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Ionic bonding

Ionic bonding is a type of chemical bonding that involves the electrostatic attraction between oppositely charged ions, or between two atoms with sharply different electronegativities, and is the primary interaction occurring in ionic compounds. It is one of the main types of bonding, along with covalent bonding and metallic bonding. Ions are atoms (or groups of atoms) with an electrostatic charge. Atoms that gain electrons make negatively charged ions (called anions). Atoms that lose electrons make positively charged ions (called cations). This transfer of electrons is known as electrovalence in contrast to covalence. In the simplest case, the cation is a metal atom and the anion is a nonmetal atom, but these ions can be more complex, e.g. molecular ions like or. In simpler words, an ionic bond results from the transfer of electrons from a metal to a non-metal to obtain a full valence shell for both atoms.

Clean ionic bonding — in which one atom or molecule completely transfers an electron to another — cannot exist: all ionic compounds have some degree of covalent bonding or electron sharing. Thus, the term "ionic bonding" is given when the ionic character is greater than the covalent character – that is, a bond in which there is a large difference in electronegativity between the two atoms, causing the bonding to be more polar (ionic) than in covalent bonding where electrons are shared more equally. Bonds with partially ionic and partially covalent characters are called polar covalent bonds.

Ionic compounds conduct electricity when molten or in solution, typically not when solid. Ionic compounds generally have a high melting point, depending on the charge of the ions they consist of. The higher the charges the stronger the cohesive forces and the higher the melting point. They also tend to be soluble in water; the stronger the cohesive forces, the lower the solubility.

Overview
Atoms that have an almost full or almost empty valence shell tend to be very reactive. Strongly electronegative atoms (such as halogens) often have only one or two empty electron states in their valence shell, and frequently bond with other atoms or gain electrons to form anions. Weakly electronegative atoms (such as alkali metals) have relatively few valence electrons, which can easily be lost to strongly electronegative atoms. As a result, weakly electronegative atoms tend to distort their electron cloud and form cations.

Properties of ionic bonds

 * They are considered to be among the strongest of all types of chemical bonds. This often causes ionic compounds to be very stable.
 * Ionic bonds have high bond energy. Bond energy is the mean amount of energy required to break the bond in the gaseous state.
 * Most ionic compounds exist in the form of a crystal structure, in which the ions occupy the corners of the crystal. Such a structure is called a crystal lattice.
 * Ionic compounds lose their crystal lattice structure and break up into ions when dissolved in water or any other polar solvent. This process is called solvation. The presence of these free ions makes aqueous ionic compound solutions good conductors of electricity. The same occurs when the compounds are heated above their melting point in a process known as melting.

Formation
Ionic bonding can result from a redox reaction when atoms of an element (usually metal), whose ionization energy is low, give some of their electrons to achieve a stable electron configuration. In doing so, cations are formed. An atom of another element (usually nonmetal) with greater electron affinity accepts one or more electrons to attain a stable electron configuration, and after accepting electrons an atom becomes an anion. Typically, the stable electron configuration is one of the noble gases for elements in the s-block and the p-block, and particular stable electron configurations for d-block and f-block elements. The electrostatic attraction between the anions and cations leads to the formation of a solid with a crystallographic lattice in which the ions are stacked in an alternating fashion. In such a lattice, it is usually not possible to distinguish discrete molecular units, so that the compounds formed are not molecular. However, the ions themselves can be complex and form molecular ions like the acetate anion or the ammonium cation. For example, common table salt is sodium chloride. When sodium (Na) and chlorine (Cl) are combined, the sodium atoms each lose an electron, forming cations (Na+), and the chlorine atoms each gain an electron to form anions (Cl−). These ions are then attracted to each other in a 1:1 ratio to form sodium chloride (NaCl).
 * Na + Cl → Na+ + Cl− → NaCl

However, to maintain charge neutrality, strict ratios between anions and cations are observed so that ionic compounds, in general, obey the rules of stoichiometry despite not being molecular compounds. For compounds that are transitional to the alloys and possess mixed ionic and metallic bonding, this may not be the case anymore. Many sulfides, e.g., do form non-stoichiometric compounds.

Many ionic compounds are referred to as salts as they can also be formed by the neutralization reaction of an Arrhenius base like NaOH with an Arrhenius acid like HCl

 * NaOH + HCl → NaCl + H2O

The salt NaCl is then said to consist of the acid rest Cl− and the base rest Na+.

The removal of electrons to form the cation is endothermic, raising the system's overall energy. There may also be energy changes associated with breaking of existing bonds or the addition of more than one electron to form anions. However, the action of the anion's accepting the cation's valence electrons and the subsequent attraction of the ions to each other releases (lattice) energy and, thus, lowers the overall energy of the system.

Ionic bonding will occur only if the overall energy change for the reaction is favorable. In general, the reaction is exothermic, but, e.g., the formation of mercuric oxide (HgO) is endothermic. The charge of the resulting ions is a major factor in the strength of ionic bonding, e.g. a salt C+A− is held together by electrostatic forces roughly four times weaker than C2+A2− according to Coulomb's law, where C and A represent a generic cation and anion respectively. The sizes of the ions and the particular packing of the lattice are ignored in this rather simplistic argument.

