Immune system

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The immune system is a network of biological processes that protects an organism against disease. Immune system_sentence_0

It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Immune system_sentence_1

Many species have two major subsystems of the immune system. Immune system_sentence_2

The innate immune system provides a preconfigured response to broad groups of situations and stimuli. Immune system_sentence_3

The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Immune system_sentence_4

Both use molecules and cells to perform their functions. Immune system_sentence_5

Nearly all organisms have some kind of immune system. Immune system_sentence_6

Bacteria have a rudimentary immune system in the form of enzymes that protect against virus infections. Immune system_sentence_7

Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. Immune system_sentence_8

These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Immune system_sentence_9

Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt to recognize pathogens more efficiently. Immune system_sentence_10

Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. Immune system_sentence_11

This process of acquired immunity is the basis of vaccination. Immune system_sentence_12

Dysfunction of the immune system can cause autoimmune diseases, inflammatory diseases and cancer. Immune system_sentence_13

Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immune system_sentence_14

In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. Immune system_sentence_15

Autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Immune system_sentence_16

Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immune system_sentence_17

Immunology covers the study of all aspects of the immune system. Immune system_sentence_18

Layered defense Immune system_section_0

The immune system protects its host from infection with layered defenses of increasing specificity. Immune system_sentence_19

Physical barriers prevent pathogens such as bacteria and viruses from entering the organism. Immune system_sentence_20

If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Immune system_sentence_21

Innate immune systems are found in all animals. Immune system_sentence_22

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. Immune system_sentence_23

Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. Immune system_sentence_24

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. Immune system_sentence_25

Immune system_table_general_0

Components of the immune systemImmune system_table_caption_0
Innate immune systemImmune system_header_cell_0_0_0 Adaptive immune systemImmune system_header_cell_0_0_1
Response is non-specificImmune system_cell_0_1_0 Pathogen and antigen specific responseImmune system_cell_0_1_1
Exposure leads to immediate maximal responseImmune system_cell_0_2_0 Lag time between exposure and maximal responseImmune system_cell_0_2_1
Cell-mediated and humoral componentsImmune system_cell_0_3_0 Cell-mediated and humoral componentsImmune system_cell_0_3_1
No immunological memoryImmune system_cell_0_4_0 Exposure leads to immunological memoryImmune system_cell_0_4_1
Found in nearly all forms of lifeImmune system_cell_0_5_0 Found only in jawed vertebratesImmune system_cell_0_5_1

Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. Immune system_sentence_26

In immunology, self molecules are components of an organism's body that can be distinguished from foreign substances by the immune system. Immune system_sentence_27

Conversely, non-self molecules are those recognized as foreign molecules. Immune system_sentence_28

One class of non-self molecules are called antigens (originally named for being antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response. Immune system_sentence_29

Surface barriers Immune system_section_1

Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. Immune system_sentence_30

The waxy cuticle of most 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. Immune system_sentence_31

Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. Immune system_sentence_32

In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. Immune system_sentence_33

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. Immune system_sentence_34

Chemical barriers also protect against infection. Immune system_sentence_35

The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Immune system_sentence_36

Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Immune system_sentence_37

Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. Immune system_sentence_38

In the stomach, gastric acid serves as a chemical defense against ingested pathogens. Immune system_sentence_39

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, changing the conditions in their environment, such as pH or available iron. Immune system_sentence_40

As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced. Immune system_sentence_41

Innate immune system Immune system_section_2

Further information: Innate immune system Immune system_sentence_42

Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. Immune system_sentence_43

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, or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens. Immune system_sentence_44

Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. Immune system_sentence_45

This system does not confer long-lasting immunity against a pathogen. Immune system_sentence_46

The innate immune system is the dominant system of host defense in most organisms, and the only one in plants. Immune system_sentence_47

Immune sensing Immune system_section_3

Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens. Immune system_sentence_48

They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death. Immune system_sentence_49

Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs). Immune system_sentence_50

TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them a curved shape. Immune system_sentence_51

Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Immune system_sentence_52

Ten toll-like receptors have been described in humans. Immune system_sentence_53

Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Immune system_sentence_54

Three major classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors. Immune system_sentence_55

Innate immune cells Immune system_section_4

Some leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. Immune system_sentence_56

The innate leukocytes include the "professional" phagocytes (macrophages, neutrophils, and dendritic cells). Immune system_sentence_57

These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. Immune system_sentence_58

The other cells involved in the innate response include innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells. Immune system_sentence_59

Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Immune system_sentence_60

Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Immune system_sentence_61

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. Immune system_sentence_62

The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Immune system_sentence_63

Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Immune system_sentence_64

Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals. Immune system_sentence_65

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Immune system_sentence_66

Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes. Immune system_sentence_67

During the acute phase of inflammation, 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. Immune system_sentence_68

Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, complement proteins, and cytokines, while they can also act as scavengers that rid the body of worn-out cells and other debris, and as antigen-presenting cells (APC) that activate the adaptive immune system. Immune system_sentence_69

Dendritic cells 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. Immune system_sentence_70

They are named for their resemblance to neuronal dendrites, as both have many spine-like projections. Immune system_sentence_71

Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system. Immune system_sentence_72

Granulocytes are leukocytes that have granules in their cytoplasm. Immune system_sentence_73

In this category are neutrophils, mast cells, basophils, and eosinophils. Immune system_sentence_74

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. Immune system_sentence_75

They are most often associated with allergy and anaphylaxis. Immune system_sentence_76

Basophils and eosinophils are related to neutrophils. Immune system_sentence_77

They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma. Immune system_sentence_78

Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. Immune system_sentence_79

These cells are defined by absence of antigen specific B or T cell receptor (TCR) because of the lack of recombination activating gene. Immune system_sentence_80

ILCs do not express myeloid or dendritic cell markers. Immune system_sentence_81

Natural killer cells (NK) are lymphocytes and a component of the innate immune system which does not directly attack invading microbes. Immune system_sentence_82

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." Immune system_sentence_83

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. Immune system_sentence_84

Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Immune system_sentence_85

Those MHC antigens are recognized by killer cell immunoglobulin receptors which essentially put the brakes on NK cells. Immune system_sentence_86

Inflammation Immune system_section_5

Further information: Inflammation Immune system_sentence_87

Inflammation is one of the first responses of the immune system to infection. Immune system_sentence_88

The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Immune system_sentence_89

Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Immune system_sentence_90

Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Immune system_sentence_91

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. Immune system_sentence_92

Growth factors and cytotoxic factors may also be released. Immune system_sentence_93

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. Immune system_sentence_94

The pattern-recognition receptors called inflammasomes are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18. Immune system_sentence_95

Humoral defenses Immune system_section_6

The complement system is a biochemical cascade that attacks the surfaces of foreign cells. Immune system_sentence_96

It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Immune system_sentence_97

Complement is the major humoral component of the innate immune response. Immune system_sentence_98

Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. Immune system_sentence_99

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. Immune system_sentence_100

This recognition signal triggers a rapid killing response. Immune system_sentence_101

The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. Immune system_sentence_102

After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. Immune system_sentence_103

This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. Immune system_sentence_104

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. Immune system_sentence_105

This deposition of complement can also kill cells directly by disrupting their plasma membrane. Immune system_sentence_106

Adaptive immune system Immune system_section_7

Further information: Adaptive immune system Immune system_sentence_107

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. Immune system_sentence_108

The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Immune system_sentence_109

Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. Immune system_sentence_110

The ability to mount these tailored responses is maintained in the body by "memory cells". Immune system_sentence_111

Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. Immune system_sentence_112

Recognition of antigen Immune system_section_8

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. Immune system_sentence_113

B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. Immune system_sentence_114

B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Immune system_sentence_115

Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. Immune system_sentence_116

