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[[Image:Antibody.svg|thumb|255px|Each antibody binds to a specific antigen; an interaction similar to a lock and key.]]

'''Antibodies''' (also known as '''immunoglobulins'''<ref name="pmid8450761">{{cite journal |author=Litman GW, Rast JP, Shamblott MJ, ''et al'' |title=Phylogenetic diversification of immunoglobulin genes and the antibody repertoire |journal=Mol. Biol. Evol. |volume=10 |issue=1 |pages=60–72 |year=1993 |pmid=8450761 |doi=}}</ref>) are [[protein]]s that are found in [[blood]] or other [[bodily fluid]]s of [[vertebrate]]s, and are used by the [[immune system]] to identify and neutralize foreign objects, such as [[bacterium|bacteria]] and [[virus]]es. They are made of a few basic structural units called ''chains''; each antibody has two large [[heavy chain]]s '''H''' and two small [[light chain]]s '''L'''. Antibodies are produced by a kind of white blood cell called a [[B cell]].  There are several different types of antibody heavy chain, and several different kinds of antibodies, which are grouped into different ''[[isotype (immunology)|isotypes]]'' 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.<ref name=Market>Eleonora Market, F. Nina Papavasiliou (2003) [http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0000016 ''V(D)J Recombination and the Evolution of the Adaptive Immune System''] [[PLoS Biology]]1(1): e16.</ref>

Although 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 to exist. This region is known as the hypervariable region. Each of these variants can bind to a different target, known as an [[antigen]].<ref name=Janeway5>{{cite book | author = [[Charles Janeway|Janeway CA, Jr]] ''et al'' | title = Immunobiology. | edition = 5th ed. | publisher = Garland Publishing | year = 2001 | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10 | isbn = 0-8153-3642-X }}</ref> This huge diversity of antibodies allows the immune system to recognize an equally wide diversity of antigens. The unique part of the antigen recognized by an antibody is called an [[epitope]]. These epitopes bind with their antibody in a highly specific interaction, called [[induced fit]], that allows antibodies to identify and bind only their unique antigen in the midst of the millions of different molecules that make up an [[organism]]. Recognition of an antigen by an antibody ''tags'' it for attack by other parts of the immune system. Antibodies can also neutralize targets directly by, for example, binding to a part of a [[pathogen]] that it needs to cause an infection.<ref name=Rhoades>{{cite book | author =  Rhoades RA, Pflanzer RG | title = Human Physiology | edition = 4th ed. | publisher = Thomson Learning | year = 2002 | isbn = 0-534-42174-1}}</ref>

The large and diverse population of antibodies is generated by random combinations of a set of [[gene]] segments that encode different antigen binding sites (or ''paratopes''), followed by random [[mutation]]s in this area of the antibody gene, which create further diversity.<ref name=Market/><ref name=diaz>{{cite journal |author=Diaz M, Casali P |title=Somatic immunoglobulin hypermutation |journal=Curr Opin Immunol |volume=14 |issue=2 |pages=235-40 |year=2002 |pmid=11869898}}</ref> Antibody genes also re-organize in a process called [[Immunoglobulin class switching|class switching]] 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. Production of antibodies is the main function of the [[Humoral immunity|humoral immune system]].<ref name=Pier>{{cite book | author =  Pier GB, Lyczak JB, Wetzler LM | title = Immunology, Infection, and Immunity | edition = | publisher = ASM Press| year = 2004 | isbn = 1-55581-246-5}}</ref>

==Antibody forms==
Antibodies occur in two forms: a [[soluble]] form [[secretion|secreted]] into the blood and [[Tissue (biology)|tissue]] fluids, and a [[cell membrane|membrane-bound]] form  attached to the surface of a [[B cell]] that is called the ''B cell receptor'' (BCR). The BCR allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.<ref>{{cite journal |author=Parker D |title=T cell-dependent B cell activation |journal=Annu Rev Immunol |volume=11 |issue= |pages=331-60 |year=1993 |pmid=8476565}}</ref>  Activated B cells [[cellular differentiation|differentiate]] into either antibody generating factories called [[plasma cell]]s that secrete soluble antibody, or into [[memory B cell|memory cell]]s that survive in the body for years afterwards to allow the immune system to remember an antigen and respond faster upon future exposures.<ref>{{cite journal |author=Borghesi L, Milcarek C |title=From B cell to plasma cell: regulation of V(D)J recombination and antibody secretion |journal=Immunol Res |volume=36 |issue=1-3 |pages=27-32 |year=2006 |pmid=17337763}}</ref>  Antibodies are, therefore, an essential component of the [[adaptive immune system]] that learns, adapts and remembers responses to invading pathogens. 