Structures
Ionic compounds in the solid state form lattice structures. The two principal factors in determining the form of the lattice are the relative charges of the ions and their relative sizes. Some structures are adopted by a number of compounds; for example, the structure of the rock salt sodium chloride is also adopted by many alkali halides, and binary oxides such as magnesium oxide. Pauling's rules provide guidelines for predicting and rationalizing the crystal structures of ionic crystals

Strength of the bonding
For a solid crystalline ionic compound the enthalpy change in forming the solid from gaseous ions is termed the lattice energy. The experimental value for the lattice energy can be determined using the Born–Haber cycle. It can also be calculated (predicted) using the Born–Landé equation as the sum of the electrostatic potential energy, calculated by summing interactions between cations and anions, and a short-range repulsive potential energy term. The electrostatic potential can be expressed in terms of the interionic separation and a constant (Madelung constant) that takes account of the geometry of the crystal. The further away from the nucleus the weaker the shield. The Born–Landé equation gives a reasonable fit to the lattice energy of, e.g., sodium chloride, where the calculated (predicted) value is −756 kJ/mol, which compares to −787 kJ/mol using the Born–Haber cycle. In aqueous solution the binding strength can be described by the Bjerrum or Fuoss equation as function of the ion charges, rather independent of the nature of the ions such as polarizability or size. The strength of salt bridges is most often evaluated by measurements of equilibria between molecules containing cationic and anionic sites, most often in solution. Equilibrium constants in water indicate additive free energy contributions for each salt bridge. Another method for the identification of hydrogen bonds also in complicated molecules is crystallography, sometimes also NMR-spectroscopy.

The attractive forces defining the strength of ionic bonding can be modeled by Coulomb's Law. Ionic bond strengths are typically (cited ranges vary) between 170 and 1500 kJ/mol.

Polarization power effects
Ions in crystal lattices of purely ionic compounds are spherical; however, if the positive ion is small and/or highly charged, it will distort the electron cloud of the negative ion, an effect summarised in Fajans' rules. This polarization of the negative ion leads to a build-up of extra charge density between the two nuclei, that is, to partial covalency. Larger negative ions are more easily polarized, but the effect is usually important only when positive ions with charges of 3+ (e.g., Al3+) are involved. However, 2+ ions (Be2+) or even 1+ (Li+) show some polarizing power because their sizes are so small (e.g., LiI is ionic but has some covalent bonding present). Note that this is not the ionic polarization effect that refers to displacement of ions in the lattice due to the application of an electric field.

Comparison with covalent bonding
In ionic bonding, the atoms are bound by attraction of oppositely charged ions, whereas, in covalent bonding, atoms are bound by sharing electrons to attain stable electron configurations. In covalent bonding, the molecular geometry around each atom is determined by valence shell electron pair repulsion VSEPR rules, whereas, in ionic materials, the geometry follows maximum packing rules. One could say that covalent bonding is more directional in the sense that the energy penalty for not adhering to the optimum bond angles is large, whereas ionic bonding has no such penalty. There are no shared electron pairs to repel each other, the ions should simply be packed as efficiently as possible. This often leads to much higher coordination numbers. In NaCl, each ion has 6 bonds and all bond angles are 90°. In CsCl the coordination number is 8. By comparison carbon typically has a maximum of four bonds.

Purely ionic bonding cannot exist, as the proximity of the entities involved in the bonding allows some degree of sharing electron density between them. Therefore, all ionic bonding has some covalent character. Thus, bonding is considered ionic where the ionic character is greater than the covalent character. The larger the difference in electronegativity between the two types of atoms involved in the bonding, the more ionic (polar) it is. Bonds with partially ionic and partially covalent character are called polar covalent bonds. For example, Na–Cl and Mg–O interactions have a few percent covalency, while Si–O bonds are usually ~50% ionic and ~50% covalent. Pauling estimated that an electronegativity difference of 1.7 (on the Pauling scale) corresponds to 50% ionic character, so that a difference greater than 1.7 corresponds to a bond which is predominantly ionic.

Ionic character in covalent bonds can be directly measured for atoms having quadrupolar nuclei (2H, 14N, 81,79Br, 35,37Cl or 127I). These nuclei are generally objects of NQR nuclear quadrupole resonance and NMR nuclear magnetic resonance studies. Interactions between the nuclear quadrupole moments Q and the electric field gradients (EFG) are characterized via the nuclear quadrupole coupling constants
 * QCC = $e^{2}q_{zz}Q⁄h$

where the eqzz term corresponds to the principal component of the EFG tensor and e is the elementary charge. In turn, the electric field gradient opens the way to description of bonding modes in molecules when the QCC values are accurately determined by NMR or NQR methods.