These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. Immune system_sentence_117

A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. Immune system_sentence_118

The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity. Immune system_sentence_119

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface and recognizes native (unprocessed) antigen without any need for antigen processing. Immune system_sentence_120

Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule. Immune system_sentence_121

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. Immune system_sentence_122

When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. Immune system_sentence_123

This is called clonal selection. Immune system_sentence_124

Antigen presentation to T lymphocytes Immune system_section_9

Both B cells and T cells carry receptor molecules that recognize specific targets. Immune system_sentence_125

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. Immune system_sentence_126

Cell mediated immunity Immune system_section_10

There are two major subtypes of T cells: the killer T cell and the helper T cell. Immune system_sentence_127

In addition there are regulatory T cells which have a role in modulating immune response. Immune system_sentence_128

Killer T cells Immune system_section_11

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. Immune system_sentence_129

As with B cells, each type of T cell recognizes a different antigen. Immune system_sentence_130

Killer T cells are activated when their T-cell receptor binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Immune system_sentence_131

Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. Immune system_sentence_132

The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. Immune system_sentence_133

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. Immune system_sentence_134

The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. Immune system_sentence_135

T cell killing of host cells is particularly important in preventing the replication of viruses. Immune system_sentence_136

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). Immune system_sentence_137

Helper T cells Immune system_section_12

Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen. Immune system_sentence_138

These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. Immune system_sentence_139

They instead control the immune response by directing other cells to perform these tasks. Immune system_sentence_140

Helper T cells express T cell receptors that recognize antigen bound to Class II MHC molecules. Immune system_sentence_141

The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (such as Lck) that are responsible for the T cell's activation. Immune system_sentence_142

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 to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Immune system_sentence_143

Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. Immune system_sentence_144

The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Immune system_sentence_145

Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. Immune system_sentence_146

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. Immune system_sentence_147

Gamma delta T cells Immune system_section_13

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. Immune system_sentence_148

The conditions that produce responses from γδ T cells are not fully understood. Immune system_sentence_149

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. Immune system_sentence_150

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. Immune system_sentence_151

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. Immune system_sentence_152

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. Immune system_sentence_153

Humoral immune response Immune system_section_14

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. Immune system_sentence_154

This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. Immune system_sentence_155

The B cell then displays these antigenic peptides on its surface MHC class II molecules. Immune system_sentence_156

This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. Immune system_sentence_157

As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. Immune system_sentence_158

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. Immune system_sentence_159

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. Immune system_sentence_160

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Immune system_sentence_161

Several layers of passive protection are provided by the mother. Immune system_sentence_162

During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Immune system_sentence_163

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. Immune system_sentence_164

This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. Immune system_sentence_165

This passive immunity is usually short-term, lasting from a few days up to several months. Immune system_sentence_166

In medicine, protective passive immunity can also be transferred artificially from one individual to another. Immune system_sentence_167

Immunological memory Immune system_section_15

Further information: Immunity (medical) Immune system_sentence_168

When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Immune system_sentence_169

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. Immune system_sentence_170

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. Immune system_sentence_171

Immunological memory can be in the form of either passive short-term memory or active long-term memory. Immune system_sentence_172

Physiological regulation Immune system_section_16

The immune system is involved in many aspects of physiological regulation in the body. Immune system_sentence_173

The immune system interacts intimately with other systems, such as the endocrine and the nervous systems. Immune system_sentence_174

The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration. Immune system_sentence_175

Hormones Immune system_section_17

Hormones can act as immunomodulators, altering the sensitivity of the immune system. Immune system_sentence_176

For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Immune system_sentence_177

Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. Immune system_sentence_178

By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Immune system_sentence_179

Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D. Immune system_sentence_180

Vitamin D Immune system_section_18

When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. Immune system_sentence_181

This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol. Immune system_sentence_182

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 calcitriol. Immune system_sentence_183