== Isotypes ==
{| class = "prettytable" style = "width:55%; float:right; font-size:90%; margin-left:15px"
|+ Antibody isotypes of mammals
| '''Name''' || '''Types''' || align="center" | '''Description''' || align="center" | '''Antibody Complexes'''
|-
| align="center" | [[IgA]] || align="center" | 2 || Found in [[mucosal]] areas, such as the [[gut]], [[respiratory tract]] and [[urogenital tract]], and prevents colonization by [[pathogen]]s.<ref>{{cite journal |author=Underdown B, Schiff J |title=Immunoglobulin A: strategic defense initiative at the mucosal surface |journal=Annu Rev Immunol |volume=4 |issue= |pages=389-417 |year=1986 |pmid=3518747}}</ref> Also found in saliva, tears, and breast milk.||  rowspan="5" |[[Image:Mono-und-Polymere.svg|170px|Some antibodies form [[protein structure|complexes]] that bind to multiple antigen molecules.]]
 |-
 | align="center" | [[IgD]] || align="center" | 1 || Functions mainly as an antigen receptor on B cells that have not been exposed to antigens.<ref name=Geisberger>{{cite journal |author=Geisberger R, Lamers M, Achatz G |title=The riddle of the dual expression of IgM and IgD |journal=Immunology |volume=118 |issue=4 |pages=429-37 |year=2006 |pmid=16895553}}</ref> Its function is less defined than other isotypes.
  |- 
 | align="center" | [[IgE]] || align="center" | 1 || Binds to [[allergens]] and triggers [[histamine]] release from [[mast cells]] and [[basophil]]s, and is involved in [[allergy]]. Also protects against [[parasitic worm]]s.<ref name=Pier/> 
 |- 
 | align="center" | [[IgG]] || align="center" | 4|| In its four forms, provides the majority of antibody-based immunity against invading pathogens.<ref name=Pier/> The only antibody capable of crossing the placenta to give passive immunity to fetus.  
 |- 
 | align="center" | [[IgM]] || align="center" | 1 || Expressed on the surface of B cells and in a secreted form with very high avidity. Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG.<ref name=Pier/><ref name=Geisberger/> 
|}
Antibodies can come in different varieties known as [[Isotype (immunology)|isotypes]] or classes.  In 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.<ref name = woof>{{cite journal |author=Woof J, Burton D |title=Human antibody-Fc receptor interactions illuminated by crystal structures |journal=Nat Rev Immunol |volume=4 |issue=2 |pages=89-99 |year=2004 |pmid=15040582}}</ref>  

The antibody isotype of a B cell changes during the cell's [[B cell#Development of B cells|development]] and [[B cell#Activation of B cells|activation]].  Immature B cells,  which have never been exposed to 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.<ref name=Goding>{{cite journal |author=Goding J |title=Allotypes of IgM and IgD receptors in the mouse: a probe for lymphocyte differentiation |journal=Contemp Top Immunobiol |volume=8 |issue= |pages=203-43 |year= |pmid=357078}}</ref>  B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and [[Cellular differentiation|differentiate]] into an antibody producing cell called a [[plasma cell]].  In this activated form, the B cell starts to produce antibody in a [[secrete]]d form rather than a [[cell membrane|membrane]]-bound form.  Some [[daughter cell]]s 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 (~150k[[Dalton (unit)|Da]]) [[globular protein|globular]] [[plasma protein]]s that are also known as immunoglobulins.  They have sugar chains added to some of their [[amino acid]] residues.<ref>{{cite journal |author=Mattu T, Pleass R, Willis A, Kilian M, Wormald M, Lellouch A, Rudd P, Woof J, Dwek R |title=The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fc alpha receptor interactions |journal=J Biol Chem |volume=273 |issue=4 |pages=2260-72 |year=1998 |pmid=9442070}}</ref> In other words, antibodies are ''[[glycoprotein]]s''.  The basic functional unit of each antibody is an immunoglobulin (Ig) [[monomer]] (containing only one Ig unit); secreted antibodies can also be [[dimer]]ic with two Ig units as with IgA, [[tetramer]]ic with four Ig units like [[teleost fish]] IgM, or [[pentamer]]ic with five Ig units, like mammalian IgM.<ref name = roux>{{cite journal |author=Roux K |title=Immunoglobulin structure and function as revealed by electron microscopy |journal=Int Arch Allergy Immunol |volume=120 |issue=2 |pages=85-99 |year=1999 |pmid=10545762}}</ref> 
[[Image:Antibody IgG2.png|thumb|right|Several immunoglobulin domains make up the two heavy chains (red and blue) and the two light chains (green and yellow) of an antibody. The immunoglobulin domains are composed of between 7 (IgC) and 9 (IgV) β-strands. See also: [http://www.emc.maricopa.edu/faculty/farabee/BIOBK/ANTIBODY.gif] ]]