In general, when ionic bonding occurs in the solid (or liquid) state, it is not possible to talk about a single "ionic bond" between two individual atoms, because the cohesive forces that keep the lattice together are of a more collective nature. This is quite different in the case of covalent bonding, where we can often speak of a distinct bond localized between two particular atoms. However, even if ionic bonding is combined with some covalency, the result is not necessarily discrete bonds of a localized character. In such cases, the resulting bonding often requires description in terms of a band structure consisting of gigantic molecular orbitals spanning the entire crystal. Thus, the bonding in the solid often retains its collective rather than localized nature. When the difference in electronegativity is decreased, the bonding may then lead to a semiconductor, a semimetal or eventually a metallic conductor with metallic bonding.

title: Ionic bonding


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IBF (disambiguation)

 * IBF, or International Boxing Federation, is one of several boxing organisations.

IBF may also refer to:

Businesses

 * International Banking Facility, a legal entity of a US bank
 * Irish Banking Federation, a banking representative body in Ireland
 * International Broadcasting Facilities, a film and music Electronic Press Kit company in London

Sports

 * International Bandy Federation, former name of Federation of International Bandy (FIB), the international governing body for bandy
 * International Badminton Federation, former name of Badminton World Federation (BWF), the international governing body for badminton
 * International Bowling Federation
 * Iran Basketball Federation, a basketball league in Iran

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: IBF (disambiguation)


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Immune system

The immune system is a network of biological systems that protects an organism from diseases. 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. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

Nearly all organisms have some kind of immune system. Bacteria have a rudimentary immune system in the form of enzymes that protect against viral infections. Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt to recognize pathogens more efficiently. Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.

Dysfunction of the immune system can cause autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. 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. 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.

Layered defense
The immune system protects its host from infection with layered defenses of increasing specificity. 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 animals. 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.

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 components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. 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.

Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. 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. Organisms cannot be completely sealed from their environments, so 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.

Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid serves as a chemical defense 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, changing the conditions in their environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.

Innate immune system
Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, 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. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. 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, and the only one in plants.

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

Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRRs), which give them a curved shape. 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. Ten toll-like receptors have been described in humans.

Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors.

Innate immune cells
Some leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the "professional" phagocytes (macrophages, neutrophils, and dendritic cells). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells.

Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. 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. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes. 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. Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, complement proteins, and cytokines. They can also act as scavengers that rid the body of worn-out cells and other debris and as antigen-presenting cells (APCs) that activate the adaptive immune system.

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

Granulocytes are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in connective tissues and mucous membranes and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. 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.

Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells are defined by the absence of antigen-specific B- or T-cell receptor (TCR) because of the lack of recombination activating gene. ILCs do not express myeloid or dendritic cell markers.

Natural killer cells (NK cells) are lymphocytes and a component of the innate immune system that does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self". This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex)—a situation that can arise in viral infections of host cells. 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, which essentially put the brakes on NK cells.

Inflammation
Inflammation is one of the first responses of the immune system to infection. 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). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have antiviral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote the healing of any damaged tissue following the removal of pathogens. 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.

Humoral defenses
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. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. 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. The speed of the response is a result of signal amplification that occurs after 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. 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 via the formation of a membrane attack complex.

Adaptive immune system
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. 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.

Recognition of antigen
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. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. 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. 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. 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. 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. When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called clonal selection.

Antigen presentation to T lymphocytes
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.

Cell mediated immunity
There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are regulatory T cells which have a role in modulating immune response.

Killer T cells
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. As with B cells, each type of T cell recognizes a different antigen. 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. 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. 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).

Helper T 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. 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 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 (such as 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 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. 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. 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.

Gamma delta T cells
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. 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.

Humoral immune response
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. 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. 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.

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 through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. 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. 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.

Immunological memory
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. T-cells recognize pathogens by small protein-based infection signals, called antigens, that bind to directly to T-cell surface receptors. B-cells use the protein, immunoglobulin, to recognize pathogens by their antigens. 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.

Physiological regulation
The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine and the nervous   systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.

Hormones
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. 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. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.

Vitamin D
Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no clinical evidence to prove that vitamin D deficiency increases the risk for immune diseases or vitamin D supplementation lowers immune disease risk. A 2011 United States Institute of Medicine report stated that "outcomes related to ... immune functioning and autoimmune disorders, and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting."

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

In people with sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.

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. 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. 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 cell activation, proliferation, and differentiation. During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. 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. This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.

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

Physical exercise
Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated. Immediately after intense exercise there is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections, but the evidence is inconclusive.

Changes at the cellular level

During exercise there is an increase in circulating white blood cells of all types. This is caused by the frictional force of blood flowing on the endothelial cell surface and catecholamines affecting β-adrenergic receptors (βARs). The number of neutrophils in the blood increases and remains raised for up to six hours and immature forms are present. Although the increase in neutrophils ("neutrophilia") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours.

The number of circulating lymphocytes (mainly natural killer cells) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of the cells die most migrate from the blood to the tissues, mainly the intestines and lungs, where pathogens are most likely to be encountered.

Some monocytes leave the blood circulation and migrate to the muscles where they differentiate and become macrophages. These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of stem cells and restorative macrophages, which are involved their maturing to muscle cells.

Repair and regeneration
The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. 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. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians such as in axolotl limb regeneration. According to one hypothesis, organisms that can regenerate (e.g., axolotls) could be less immunocompetent than organisms that cannot regenerate.

