Antibody
Overview
 
An antibody, also known as an immunoglobulin, is a large Y-shaped protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 used by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 to identify and neutralize foreign objects such as bacteria and virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

es. The antibody recognizes a unique part of the foreign target, termed an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

. Each tip of the "Y" of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...

 (similarly analogous to a key) on an antigen, allowing these two structures to bind together with precision.
Encyclopedia
An antibody, also known as an immunoglobulin, is a large Y-shaped protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 used by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 to identify and neutralize foreign objects such as bacteria and virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

es. The antibody recognizes a unique part of the foreign target, termed an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

. Each tip of the "Y" of an antibody contains a paratope (a structure analogous to a lock) that is specific for one particular epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...

 (similarly analogous to a key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly (for example, by blocking a part of a microbe that is essential for its invasion and survival). The production of antibodies is the main function of the humoral immune system.

Antibodies are produced by a type of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

 called a plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

. Antibodies can occur in two physical forms, a soluble form that is secreted from the cell, and a membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

-bound form that is attached to the surface of a B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

 and is referred to as the B cell receptor (BCR). The BCR is only found on the surface of B cells and facilitates the activation of these cells and their subsequent differentiation into either antibody factories called plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

s, or memory B cell
Memory B cell
Memory B cells are a B cell sub-type that are formed following primary infection.-Primary response, paratopes, and epitopes:In wake of first infection involving a particular antigen, the responding naïve cells proliferate to produce a colony of cells, most of which differentiate into the plasma...

s that will survive in the body and remember that same antigen so the B cells can respond faster upon future exposure. In most cases, interaction of the B cell with a T helper cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

 is necessary to produce full activation of the B cell and, therefore, antibody generation following antigen binding. Soluble antibodies are released into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 and tissue fluids, as well as many secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...

s to continue to survey for invading microorganisms.

Antibodies are glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s belonging to the immunoglobulin superfamily
Immunoglobulin superfamily
The immunoglobulin superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins ; they all possess a...

; the terms antibody and immunoglobulin are often used interchangeably. Antibodies are typically made of basic structural units—each with two large heavy chain
Heavy chain
]The immunoglobulin heavy chain is the large polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains. Several different types of heavy chain exist that define the class or isotype of an antibody. These heavy chain types vary...

s and two small light chains
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...

. There are several different types of antibody heavy chains, and several different kinds of antibodies, which are grouped into different isotypes
Isotype (immunology)
An isotype usually refers to any related proteins/genes from a particular gene family. In immunology, the "immunoglobulin isotype" refers to the genetic variations or differences in the constant regions of the heavy and light chains...

based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.

Though the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures, or antigen binding sites, to exist. This region is known as the hypervariable region. Each of these variants can bind to a different target, known as an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

. This enormous diversity of antibodies allows the immune system to recognize an equally wide variety of antigens. The large and diverse population of antibodies is generated by random combinations of a set of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 segments that encode different antigen binding sites (or paratopes), followed by random mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s in this area of the antibody gene, which create further diversity. Antibody genes also re-organize in a process called class switching
Immunoglobulin class switching
Immunoglobulin class switching is a biological mechanism that changes a B cell's production of antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG...

 that changes the base of the heavy chain to another, creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to be used by several different parts of the immune system.

Forms

Surface immunoglobulin (Ig) is attached to the membrane of the effector B cells by its transmembrane region, while antibodies are the secreted form of Ig and lack the trans membrane region so that antibodies can be secreted into the bloodstream and body cavities. As a result, surface Ig and antibodies are identical except for the transmembrane regions. Therefore, they are considered two forms of antibodies: soluble form or membrane-bound form (Parham 21-22).

The membrane-bound form of an antibody may be called a surface immunoglobulin (sIg) or a membrane immunoglobulin (mIg). It is part of the B cell receptor (BCR), which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation. The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β heterodimers, which are capable of signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

. A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface. Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate the BCRs from most other cell signaling receptors.
These patches may improve the efficiency of the cellular immune response
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...

. In humans, the cell surface is bare around the B cell receptors for several thousand ångstroms, which further isolates the BCRs from competing influences.

Isotypes

Antibody isotypes of mammals
Name Types Description Antibody Complexes
IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....