Only after binding to calcitriol can T-cells perform their intended function. Immune system_sentence_184

Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages. Immune system_sentence_185

Vitamin D deficiency may increase the risk of severe respiratory tract infections. Immune system_sentence_186

A 2020 review found that vitamin D deficiency was not associated with a higher probability of becoming infected with COVID-19 disease, but indicated that vitamin D deficiency and severity of the disease were related, including increases in hospitalization and mortality rates. Immune system_sentence_187

Sleep and rest Immune system_section_19

The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Immune system_sentence_188

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. Immune system_sentence_189

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. Immune system_sentence_190

In people suffering from sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Immune system_sentence_191

Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation, shift work. Immune system_sentence_192

As a result, these disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma. Immune system_sentence_193

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 innate and adaptive immunity. Immune system_sentence_194

First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine causes increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. Immune system_sentence_195

These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. Immune system_sentence_196

These cytokines then stimulate immune functions such as immune cell activation, proliferation, and differentiation. Immune system_sentence_197

It is during this time that undifferentiated, or less differentiated, like naïve and central memory T cells, peak (that is, during a time of a slowly evolving adaptive immune response). Immune system_sentence_198

In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the Th1/Th2 cytokine balance towards one that supports Th1, an increase in overall Th cell proliferation, and naïve T cell migration to lymph nodes. Immune system_sentence_199

This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses. Immune system_sentence_200

During wake periods differentiated effector cells, such as cytotoxic natural killer cells and cytotoxic T lymphocytes, peak to elicit an effective response against any intruding pathogens. Immune system_sentence_201

Anti-inflammatory molecules, such as cortisol and catecholamines, also peak during awake active times. Immune system_sentence_202

Inflammation would cause serious cognitive and physical impairments if it were to occur during wake times, and inflammation may occur during sleep times due to the presence of melatonin. Immune system_sentence_203

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. Immune system_sentence_204

Nutrition and diet Immune system_section_20

Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect immune function. Immune system_sentence_205

More moderate malnutrition, as well as specific trace mineral and nutrient deficiencies, can also compromise the immune response. Immune system_sentence_206

Foods rich in certain fatty acids may foster a healthy immune system, and fetal undernourishment can cause a lifelong impairment of the immune system. Immune system_sentence_207

Repair and regeneration Immune system_section_21

The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Immune system_sentence_208

Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. Immune system_sentence_209

The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune system_sentence_210

Immune components and pathways are involved in regeneration as well, for example in amphibians. Immune system_sentence_211

According to one hypothesis, organisms that can regenerate could be less immunocompetent than organisms that cannot regenerate. Immune system_sentence_212

Disorders of human immunity Immune system_section_22

Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities. Immune system_sentence_213

Immunodeficiencies Immune system_section_23

Further information: Immunodeficiency Immune system_sentence_214

Immunodeficiencies occur when one or more of the components of the immune system are inactive. Immune system_sentence_215

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. Immune system_sentence_216

In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function, while malnutrition is the most common cause of immunodeficiency in developing countries. Immune system_sentence_217

Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Immune system_sentence_218

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. Immune system_sentence_219

Immunodeficiencies can also be inherited or 'acquired'. Immune system_sentence_220

Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations. Immune system_sentence_221

Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. Immune system_sentence_222

AIDS and some types of cancer cause acquired immunodeficiency. Immune system_sentence_223

Autoimmunity Immune system_section_24

Further information: Autoimmunity Immune system_sentence_224

Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune disorders. Immune system_sentence_225

Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Immune system_sentence_226

Under normal circumstances, many T cells and antibodies react with "self" peptides. Immune system_sentence_227

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. Immune system_sentence_228

Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immune system_sentence_229

Hypersensitivity Immune system_section_25

Further information: Hypersensitivity Immune system_sentence_230

Hypersensitivity is an immune response that damages the body's own tissues. Immune system_sentence_231