Disorders of human immunity
Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.

Immunodeficiencies
Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. 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. 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. Immunodeficiencies can also be inherited or 'acquired'. 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. 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.

Autoimmunity
Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune diseases. 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. 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. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus.

Hypersensitivity
Hypersensitivity is an immune response that damages the body's own tissues. It is 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. Type II hypersensitivity occurs when antibodies bind to antigens on the individual's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. 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. These reactions are mediated by T cells, monocytes, and macrophages.

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

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). 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. 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.

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

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

Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs and can have many undesirable side effects, such as central obesity, hyperglycemia, and osteoporosis. Their use is tightly controlled. 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. This killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.

Immunostimulation
Claims made by marketers of various products and alternative health providers, such as chiropractors, homeopaths, and acupuncturists to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.

Vaccination
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 to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. 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.

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

Tumor immunology
Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; 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. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (for example, melanocytes) into tumors called melanomas. 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.

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

Some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. 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. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.

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

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

Evolution of the immune system
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 systems evolved in deuterostomes as shown in the cladogram.

Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. 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. Prokaryotes (bacteria and archea) 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. Prokaryotes also possess other defense mechanisms. Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.

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. 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.

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Individual plant cells respond to molecules associated with pathogens known as pathogen-associated molecular patterns or PAMPs. 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 is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.

Alternative adaptive immune system
Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (for example, immunoglobulins and T-cell receptors) exist only in jawed vertebrates. A distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.

Manipulation by pathogens
The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. 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.

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 spp.) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, such as the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. 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).

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. 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. 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.

History of immunology

Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. 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. 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. 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.

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

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

title: Immune system


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Immunology

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

Immunology charts, measures, and contextualizes the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders (such as autoimmune diseases, hypersensitivities, immune deficiency, and transplant rejection ); and the physical, chemical, and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Immunology has applications in numerous disciplines of medicine, particularly in the fields of organ transplantation, oncology, rheumatology, virology, bacteriology, parasitology, psychiatry, and dermatology.

The term was coined by Russian biologist Ilya Ilyich Mechnikov, who advanced studies on immunology and received the Nobel Prize for his work in 1908 with Paul Ehrlich "in recognition of their work on immunity". He pinned small thorns into starfish larvae and noticed unusual cells surrounding the thorns. This was the active response of the body trying to maintain its integrity. It was Mechnikov who first observed the phenomenon of phagocytosis, in which the body defends itself against a foreign body. Ehrlich accustomed mice to the poisons ricin and abrin. After feeding them with small but increasing dosages of ricin he ascertained that they had become "ricin-proof". Ehrlich interpreted this as immunization and observed that it was abruptly initiated after a few days and was still in existence after several months.

Prior to the designation of immunity, from the etymological root immunis, which is Latin for 'exempt', early physicians characterized organs that would later be proven as essential components of the immune system. The important lymphoid organs of the immune system are the thymus, bone marrow, and chief lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and liver. However, many components of the immune system are cellular in nature, and not associated with specific organs, but rather embedded or circulating in various tissues located throughout the body.

Classical immunology
Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. 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. Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired or adaptive immune system. The latter is further divided into humoral (or antibody) and cell-mediated components.

The immune system has the capability of self and non-self-recognition. An antigen is a substance that ignites the immune response. The cells involved in recognizing the antigen are Lymphocytes. Once they recognize, they secrete antibodies. Antibodies are proteins that neutralize the disease-causing microorganisms. Antibodies do not directly kill pathogens, but instead, identify antigens as targets for destruction by other immune cells such as phagocytes or NK cells.

The (antibody) response is defined as the interaction between antibodies and antigens. Antibodies are specific proteins released from a certain class of immune cells known as B lymphocytes, while antigens are defined as anything that elicits the generation of antibodies (antibody generators). Immunology rests on an understanding of the properties of these two biological entities and the cellular response to both.

It is now getting clear that the immune responses contribute to the development of many common disorders not traditionally viewed as immunologic, including metabolic, cardiovascular, cancer, and neurodegenerative conditions like Alzheimer's disease. Besides, there are direct implications of the immune system in the infectious diseases (tuberculosis, malaria, hepatitis, pneumonia, dysentery, and helminth infestations) as well. Hence, research in the field of immunology is of prime importance for the advancements in the fields of modern medicine, biomedical research, and biotechnology.

Immunological research continues to become more specialized, pursuing non-classical models of immunity and functions of cells, organs and systems not previously associated with the immune system (Yemeserach 2010).

Diagnostic immunology
The specificity of the bond between antibody and antigen has made the antibody an excellent tool for the detection of substances by a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with an isotopic (radio) or fluorescent label or with a color-forming enzyme in order to detect it. However, the similarity between some antigens can lead to false positives and other errors in such tests by antibodies cross-reacting with antigens that are not exact matches.

Immunotherapy
The use of immune system components or antigens to treat a disease or disorder is known as immunotherapy. Immunotherapy is most commonly used to treat allergies, autoimmune disorders such as Crohn's disease, Hashimoto's thyroiditis and rheumatoid arthritis, and certain cancers. Immunotherapy is also often used for patients who are immunosuppressed (such as those with HIV) and people with other immune deficiencies. This includes regulating factors such as IL-2, IL-10, GM-CSF B, IFN-α.