 
2 Found in mucosal areas, such as the gut
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...

, respiratory tract
Respiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...

 and urogenital tract, and prevents colonization by pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s. Also found in saliva, tears, and breast milk.
IgD
IGD
IGD can refer to:*Internet Gateway Device as defined in UPnP.*İGD, İlerici Gençler Derneği, Progressive Young Association of Turkey*Immunoglobulin D, an antibody protein involved in the maturation of B cells....

 
1 Functions mainly as an antigen receptor on B cells that have not been exposed to antigens. It has been shown to activate basophils and mast cells to produce antimicrobial factors.
IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...

 
1 Binds to allergens and triggers histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

 release from mast cells and basophils, and is involved in allergy
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

. Also protects against parasitic worm
Parasitic worm
Parasitic worms or helminths are a division of eukaryoticparasites that, unlike external parasites such as lice and fleas, live inside their host. They are worm-like organisms that live and feed off living hosts, receiving nourishment and protection while disrupting their hosts' nutrient...

s.
IgG  4 In its four forms, provides the majority of antibody-based immunity against invading pathogens. The only antibody capable of crossing the placenta to give passive immunity to fetus.
IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...

 
1 Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high avidity
Avidity
In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...

. Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG.

Antibodies can come in different varieties known as isotypes
Isotype (immunology)
An isotype usually refers to any related proteins/genes from a particular gene family. In immunology, the "immunoglobulin isotype" refers to the genetic variations or differences in the constant regions of the heavy and light chains...

 or classes. In placental
Eutheria
Eutheria is a group of mammals consisting of placental mammals plus all extinct mammals that are more closely related to living placentals than to living marsupials . They are distinguished from noneutherians by various features of the feet, ankles, jaws and teeth...

 mammals there are five antibody isotypes known as IgA, IgD, IgE, IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.

The antibody isotype of a B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...

 changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity—the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen. B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

 into an antibody producing cell called a plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system.

Structure

Antibodies are heavy (~150 kDa) globular
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...

 plasma proteins. They have sugar chains added to some of their amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 residues. In other words, antibodies are glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s
. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...

 (containing only one Ig unit); secreted antibodies can also be dimeric
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

 with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentamer
Pentamer
A pentamer is a thing composed out of five sub-units.In chemistry, it applies to molecules made of five monomers.In biochemistry, it applies to macromolecules, in particular to pentameric proteins, made of five proteic sub-units....

ic with five Ig units, like mammalian IgM.
The variable parts of an antibody are its V regions, and the constant part is its C region.

Immunoglobulin domains

The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

s.
Each chain is composed of structural domains called immunoglobulin domain
Immunoglobulin domain
The immunoglobulin domain is a type of protein domain that consists of a 2-layer sandwich of between 7 and 9 antiparallel β-strands arranged in two β-sheets with a Greek key topology....

s. These domains contain about 70-110 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function. They have a characteristic immunoglobulin fold in which two beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...

s create a “sandwich” shape, held together by interactions between conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

s and other charged amino acids.

Heavy chain

There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ. The type of heavy chain present defines the class of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s.
In bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...

s, the major serum antibody, also found in yolk, is called IgY
Immunoglobulin Y
Immunoglobulin Y is a type of immunoglobulin which is the major antibody in bird, reptile, and lungfish blood. It is also found in high concentrations in chicken egg yolk...

. It is quite different from mammalian IgG. However, in some older literature and even on some commercial life sciences product websites it is still called "IgG", which is incorrect and can be confusing.

Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone
Clone (B-cell biology)
The process of immunological B-cell maturation involves transformation from an undifferentiated B cell to one that secretes antibodies with particular specificity...

. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.

Light chain

In mammals there are two types of immunoglobulin light chain
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...

, which are called lambda (λ) and kappa (κ). A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι) chain, are found in lower vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

s like Chondrichthyes
Chondrichthyes
Chondrichthyes or cartilaginous fishes are jawed fish with paired fins, paired nares, scales, two-chambered hearts, and skeletons made of cartilage rather than bone...

 and Teleostei
Teleostei
Teleostei is one of three infraclasses in class Actinopterygii, the ray-finned fishes. This diverse group, which arose in the Triassic period, includes 20,000 extant species in about 40 orders; most living fishes are members of this group...

.