It is divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Immune system_sentence_232

Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Immune system_sentence_233

Symptoms can range from mild discomfort to death. Immune system_sentence_234

Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen. Immune system_sentence_235

Type II hypersensitivity occurs when antibodies bind to antigens on the individual's own cells, marking them for destruction. Immune system_sentence_236

This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune system_sentence_237

Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Immune system_sentence_238

Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Immune system_sentence_239

Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis. Immune system_sentence_240

These reactions are mediated by T cells, monocytes, and macrophages. Immune system_sentence_241

Idiopathic inflammation Immune system_section_26

Further information: Immune-mediated inflammatory diseases Immune system_sentence_242

Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause. Immune system_sentence_243

Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Immune system_sentence_244

Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Immune system_sentence_245

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. Immune system_sentence_246

Growth factors and cytotoxic factors may also be released. Immune system_sentence_247

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. Immune system_sentence_248

Manipulation in medicine Immune system_section_27

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer. Immune system_sentence_249

Immunosuppression Immune system_section_28

Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent rejection after an organ transplant. Immune system_sentence_250

Anti-inflammatory drugs are often used to control the effects of inflammation. Immune system_sentence_251

Glucocorticoids are the most powerful of these drugs and can have many undesirable side effects, such as central obesity, hyperglycemia, and osteoporosis. Immune system_sentence_252

Their use is tightly controlled. Immune system_sentence_253

Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine. Immune system_sentence_254

Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. Immune system_sentence_255

This killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immune system_sentence_256

Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways. Immune system_sentence_257

Immunostimulation Immune system_section_29

Main articles: Immunotherapy and Vaccination Immune system_sentence_258

Vaccination Immune system_section_30

Long-term active memory is acquired following infection by activation of B and T cells. Immune system_sentence_259

Active immunity can also be generated artificially, through vaccination. Immune system_sentence_260

The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. Immune system_sentence_261

This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. Immune system_sentence_262

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. Immune system_sentence_263

Many vaccines are based on acellular components of micro-organisms, including harmless toxin components. Immune system_sentence_264

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. Immune system_sentence_265

Tumor immunology Immune system_section_31

Further information: Cancer immunology Immune system_sentence_266

Another important role of the immune system is to identify and eliminate tumors. Immune system_sentence_267

This is called immune surveillance. Immune system_sentence_268

The transformed cells of tumors express antigens that are not found on normal cells. Immune system_sentence_269

To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. Immune system_sentence_270

The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cancer of the cervix, vulva, vagina, penis, anus, mouth, and throat, while others are the organism's own proteins that occur at low levels in normal cells but reach high levels in tumor cells. Immune system_sentence_271

One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (for example, melanocytes) into tumors called melanomas. Immune system_sentence_272

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. Immune system_sentence_273

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. Immune system_sentence_274

Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. Immune system_sentence_275

This allows killer T cells to recognize the tumor cell as abnormal. Immune system_sentence_276

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. Immune system_sentence_277

Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system. Immune system_sentence_278

Some tumors evade the immune system and go on to become cancers. Immune system_sentence_279

Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Immune system_sentence_280

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. Immune system_sentence_281

In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells. Immune system_sentence_282

Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. Immune system_sentence_283

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. Immune system_sentence_284

Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. Immune system_sentence_285

The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10. Immune system_sentence_286

Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumors. Immune system_sentence_287

Predicting immunogenicity Immune system_section_32

Some drugs can cause a neutralizing immune response, meaning that the immune system produces neutralizing antibodies that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. Immune system_sentence_288

This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). Immune system_sentence_289

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. Immune system_sentence_290

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. Immune system_sentence_291

Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; 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. Immune system_sentence_292

A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells. Immune system_sentence_293

The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. Immune system_sentence_294

Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response. Immune system_sentence_295

Evolution and other mechanisms Immune system_section_33

Further information: Innate immune system § Other forms of innate immunity Immune system_sentence_296