Clinical immunology
Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune reactions play a part in the pathology and clinical features.

The diseases caused by disorders of the immune system fall into two broad categories: Other immune system disorders include various hypersensitivities (such as in asthma and other allergies) that respond inappropriately to otherwise harmless compounds.
 * immunodeficiency, in which parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease and primary immune diseases);
 * autoimmunity, in which the immune system attacks its own host's body (examples include systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's disease and myasthenia gravis).

The most well-known disease that affects the immune system itself is AIDS, an immunodeficiency characterized by the suppression of CD4+ ("helper") T cells, dendritic cells and macrophages by the human immunodeficiency virus (HIV).

Clinical immunologists also study ways to prevent the immune system's attempts to destroy allografts (transplant rejection).

Clinical immunology and allergy is usually a subspecialty of internal medicine or pediatrics. Fellows in Clinical Immunology are typically exposed to many of the different aspects of the specialty and treat allergic conditions, primary immunodeficiencies and systemic autoimmune and autoinflammatory conditions. As part of their training fellows may do additional rotations in rheumatology, pulmonology, otorhinolaryngology, dermatology and the immunologic lab.

Clinical and pathology immunology
When health conditions worsen to emergency status, portions of immune system organs, including the thymus, spleen, bone marrow, lymph nodes, and other lymphatic tissues, can be surgically excised for examination while patients are still alive.

Theoretical immunology
Immunology is strongly experimental in everyday practice but is also characterized by an ongoing theoretical attitude. Many theories have been suggested in immunology from the end of the nineteenth century up to the present time. The end of the 19th century and the beginning of the 20th century saw a battle between "cellular" and "humoral" theories of immunity. According to the cellular theory of immunity, represented in particular by Elie Metchnikoff, it was cells – more precisely, phagocytes – that were responsible for immune responses. In contrast, the humoral theory of immunity, held by Robert Koch and Emil von Behring, among others, stated that the active immune agents were soluble components (molecules) found in the organism's "humors" rather than its cells.

In the mid-1950s, Macfarlane Burnet, inspired by a suggestion made by Niels Jerne, formulated the clonal selection theory (CST) of immunity. On the basis of CST, Burnet developed a theory of how an immune response is triggered according to the self/nonself distinction: "self" constituents (constituents of the body) do not trigger destructive immune responses, while "nonself" entities (e.g., pathogens, an allograft) trigger a destructive immune response. The theory was later modified to reflect new discoveries regarding histocompatibility or the complex "two-signal" activation of T cells. The self/nonself theory of immunity and the self/nonself vocabulary have been criticized, but remain very influential.

More recently, several theoretical frameworks have been suggested in immunology, including "autopoietic" views, "cognitive immune" views, the "danger model" (or "danger theory"), and the "discontinuity" theory. The danger model, suggested by Polly Matzinger and colleagues, has been very influential, arousing many comments and discussions.

Developmental immunology
The body's capability to react to antigens depends on a person's age, antigen type, maternal factors and the area where the antigen is presented. Neonates are said to be in a state of physiological immunodeficiency, because both their innate and adaptive immunological responses are greatly suppressed. Once born, a child's immune system responds favorably to protein antigens while not as well to glycoproteins and polysaccharides. In fact, many of the infections acquired by neonates are caused by low virulence organisms like Staphylococcus and Pseudomonas. In neonates, opsonic activity and the ability to activate the complement cascade is very limited. For example, the mean level of C3 in a newborn is approximately 65% of that found in the adult. Phagocytic activity is also greatly impaired in newborns. This is due to lower opsonic activity, as well as diminished up-regulation of integrin and selectin receptors, which limit the ability of neutrophils to interact with adhesion molecules in the endothelium. Their monocytes are slow and have a reduced ATP production, which also limits the newborn's phagocytic activity. Although, the number of total lymphocytes is significantly higher than in adults, the cellular and humoral immunity is also impaired. Antigen-presenting cells in newborns have a reduced capability to activate T cells. Also, T cells of a newborn proliferate poorly and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-g which limits their capacity to activate the humoral response as well as the phagocitic activity of macrophage. B cells develop early during gestation but are not fully active.

Maternal factors also play a role in the body's immune response. At birth, most of the immunoglobulin present is maternal IgG. These antibodies are transferred from the placenta to the fetus using the FcRn (neonatal Fc receptor). Because IgM, IgD, IgE and IgA do not cross the placenta, they are almost undetectable at birth. Some IgA is provided by breast milk. These passively-acquired antibodies can protect the newborn for up to 18 months, but their response is usually short-lived and of low affinity. These antibodies can also produce a negative response. If a child is exposed to the antibody for a particular antigen before being exposed to the antigen itself then the child will produce a dampened response. Passively acquired maternal antibodies can suppress the antibody response to active immunization. Similarly, the response of T-cells to vaccination differs in children compared to adults, and vaccines that induce Th1 responses in adults do not readily elicit these same responses in neonates. Between six and nine months after birth, a child's immune system begins to respond more strongly to glycoproteins, but there is usually no marked improvement in their response to polysaccharides until they are at least one year old. This can be the reason for distinct time frames found in vaccination schedules.