CDRs, Fv, Fab and Fc Regions

Some parts of an antibody have unique functions. The arms of the Y, for example, contain the sites that can bind two antigens (in general identical) and, therefore, recognize specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody.
The paratope
Paratope
The paratope is the part of an antibody which recognises an antigen, the antigen-binding site of an antibody. It is a small region of the antibody's Fv region and contains parts of the antibody's heavy and light chains....

 is shaped at the amino terminal end
N-terminal end
The N-terminus refers to the start of a protein or polypeptide terminated by an amino acid with a free amine group . The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus...

 of the antibody monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...

 by the variable domains from the heavy and light chains. The variable domain is also referred to as the FV region and is the most important region for binding to antigens. More specifically, variable loops of β-strands, three each on the light (VL) and heavy (VH) chains are responsible for binding to the antigen. These loops are referred to as the complementarity determining region
Complementarity determining region
Complementarity determining regions are regions within antibodies or T cell receptors where these proteins complement an antigen's shape. Thus, CDRs determine the protein's affinity and specificity for specific antigens...

s (CDRs).
The structures of these CDRs have been clustered and classified by Chothia et al.

and more recently by North et al.
In the framework of the immune network theory
Immune network theory
The immune network theory is a theory of how the adaptive immune system works, that has been developed since 1974 mainly by Niels Jerne and Geoffrey W. Hoffmann. The theory states that the immune system is an interacting network of lymphocytes and molecules that have variable regions...

, CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes.

The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. Thus, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen, by binding to a specific class of Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....

s, and other immune molecules, such as complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

 proteins. By doing this, it mediates different physiological effects including recognition of opsonized particles, lysis
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....

 of cells, and degranulation
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...

 of mast cells, basophils and eosinophils.

Function

Activated B cells differentiate
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

 into either antibody-producing cells called plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

s that secrete soluble antibody or memory cells
Memory B cell
Memory B cells are a B cell sub-type that are formed following primary infection.-Primary response, paratopes, and epitopes:In wake of first infection involving a particular antigen, the responding naïve cells proliferate to produce a colony of cells, most of which differentiate into the plasma...

 that survive in the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures.

At the prenatal and neonatal stages of life, the presence of antibodies is provided by passive immunization from the mother. Early endogenous antibody production varies for different kinds of antibodies, and usually appear within the first years of life. Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

 (an example is a virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 capsid protein
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...

 fragment). Antibodies contribute to immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 in three ways: they prevent pathogens from entering or damaging cells by binding to them; they stimulate removal of pathogens by macrophages and other cells by coating the pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

.

Activation of complement

Antibodies that bind to surface antigens on, for example, a bacterium attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...

s in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex
Complement membrane attack complex
The membrane attack complex is typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the alternative pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane...

 to assist antibodies to kill the bacterium directly.

Activation of effector cells

To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate
Agglutination (biology)
Agglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue."This occurs in biology in three main examples:...

. Since an antibody has at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.

Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...

s and neutrophils will degranulate
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...

, natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...

s will release cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens.

Natural antibodies

Humans and higher primates also produce “natural antibodies” which are present in serum before viral infection. Natural antibodies have been defined as antibodies that are produced without any previous infection, vaccination, other foreign antigen exposure or passive immunization. These antibodies can activate the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Many natural antibodies are directed against the disaccharide galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....

 α(1,3)-galactose (α-Gal), which is found as a terminal sugar on glycosylated cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut. Rejection of xenotransplantated organs is thought to be, in part, the result of natural antibodies circulating in the serum of the recipient binding to α-Gal antigens expressed on the donor tissue.

Immunoglobulin diversity

Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens. It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.

Domain variability

The region (locus) of a chromosome that encodes an antibody is large and contains several distinct genes for each domain of the antibody—the locus containing heavy chain genes (IGH@
IGH@
Immunoglobulin heavy locus, also known as IGH@, is a region on human chromosome 14 that contains a gene for the heavy chains of human antibodies .-Further reading:...

) is found on chromosome 14, and the loci containing lambda and kappa light chain genes (IGL@
IGL@
Immunoglobulin lambda locus, also known as IGL@, is a region on human chromosome 22 that contains genes for the lambda light chains of antibodies .- Function :...

 and IGK@
IGK@
Immunoglobulin kappa locus, also known as IGK@, is a region on human chromosome 2 that contains genes for the kappa light chains of antibodies ....

) are found on chromosomes 22 and 2 in humans. One of these domains is called the variable domain, which is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells. Differences, between the variable domains, are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity determining region
Complementarity determining region
Complementarity determining regions are regions within antibodies or T cell receptors where these proteins complement an antigen's shape. Thus, CDRs determine the protein's affinity and specificity for specific antigens...

s (CDR1, CDR2 and CDR3). CDRs are supported within the variable domains by conserved framework regions. The heavy chain locus contains about 65 different variable domain genes that all differ in their CDRs. Combining these genes with an array of genes for other domains of the antibody generates a large cavalry of antibodies with a high degree of variability. This combination is called V(D)J recombination discussed below.