===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]]s.<ref name = woof/>  
Each chain is composed of [[structural domain]]s called Ig domains.  These domains contain about 70-110 [[amino acid]]s and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function.<ref>{{cite journal |author=Barclay A |title=Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules |journal=Semin Immunol |volume=15 |issue=4 |pages=215-23 |year=2003 |id=PMID 14690046}}</ref>  They possess a characteristic [[immunoglobulin fold]] in which two [[beta sheet]]s create a “sandwich” shape, held together by interactions between conserved [[cysteine]]s and other charged amino acids.  

===Heavy chain===
{{details|heavy chain}}
There are five types of mammalian Ig [[heavy chain]] denoted by the Greek letters: α, δ, ε, γ, and μ.<ref name=Janeway5/> The type of heavy chain present defines the ''class'' of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.<ref name=Rhoades/> 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]]s.<ref name=Janeway5/> 
[[Image:Immunoglobulin basic unit.svg|thumb|1. [[Fragment antigen binding|Fab region]]<BR>2. [[Fragment crystallizable region|Fc region]]<BR>3. [[Heavy chain]] with one variable (V<sub>H</sub>) domain followed by a constant domain (C<sub>H</sub>1), a hinge region, and two more constant (C<sub>H</sub>2 and C<sub>H</sub>3) domains.<BR>4. [[Light chain]] with one variable (V<sub>L</sub>) and one constant (C<sub>L</sub>) domain<BR>5. Antigen binding site (paratope)<BR>6. Hinge regions.]]

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 [[Structural domain|domains]], and a hinge region for added flexibility;<ref name = woof/> heavy chains μ and ε have a constant region composed of ''four'' immunoglobulin domains.<ref name=Janeway5/>  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 [[Clone (B-cell biology)|B cell clone]]. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.

===Light chain===
{{details|light chain}}
In mammals there are two types of [[light chain]], which are called lambda (λ) and kappa (κ).<ref name=Janeway5/> 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.<ref name=Janeway5/> 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]]s like [[Chondrichthyes]] and [[Teleostei]].

===Fab and Fc Regions===

Some parts of an antibody have unique functions.  The tip of the Y, for example, contains the site that binds antigen and, therefore, recognizes specific foreign objects. This region of the antibody is called the ''[[Fab region|Fab (fragment, antigen binding) region]]''. It is composed of one constant and one variable domain from each heavy and light chain of the antibody.<ref name= putnam79>{{cite journal |author=Putnam FW, Liu YS, Low TL |title=Primary structure of a human IgA1 immunoglobulin. IV. Streptococcal IgA1 protease, digestion, Fab and Fc fragments, and the complete amino acid sequence of the alpha 1 heavy chain|journal= J Biol Chem|volume=254 |issue=8 |pages=2865-74|year=1979 |pmid=107164}}</ref> The paratope is shaped at the [[N-terminal end|amino terminal end]] of the antibody [[monomer]] by the variable domains from the heavy and light chains.