During adolescence, the human body undergoes various physical, physiological and immunological changes triggered and mediated by hormones, of which the most significant in females is 17-β-estradiol (an estrogen) and, in males, is testosterone. Estradiol usually begins to act around the age of 10 and testosterone some months later. There is evidence that these steroids not only act directly on the primary and secondary sexual characteristics but also have an effect on the development and regulation of the immune system, including an increased risk in developing pubescent and post-pubescent autoimmunity. There is also some evidence that cell surface receptors on B cells and macrophages may detect sex hormones in the system.

The female sex hormone 17-β-estradiol has been shown to regulate the level of immunological response, while some male androgens such as testosterone seem to suppress the stress response to infection. Other androgens, however, such as DHEA, increase immune response. As in females, the male sex hormones seem to have more control of the immune system during puberty and post-puberty than during the rest of a male's adult life.

Physical changes during puberty such as thymic involution also affect immunological response.

Ecoimmunology and behavioural immunity
Ecoimmunology, or ecological immunology, explores the relationship between the immune system of an organism and its social, biotic and abiotic environment.

More recent ecoimmunological research has focused on host pathogen defences traditionally considered "non-immunological", such as pathogen avoidance, self-medication, symbiont-mediated defenses, and fecundity trade-offs. Behavioural immunity, a phrase coined by Mark Schaller, specifically refers to psychological pathogen avoidance drivers, such as disgust aroused by stimuli encountered around pathogen-infected individuals, such as the smell of vomit. More broadly, "behavioural" ecological immunity has been demonstrated in multiple species. For example, the Monarch butterfly often lays its eggs on certain toxic milkweed species when infected with parasites. These toxins reduce parasite growth in the offspring of the infected Monarch. However, when uninfected Monarch butterflies are forced to feed only on these toxic plants, they suffer a fitness cost as reduced lifespan relative to other uninfected Monarch butterflies. This indicates that laying eggs on toxic plants is a costly behaviour in Monarchs which has probably evolved to reduce the severity of parasite infection.

Symbiont-mediated defenses are also heritable across host generations, despite a non-genetic direct basis for the transmission. Aphids, for example, rely on several different symbionts for defense from key parasites, and can vertically transmit their symbionts from parent to offspring. Therefore, a symbiont that successfully confers protection from a parasite is more likely to be passed to the host offspring, allowing coevolution with parasites attacking the host in a way similar to traditional immunity.

The preserved immune tissues of extinct species, such as the thylacine (Thylacine cynocephalus), can also provide insights into their biology.

Cancer immunology
The study of the interaction of the immune system with cancer cells can lead to diagnostic tests and therapies with which to find and fight cancer. The immunology concerned with physiological reaction characteristic of the immune state.

Reproductive immunology
This area of the immunology is devoted to the study of immunological aspects of the reproductive process including fetus acceptance. The term has also been used by fertility clinics to address fertility problems, recurrent miscarriages, premature deliveries and dangerous complications such as pre-eclampsia.

title: Immunology


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IPA

IPA commonly refers to:

 * International Phonetic Alphabet, a system of phonetic notation
 * International Phonetic Association, behind the alphabet
 * India pale ale, a style of beer
 * Isopropyl alcohol, a chemical compound

IPA may also refer to:

International

 * Insolvency Practitioners Association, of the UK and Ireland
 * Institute of Public Administration (disambiguation)
 * International Permafrost Association
 * International Play Association
 * International Police Association
 * International Polka Association
 * International Presentation Association, network of Presentation Sisters
 * International Psychoanalytical Association
 * International Publishers Association, representing book and journal publishing

Australia

 * Institute of Public Accountants
 * Institute of Public Affairs

India

 * Indian Pharmacist Association
 * Indian Polo Association

United Kingdom

 * Infrastructure and Projects Authority
 * Institute of Practitioners in Advertising
 * Involvement and Participation Association, for employee involvement in the workplace

United States

 * Independence Party of America
 * Independent Pilots Association
 * Independent practice association, of physicians
 * Innovations for Poverty Action
 * Innovative Products of America, a tool manufacturer
 * Institute for Propaganda Analysis
 * Island Pacific Academy, Hawaii

Other

 * Independent Psychiatric Association of Russia
 * Institute of Public Affairs, Poland
 * Instituto Superior Autónomo de Estudos Politécnicos, Portugal

Science

 * 3-Indolepropionic acid, a biological substance
 * Ipa (spider), a genus of spiders

Technology

 * .ipa, extension for Apple iOS applications
 * "Identity, Policy, and Audit", as in FreeIPA
 * Intermediate power amplifier of a radio transmitter

Other uses

 * Important Plant Areas, a UK programme
 * Indigenous Protected Area, Australia
 * Instrument for Pre-Accession Assistance, EU funding programme
 * Interaction Process Analysis
 * Interpretative phenomenological analysis to psychological qualitative research
 * Investigatory Powers Act 2016, a piece of UK legislation

title: IPA


text:
Ice beer

Ice beer is a beer that has undergone some degree of freezing during production. These beers generally have a higher alcohol content, and lower price relative to it.