V(D)J recombination

Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments. These segments are called variable (V), diversity (D) and joining (J) segments. V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...

. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

s of mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.

After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion
Allelic exclusion
Allelic exclusion is a process by which only one allele of a gene is expressed while the other allele is silenced. For most genes, the individual inherits one copy of each gene from each parent....

) thus each B cell can produce antibodies containing only one kind of variable chain.

Somatic hypermutation and affinity maturation

For more details on this topic, see Somatic hypermutation
Somatic hypermutation
Somatic hypermutation is a mechanism inside cells that is part of the way the immune system adapts to the new foreign elements that confront it . SHM diversifies the receptors used by the immune system to recognize foreign elements and allows the immune system to adapt its response to new threats...

 and Affinity maturation
Affinity maturation
In immunology, affinity maturation is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. A secondary response...



Following activation with antigen, B cells begin to proliferate
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...

 rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

 change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 differences in the variable domains of their antibody chains.

This serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity
Chemical affinity
In chemical physics and physical chemistry, chemical affinity is the electronic property by which dissimilar chemical species are capable of forming chemical compounds...

. Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity). B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells.

Class switching

Isotype or class switching
Immunoglobulin class switching
Immunoglobulin class switching is a biological mechanism that changes a B cell's production of antibody from one class to another, for example, from an isotype called IgM to an isotype called IgG...

 is a biological process
Biological process
A biological process is a process of a living organism. Biological processes are made up of any number of chemical reactions or other events that results in a transformation....

 occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG). The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naïve B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function, therefore, after activation, an antibody with a IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.

Class switching occurs in the heavy chain gene locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

 by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

 motifs, called switch (S) regions, found in DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s at two selected S-regions. The variable domain exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...

 is rejoined through a process called non-homologous end joining
Non-homologous end joining
Non-homologous end joining is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homologous recombination, which requires a homologous sequence to guide...

 (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype.

Disease diagnosis and therapy

Detection of particular antibodies is a very common form of medical diagnostics
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

, and applications such as serology
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...

 depend on these methods. For example, in biochemical assays for disease diagnosis, a titer
Titer
A titer is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a positive...

 of antibodies directed against Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...

 or Lyme disease
Lyme disease
Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...

 is estimated from the blood. If those antibodies are not present, either the person is not infected, or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed. In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry
Nephelometry
Nephelometry is a technique used in immunology to determine levels of IgM, IgG, and IgA.It is performed by measuring the turbidity in a water sample by passing light through the sample being measured...

 (or turbidimetry) to characterize the antibody profile of patient. Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 damage in patients whom the diagnosis is unclear. For example, elevated IgA indicates alcoholic cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

, elevated IgM indicates viral hepatitis
Viral hepatitis
Viral hepatitis is liver inflammation due to a viral infection. It may present in acute or chronic forms. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E...

 and primary biliary cirrhosis
Primary biliary cirrhosis
Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...

, while IgG is elevated in viral hepatitis, autoimmune hepatitis
Autoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...

 and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...

s; many can be detected through blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....

s. Antibodies directed against red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

 surface antigens in immune mediated hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...

 are detected with the Coombs test
Coombs test
Coombs test refers to two clinical blood tests used in immunohematology and immunology...

. The Coombs test is also used for antibody screening in blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...

 preparation and also for antibody screening in antenatal women.
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...

, immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...

, Western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...

, immunodiffusion
Immunodiffusion
Immunodiffusion is a diagnostic test which involves diffusion through a substance such as agar.Two commonly known forms are Ouchterlony double immunodiffusion and radial immunodiffusion....

, immunoelectrophoresis
Immunoelectrophoresis
Immunoelectrophoresis is a general name for a number of biochemical methods for separation and characterization of proteins based on electrophoresis and reaction with antibodies. All variants of immunoelectrophoresis require immunoglobulins, also known as antibodies reacting with the proteins to be...

, and magnetic immunoassay
Magnetic immunoassay
Magnetic immunoassay is a novel type of diagnostic immunoassay using magnetic beads as labels in lieu of conventional enzymes , radioisotopes or fluorescent moieties . This assay involves the specific binding of an antibody to its antigen, where a magnetic label is conjugated to one element of...