Evolution of the immune system Immune system_section_34

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. Immune system_sentence_297

Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune system_sentence_298

Immune systems appear even in the structurally simplest forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Immune system_sentence_299

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. Immune system_sentence_300

Prokaryotes also possess other defense mechanisms. Immune system_sentence_301

Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few. Immune system_sentence_302

Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Immune system_sentence_303

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. Immune system_sentence_304

The complement system and phagocytic cells are also used by most forms of invertebrate life. Immune system_sentence_305

Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses. Immune system_sentence_306

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Immune system_sentence_307

Individual plant cells respond to molecules associated with pathogens known as pathogen-associated molecular patterns or PAMPs. Immune system_sentence_308

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. Immune system_sentence_309

Systemic acquired resistance is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. Immune system_sentence_310

RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication. Immune system_sentence_311

Alternative adaptive immune system Immune system_section_35

Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Immune system_sentence_312

Many of the classical molecules of the adaptive immune system (for example, immunoglobulins and T-cell receptors) exist only in jawed vertebrates. Immune system_sentence_313

A distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. Immune system_sentence_314

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. Immune system_sentence_315

These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity. Immune system_sentence_316

Manipulation by pathogens Immune system_section_36

The success of any pathogen depends on its ability to elude host immune responses. Immune system_sentence_317

Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. Immune system_sentence_318

Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. Immune system_sentence_319

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. Immune system_sentence_320

These proteins are often used to shut down host defenses. Immune system_sentence_321

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). Immune system_sentence_322

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. Immune system_sentence_323

Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium spp.) and leishmaniasis (Leishmania spp.). Immune system_sentence_324

Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Immune system_sentence_325

Many pathogens secrete compounds that diminish or misdirect the host's immune response. Immune system_sentence_326

Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Immune system_sentence_327

Such biofilms are present in many successful infections, such as the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Immune system_sentence_328

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). Immune system_sentence_329

The mechanisms used to evade the adaptive immune system are more complicated. Immune system_sentence_330

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. Immune system_sentence_331

This is called antigenic variation. Immune system_sentence_332

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. Immune system_sentence_333

These frequent changes in antigens may explain the failures of vaccines directed at this virus. Immune system_sentence_334

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. Immune system_sentence_335

Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. Immune system_sentence_336

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. Immune system_sentence_337

History of immunology Immune system_section_37

Further information: History of immunology Immune system_sentence_338

Immunology is a science that examines the structure and function of the immune system. Immune system_sentence_339

It originates from medicine and early studies on the causes of immunity to disease. Immune system_sentence_340

The earliest known reference to immunity was during the plague of Athens in 430 BC. Immune system_sentence_341

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. Immune system_sentence_342

In the 18th century, Pierre-Louis Moreau de Maupertuis experimented with scorpion venom and observed that certain dogs and mice were immune to this venom. Immune system_sentence_343

In the 10th century, Persian physician al-Razi (also known as Rhazes) wrote the first recorded theory of acquired immunity, noting that a smallpox bout protected its survivors from future infections. Immune system_sentence_344

Although he explained the immunity in terms of "excess moisture" being expelled from the blood—therefore preventing a second occurrence of the disease—this theory explained many observations about smallpox known during this time. Immune system_sentence_345

These and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Immune system_sentence_346

Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. Immune system_sentence_347

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. Immune system_sentence_348

Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed. Immune system_sentence_349

Immunology made a great advance towards the end of the 19th century, through rapid developments in the study of humoral immunity and cellular immunity. Immune system_sentence_350

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 joint Nobel Prize in 1908, along with the founder of cellular immunology, Elie Metchnikoff. Immune system_sentence_351

In 1974, Niels Kaj Jerne developed the immune network theory; he shared a Nobel Prize in 1984 with Georges J. F. Köhler and César Milstein for theories related to the immune system. Immune system_sentence_352

See also Immune system_section_38

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: system.