The process of "icing" beer involves lowering the temperature until ice crystals form. Since ethanol has a much lower freezing point (-114 °C; -173.2 °F) than water (0 °C; 32 °F), when the ice is removed the alcohol concentration of the beer increases. The process is known as fractional freezing or freeze distillation.

History

Ice beer was developed by brewing a strong, dark lager, then freezing the beer and removing some of the ice. This concentrates the aroma and taste of the beer, and also raises the alcoholic strength of the finished beer. This produces a beer with 12 to 15 per cent alcohol. In North America, water would be added to lower the alcohol level.

Eisbock was introduced to Canada in 1989 by the microbrewery Niagara Falls Brewing Company. The brewers started with a strong dark lager (15.3 degrees Plato/1.061 original gravity, 6% alcohol by volume), then used the traditional method of freezing and removing ice to concentrate aroma and flavours while increasing the alcoholic strength to 8% ABV. Niagara Falls Eisbock was released annually as a seasonal winter beer; each year the label would feature a different historic view of nearby Niagara Falls in winter. This continued each year until the company was sold in 1994.

Despite this precedent, the large Canadian brewer Molson (now part of Molson Coors) claimed to have made the first ice beer in North America when it introduced Canadian Ice in April 1993. However, Molson's main competitor in Canada, Labatt (now part of Anheuser-Busch InBev), claimed to have patented the ice beer process earlier. When Labatt introduced an ice beer in August 1993, capturing a 10% market share in Canada, this instigated the so-called "Ice Beer Wars" of the 1990s.

Labatt had patented a specific method for making ice beer in 1997, 1998 and 2000, "A process for chill-treating, which is exemplified by a process for preparing a fermented malt beverage wherein brewing materials are mashed with water and the resulting mash is heated and wort separated therefrom. The wort is boiled cooled and fermented, and the beer is subjected to a finishing stage, which includes aging, to produce the final beverage. The improvement comprises subjecting the beer to a cold stage comprising rapidly cooling the beer to a temperature of about its freezing point in such a manner that ice crystals are formed therein in only minimal amounts. The resulting cooled beer is then mixed for a short period of time with a beer slurry containing ice crystals, without any appreciable collateral increase in the amount of ice crystals in the resulting mixture. Finally, the so-treated beer is extracted from the mixture."

Miller acquired the U.S. marketing and distribution rights to Molson's products, and first introduced the Molson product in the United States in August 1993 as Molson Ice. Miller also introduced the Icehouse brand under the Plank Road Brewery brand name shortly thereafter, and it is still sold nationwide.

Anheuser-Busch introduced Bud Ice (5.5% ABV) in 1994, and it remains one of the country's top selling ice beers. Bud Ice has a somewhat lower alcohol content than most other ice beer brands. In 1995, Anheuser-Busch also introduced two other major brands: Busch Ice (5.9% ABV, introduced 1995) and Natural Ice (also 5.9% ABV, also introduced in 1995). Natural Ice is the No. 1 selling ice beer brand in the United States; its low price makes it very popular on college campuses all over the country. Keystone Ice, a value-based subdivision of Coors, also produces a 5.9% ABV brew labeled Keystone Ice.

Common ice beer brands in Canada in 2017, with approximately 5.5 to 6 per cent alcohol content, include Carling Ice, Molson Keystone Ice, Molson's Black Ice, Busch Ice, Old Milwaukee Ice, Brick's Laker Ice and Labatt Ice. There is a Labatt Maximum Ice too, with 7.1 per cent alcohol.

Characteristics and regulation
The ice beers are typically known for their high alcohol-to-price ratio. In some areas, a substantial number of ice beer products are considered to often be bought by "street drunks," and are prohibited for sale. For example, most of the products that are explicitly listed as prohibited in the beer and malt liquor category in the Seattle area are ice beers.

title: Ice beer


text:
Identity element

In mathematics, an identity element or neutral element of a binary operation is an element that leaves unchanged every element when the operation is applied. For example, 0 is an identity element of the addition of real numbers. This concept is used in algebraic structures such as groups and rings. The term identity element is often shortened to identity (as in the case of additive identity and multiplicative identity) when there is no possibility of confusion, but the identity implicitly depends on the binary operation it is associated with.

Definitions
Let $(S, ∗)$ be a set $S$ equipped with a binary operation ∗. Then an element $e$ of $S$ is called a if $e ∗ s = s$ for all $s$ in $S$, and a  if $s ∗ e = s$ for all $s$ in $S$. If $e$ is both a left identity and a right identity, then it is called a ', or simply an '.

An identity with respect to addition is called an Additive identity (often denoted as 0) and an identity with respect to multiplication is called a  (often denoted as 1). These need not be ordinary addition and multiplication—as the underlying operation could be rather arbitrary. In the case of a group for example, the identity element is sometimes simply denoted by the symbol $$e$$. The distinction between additive and multiplicative identity is used most often for sets that support both binary operations, such as rings, integral domains, and fields. The multiplicative identity is often called  in the latter context (a ring with unity). This should not be confused with a unit in ring theory, which is any element having a multiplicative inverse. By its own definition, unity itself is necessarily a unit.