. Antibodies raised against human chorionic gonadotropin are used in over the counter pregnancy tests.
Targeted monoclonal antibody therapy
Monoclonal antibody therapy
Monoclonal antibody therapy is the use of monoclonal antibodies to specifically bind to target cells or proteins. This may then stimulate the patient's immune system to attack those cells...

 is employed to treat diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...

, and many forms of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 including non-Hodgkin's lymphoma, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....

, head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...

 and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

.
Some immune deficiencies, such as X-linked agammaglobulinemia
X-linked agammaglobulinemia
X-linked agammaglobulinemia is a rare X-linked genetic disorder that was discovered in 1952 which affects the body's ability to fight infection. XLA is an X-linked disorder, and therefore is more common in males...

 and hypogammaglobulinemia
Hypogammaglobulinemia
Hypogammaglobulinemia is a type of immune disorder characterized by a reduction in all types of gamma globulins.Hypogammaglobulinemia is a characteristic of common variable immunodeficiency.-Terminology:...

, result in partial or complete lack of antibodies. These diseases are often treated by inducing a short term form of immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 called passive immunity
Passive immunity
Passive immunity is the transfer of active humoral immunity in the form of readymade antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and can also be induced artificially, when high levels...

. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

, pooled immunoglobulin or monoclonal antibodies, into the affected individual.

Prenatal therapy

Rhesus factor, also known as Rhesus D (RhD) antigen, is an antigen found on red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

s; individuals that are Rhesus-positive (Rh+) have this antigen on their red blood cells and individuals that are Rhesus-negative (Rh–) do not. During normal childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...

, delivery trauma or complications during pregnancy, blood from a fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...

 can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

, and any subsequent pregnancies, at risk for hemolytic disease of the newborn
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...

.

Rho(D) immune globulin
Rho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...

 antibodies are specific for human Rhesus D (RhD) antigen. Anti-RhD antibodies are administered as part of a prenatal treatment regimen
Prenatal care
Prenatal care refers to the medical and nursing care recommended for women before and during pregnancy. The aim of good prenatal care is to detect any potential problems early, to prevent them if possible , and to direct the woman to appropriate specialists, hospitals, etc...

 to prevent sensitization that may occur when a Rhesus-negative mother has a Rhesus-positive fetus. Treatment of a mother with Anti-RhD antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. Importantly, this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent babies. Rho(D) Immune Globulin treatment prevents sensitization that can lead to Rh disease
Rh disease
Rh disease is one of the causes of hemolytic disease of the newborn...

, but does not prevent or treat the underlying disease itself.

Research applications

Specific antibodies are produced by injecting an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

 into a mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

, such as a mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

, rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

, rabbit
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...

, goat
Goat
The domestic goat is a subspecies of goat domesticated from the wild goat of southwest Asia and Eastern Europe. The goat is a member of the Bovidae family and is closely related to the sheep as both are in the goat-antelope subfamily Caprinae. There are over three hundred distinct breeds of...

, sheep, or horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

 for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies—multiple antibodies that bind to the same antigen—in the serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

, which can now be called antiserum
Antiserum
Antiserum is blood serum containing polyclonal antibodies. Antiserum is used to pass on passive immunity to many diseases. Passive antibody transfusion from a previous human survivor is the only known effective treatment for Ebola infection .The most common use of antiserum in humans is as...

. Antigens are also injected into chicken
Chicken
The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...

s for generation of polyclonal antibodies in egg yolk
Egg yolk
An egg yolk is a part of an egg which feeds the developing embryo. The egg yolk is suspended in the egg white by one or two spiral bands of tissue called the chalazae...

. To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

s are isolated from the animal and immortalized
Biological immortality
Biological immortality refers to a stable rate of mortality as a function of chronological age. Some individual cells and entire organisms in some species achieve this state either throughout their existence or after living long enough. This requires that death occur from injury or disease rather...

 by fusing them with a cancer cell line. The fused cells are called hybridoma
Hybridoma
Hybridoma technology is a technology of forming hybrid cell lines by fusing a specific antibody-producing B cell with a myeloma cell that is selected for its ability to grow in tissue culture and for an absence of antibody chain synthesis...

s, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning
Dilution cloning
Dilution cloning describes the process of obtaining a monoclonal cell population starting from a polyclonal mass of cells.This is achieved by setting up a series of increasing dilutions of the parent cell culture...

 to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....

