity[edit]
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[edit]
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.
[69][70] In
developed countries,
obesity,
alcoholism, and drug use are common causes of poor immune function.
[70] However,
malnutrition is the most common cause of immunodeficiency in
developing countries.
[70] 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.
[71]
Immunodeficiencies can also be inherited or '
acquired'.
[14] 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.
[72][73]
Autoimmunity[edit]
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.
[74] 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.
[60]
Hypersensitivity[edit]
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.
[75] 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.
[75] Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.
[75] 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.
[75]
Other mechanisms[edit]
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.
[76] 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.
[77][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[edit]
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. 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-β, 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[edit]
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[edit]
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-α 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 lowered immune response, then 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, which 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 naïve 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 T
h1, an increase in overall T
h cell proliferation, and naïve 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, 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.
[112][113]
Nutrition and diet[edit]
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.
[114][page needed]
Foods rich in certain
fatty acids may foster a healthy immune system.
[115] Likewise,
fetal undernourishment can cause a lifelong impairment of the immune system.
[116]
Manipulation in medicine[edit]
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.
[35][117]
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.
[118] 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.
[117] Immunosuppressive drugs such as
cyclosporin prevent T cells from responding to signals correctly by inhibiting
signal transduction pathways.
[119]
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;
[120] 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.
[121] A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.
[122] The emerging field of
bioinformatics-based studies of immunogenicity is referred to as
immunoinformatics.
[123] Immunoproteomics is the study of large sets of proteins (
proteomics) involved in the immune response.
Manipulation by pathogens[edit]
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.
[124] Bacteria often overcome physical barriers by secreting
enzymes that digest the barrier, for example, by using a
type II secretion system.
[125] 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.
[126]
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.
[127] Many pathogens secrete compounds that diminish or misdirect the host's immune response.
[124] 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.
[128] 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).
[129]
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.
[130] 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.
[131] 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.
[132]
See also[edit]
 | Wikimedia Commons has media related to Immunology. |
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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