Properties
In the example S = {e,f} with the equalities given, S is a semigroup. It demonstrates the possibility for $J_{m, n}$ to have several left identities. In fact, every element can be a left identity. In a similar manner, there can be several right identities. But if there is both a right identity and a left identity, then they must be equal, resulting in a single two-sided identity.

To see this, note that if $m$ is a left identity and $n$ is a right identity, then $δ$. In particular, there can never be more than one two-sided identity: if there were two, say $n$ and $n$, then ${e, f}$ would have to be equal to both $m$ and $n$.

It is also quite possible for $e ∗ e = f ∗ e = e$ to have no identity element, such as the case of even integers under the multiplication operation. Another common example is the cross product of vectors, where the absence of an identity element is related to the fact that the direction of any nonzero cross product is always orthogonal to any element multiplied. That is, it is not possible to obtain a non-zero vector in the same direction as the original. Yet another example of structure without identity element involves the additive semigroup of positive natural numbers.

title: Identity element


text:
Talk:IEEE

What about famous IEEE standards such as IEEE 1394 (a.k.a. "firewire" or "i-link")? And what does the IEEE do? If Apple developed the firewire technology, what did IEEE do? standardize it? rubber stamp it? Would IEEE 1394 be a ... standard? Protocol? Technology? I see the description here, and I use it for DV editing, but I don't feel comfortable writing about it. anyone?

title: Talk:IEEE


text:
Instrumental

An instrumental or instrumental song is music normally without any vocals, although it might include some inarticulate vocals, such as shouted backup vocals in a big band setting. Through semantic widening, a broader sense of the word song may refer to instrumentals. The music is primarily or exclusively produced using musical instruments. An instrumental can exist in music notation, after it is written by a composer; in the mind of the composer (especially in cases where the composer themselves will perform the piece, as in the case of a blues solo guitarist or a folk music fiddle player); as a piece that is performed live by a single instrumentalist or a musical ensemble, which could range in components from a duo or trio to a large big band, concert band or orchestra.

In a song that is otherwise sung, a section that is not sung but which is played by instruments can be called an instrumental interlude, or, if it occurs at the beginning of the song, before the singer starts to sing, an instrumental introduction. If the instrumental section highlights the skill, musicality, and often the virtuosity of a particular performer (or group of performers), the section may be called a "solo" (e.g., the guitar solo that is a key section of heavy metal music and hard rock songs). If the instruments are percussion instruments, the interlude can be called a percussion interlude or "percussion break". These interludes are a form of break in the song.

In popular music
In commercial popular music, instrumental tracks are sometimes renderings, remixes of a corresponding release that features vocals, but they may also be compositions originally conceived without vocals. One example of a genre in which both vocal/instrumental and solely instrumental songs are produced is blues. A blues band often uses mostly songs that have lyrics that are sung, but during the band's show, they may also perform instrumental songs which only include electric guitar, harmonica, upright bass/electric bass and drum kit.

Borderline cases
Some recordings which include brief or non-musical use of the human voice are typically considered instrumentals. Examples include songs with the following:
 * Short verbal interjections (as in "Tequila", "Topsy", "Wipe Out", "The Hustle", or "Bentley's Gonna Sort You Out")
 * Repetitive nonsense words (e.g., "la la..." (as in "Calcutta") or "Woo Hoo")
 * Non-musical spoken passages in the background of the track (e.g., "To Live Is to Die" by Metallica or "Wasteland" by Chelsea Grin)
 * Wordless vocal effects, such as drones (e.g., "Rockit" or "Flying")
 * Vocal percussion, such as beatbox B-sides on rap singles
 * Yelling (e.g. "Cry for a Shadow")
 * Yodeling (e.g., "Hocus Pocus")
 * Whistling (e.g., "I Was Kaiser Bill's Batman" or "Colonel Bogey March")
 * Spoken statements at the end of the track (e.g., "God Bless the Children of the Beast" by Mötley Crüe or "For the Love of God" by Steve Vai)
 * Non-musical vocal recordings taken from other media (e.g., "Vampires" by Godsmack)
 * Field recordings which may or may not contain non-lyrical words (e.g., many songs by Godspeed You! Black Emperor and other post-rock bands)

Songs including actual musical—rhythmic, melodic, and lyrical—vocals might still be categorized as instrumentals if the vocals appear only as a short part of an extended piece (e.g., "Unchained Melody" (Les Baxter), "Batman Theme", "TSOP (The Sound of Philadelphia)", "Pick Up the Pieces", "The Hustle", "Fly, Robin, Fly", "Get Up and Boogie", "Do It Any Way You Wanna", and "Gonna Fly Now"), though this definition is loose and subjective.

Falling just outside of that definition is "Theme from Shaft" by Isaac Hayes.

"Better Off Alone", which began as an instrumental by DJ Jurgen, had vocals by Judith Pronk, who would become a seminal part of Alice Deejay, added in later releases of the track.

title: Instrumental