. Polyclonal and monoclonal antibodies are often purified using Protein A/G
Protein A/G
Protein A/G is a recombinant fusion protein that combines IgG binding domains of both Protein A and Protein G. Protein A/G contains four Fc binding domains from Protein A and two from Protein G, yielding a final mass of 50,460 daltons...

 or antigen-affinity chromatography
Affinity chromatography
Affinity chromatography is a method of separating biochemical mixtures and based on a highly specific interaction such as that between antigen and antibody, enzyme and substrate, or receptor and ligand.-Uses:Affinity chromatography can be used to:...

.

In research, purified antibodies are used in many applications. They are most commonly used to identify and locate intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...

 and extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...

 proteins. Antibodies are used in flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...

 to differentiate cell types by the proteins they express; different types of cell express different combinations of cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...

 molecules on their surface, and produce different intracellular and secretable proteins. They are also used in immunoprecipitation
Immunoprecipitation
Immunoprecipitation is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins...

 to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate, in Western blot
Western blot
The western blot is a widely used analytical technique used to detect specific proteins in the given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native proteins by 3-D structure or denatured proteins by the length of the polypeptide...

 analyses to identify proteins separated by electrophoresis
Electrophoresis
Electrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...

, and in immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...

 or immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...

 to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...

. Proteins can also be detected and quantified with antibodies, using ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...

 and ELISPOT
ELISPOT
The Enzyme-linked immunosorbent spot assay is a common method for monitoring immune responses in humans and animals. It was developed by Cecil Czerkinsky in 1983....

 techniques.

Structure prediction

The importance of antibodies in health care and the biotechnology
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 industry demands knowledge of their structures at high resolution
Image resolution
Image resolution is an umbrella term that describes the detail an image holds. The term applies to raster digital images, film images, and other types of images. Higher resolution means more image detail....

. This information is used for protein engineering
Protein engineering
Protein engineering is the process of developing useful or valuable proteins. It is a young discipline, with much research taking place into the understanding of protein folding and recognition for protein design principles....

, modifying the antigen binding affinity, and identifying an epitope, of a given antibody. X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...

 is one commonly used method for determining antibody structures. However, crystallizing an antibody is often laborious and time consuming. Computational approaches provide a cheaper and faster alternative to crystallography, but their results are more equivocal since they do not produce empirical structures. Online web servers such as Web Antibody Modeling (WAM) and Prediction of Immunoglobulin Structure (PIGS) enables computational modeling of antibody variable regions. Rosetta Antibody is a novel antibody FV region structure prediction server
Server (computing)
In the context of client-server architecture, a server is a computer program running to serve the requests of other programs, the "clients". Thus, the "server" performs some computational task on behalf of "clients"...

, which incorporates sophisticated techniques to minimize CDR loops and optimize the relative orientation of the light and heavy chains, as well as homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 models that predict successful docking of antibodies with their unique antigen.

History

The first use of the term "antibody" occurred in a text by Paul Ehrlich
Paul Ehrlich
Paul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...

. The term Antikörper (the German word for antibody) appears in the conclusion of his article "Experimental Studies on Immunity", published in October 1891, which states that "if two substances give rise to two different antikörper, then they themselves must be different". However, the term was not accepted immediately and several other terms for antibody were proposed; these included Immunkörper, Amboceptor, Zwischenkörper, substance sensibilisatrice, copula, Desmon, philocytase, fixateur, and Immunisin. The word antibody has formal analogy to the word antitoxin
Antitoxin
An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria. Although they are most effective in neutralizing toxins, they can kill bacteria and other microorganisms. Antitoxins are made within organisms, but can be...

and a similar concept to Immunkörper.

The study of antibodies began in 1890 when Kitasato Shibasaburō
Kitasato Shibasaburō
Baron was a Japanese physician and bacteriologist. He is remembered as the co-discoverer of the infectious agent of bubonic plague in Hong Kong in 1894, almost simultaneously with Alexandre Yersin.-Biography:...

 described antibody activity against diphtheria
Diphtheria
Diphtheria is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is characterized by sore throat, low fever, and an adherent membrane on the tonsils, pharynx, and/or nasal cavity...

 and tetanus toxins. Kitasato put forward the theory of humoral immunity
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...

, proposing that a mediator in serum could react with a foreign antigen. His idea prompted Paul Ehrlich to propose the side chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as “side chains”) on the surface of cells could bind specifically to toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

s – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies. Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright
Almroth Wright
Sir Almroth Edward Wright, KBE, CB was a British bacteriologist and immunologist.He is notable for developing a system of anti-typhoid fever inoculation, recognizing early on that antibiotics would create resistant bacteria and being a strong advocate for preventive medicine.-Biography:Wright was...

 suggested that soluble antibodies coated bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 to label them for phagocytosis and killing; a process that he named opsonin
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

ization.

In the 1920s, Michael Heidelberger
Michael Heidelberger
Michael Heidelberger was an American immunologist who is regarded as the father of modern immunology. He and Oswald Avery showed that the polysaccharides of pneumococcus are antigens, enabling him to show that antibodies are proteins...

 and Oswald Avery
Oswald Avery
Oswald Theodore Avery ForMemRS was a Canadian-born American physician and medical researcher. The major part of his career was spent at the Rockefeller University Hospital in New York City...

 observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein. The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack
John Marrack
Professor John Richardson Marrack, DSO, MC was the Emeritus Professor of Chemical Pathology in the University of London, visiting professor to the University of Texas and known for his book Antigens and Antibodies ....

. The next major advance was in the 1940s, when Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...

 confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition. In 1948, Astrid Fagreaus discovered that B cells, in the form of plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...

s, were responsible for generating antibodies.

Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman
Gerald Edelman
Gerald Maurice Edelman is an American biologist who shared the 1972 Nobel Prize in Physiology or Medicine for work with Rodney Robert Porter on the immune system. Edelman's Nobel Prize-winning research concerned discovery of the structure of antibody molecules...

 and Joseph Gally of the antibody light chain
Immunoglobulin light chain
]The immunoglobulin light chain is the small polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains.-In humans:...

, and their realization that this protein was the same as the Bence-Jones protein described in 1845 by Henry Bence Jones
Henry Bence Jones
Henry Bence Jones was an English physician and chemist.- Biography :He was born at Thorington Hall, Yoxley, Suffolk, the son of Lieutenant Colonel William Jones, an officer in the 5th Dragoon Guards, and Matilda Bence...

. Edelman went on to discover that antibodies are composed of disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter. Together, these scientists deduced the structure and complete amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

. The Fv fragment was prepared and characterized by David Givol. While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....

) and David S. Rowe and John L. Fahey identified IgD, and IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...

 was identified by Kimishige Ishizaka
Kimishige Ishizaka
Dr is a Japanese scientist who discovered the antibody class IgE in 1966. His work has been regarded as a major breakthrough in the understanding of allergy. He was awarded the 1973 Gairdner Foundation International Award and the 2000 Japan Prize for his work in immunology. He was elected a member...

 and Teruko Ishizaka as a class of antibodies involved in allergic reactions. Genetic studies identifying the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was by Susumu Tonegawa
Susumu Tonegawa
Susumu Tonegawa is a Japanese scientist who won the Nobel Prize for Physiology or Medicine in 1987 for his discovery of the genetic mechanism that produces antibody diversity. Although he won the Nobel Prize for his work in immunology, Tonegawa is a molecular biologist by training...

 in 1976.

External links

  • Mike's Immunoglobulin Structure/Function Page at University of Cambridge
    University of Cambridge
    The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally...

  • Antibodies as the PDB molecule of the month Discussion of the structure of antibodies at Protein Data Bank
    Protein Data Bank
    The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....

  • Microbiology and Immunology On-line Textbook at University of South Carolina
    University of South Carolina
    The University of South Carolina is a public, co-educational research university located in Columbia, South Carolina, United States, with 7 surrounding satellite campuses. Its historic campus covers over in downtown Columbia not far from the South Carolina State House...

  • A hundred years of antibody therapy History and applications of antibodies in the treatment of disease at University of Oxford
    University of Oxford
    The University of Oxford is a university located in Oxford, United Kingdom. It is the second-oldest surviving university in the world and the oldest in the English-speaking world. Although its exact date of foundation is unclear, there is evidence of teaching as far back as 1096...

  • How Lymphocytes Produce Antibody from Cells Alive!
  • Antibody applications Fluorescent antibody image library, University of Birmingham
    University of Birmingham
    The University of Birmingham is a British Redbrick university located in the city of Birmingham, England. It received its royal charter in 1900 as a successor to Birmingham Medical School and Mason Science College . Birmingham was the first Redbrick university to gain a charter and thus...

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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