The base of the Y plays a role in modulating immune cell activity.  This region is called the ''[[Fc region|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.<ref name=Janeway5/> By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen.<ref>{{cite journal |author=Huber R |title=Spatial structure of immunoglobulin molecules |journal=Klin Wochenschr |volume=58 |issue=22 |pages=1217-31 |year=1980 |pmid=6780722}}</ref> The Fc region also binds to various cell [[receptor (biochemistry)|receptor]]s, such as [[Fc receptor]]s, and other immune molecules, such as [[Complement system|complement]] proteins. By doing this, it mediates different [[physiological]] effects including [[opsonization]], cell [[lysis]], and [[degranulation]] of [[mast cells]], [[basophils]] and [[eosinophils]].<ref name = woof/><ref>{{cite journal |author=Heyman B |title=Complement and Fc-receptors in regulation of the antibody response |journal=Immunol Lett |volume=54 |issue=2-3 |pages=195-9 |year=1996 |pmid=9052877}}</ref>

==Function== 
{{further|[[Immune system]]}}
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]], a [[virus]] [[capsid|hull protein]] fragment, for example. Antibodies contribute to [[immunity (medical)|immunity]] in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by [[macrophages]] and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other [[immune response]]s such as the [[complement system|complement pathway]].<ref name=Ravetch>{{cite journal |author=Ravetch J, Bolland S |title=IgG Fc receptors |journal=Annu Rev Immunol |volume=19 |issue= |pages=275-90 |year=2001 |pmid=11244038}}</ref>

===Activation of complement=== 
Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the [[complement cascade]] with their [[antibody#Fc region|Fc region]] and initiate activation of the "classical" complement system.<ref name=Ravetch/>  This results in the killing of bacteria in two ways.<ref name=Pier/>  First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes 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 [[Complement membrane attack complex|membrane attack complex]] to assist antibodies to kill the  bacterium directly.<ref>{{cite journal |author=Rus H, Cudrici C, Niculescu F |title=The role of the complement system in innate immunity |journal=Immunol Res |volume=33 |issue=2 |pages=103-12 |year=2005 |pmid=16234578}}</ref>

===Activation of effector cells===
To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to [[Agglutination (biology)|agglutinate]]. Since an antibody possesses 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.<ref name=Pier/> 

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 [[phagocytosis|phagocytose]], [[mast cell]]s and [[neutrophil]]s will [[degranulation|degranulate]], [[natural killer cell]]s will release [[cytokine]]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.<ref name=Janeway5/>

[[Image:IgM white background.png|thumb|left|The secreted mammalian [[IgM]] has five Ig units. Each Ig unit (labeled 1) has two epitope binding [[Fab region]]s, so IgM is capable of binding up to 10 epitopes.]]

== 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.<ref>{{cite journal |author=Mian I, Bradwell A, Olson A |title=Structure, function and properties of antibody binding sites |journal=J Mol Biol |volume=217 |issue=1 |pages=133-51 |year=1991 |pmid=1988675}}</ref>  It has been estimated  that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen.<ref name="pmid8612345">{{cite journal |author=Fanning LJ, Connor AM, Wu GE |title=Development of the immunoglobulin repertoire |journal=Clin. Immunol. Immunopathol. |volume=79 |issue=1 |pages=1-14 |year=1996 |pmid=8612345 |doi=}}</ref> Although a huge repertoire of different antibodies is generated in a single individual, the number of [[gene]]s available to make these proteins is limited.  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.<ref name = namazee>{{cite journal |author=Nemazee D |title=Receptor editing in lymphocyte development and central tolerance |journal=Nat Rev Immunol |volume=6 |issue=10 |pages=728-40 |year=2006 |pmid=16998507}}</ref>
[[Image:VDJ recombination.png|thumb|250px|right|Simplistic overview of V(D)J recombination of immunoglobulin heavy chains]]

===V(D)J recombination===
{{details|V%28D%29J 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.<ref name = namazee/>  V, D and J segments are found in [[heavy chain|Ig heavy chains]], but only V and J segments are found in [[light chain|Ig light chains]]. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the [[genome]]s of [[mammal]]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 [[wikt:paratope|paratopes]], and thus different antigen specificities.<ref name=Market/>

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]]) thus each B cell can produce antibodies containing only one kind of variable chain.<ref>{{cite journal |author=Bergman Y, Cedar H |title=A stepwise epigenetic process controls immunoglobulin allelic exclusion |journal=Nat Rev Immunol |volume=4 |issue=10 |pages=753-61 |year=2004 |pmid=15459667}}</ref><ref name=Janeway5/>

===Somatic hypermutation and affinity maturation===
:''For more details on this topic, see [[Somatic hypermutation]] and [[Affinity maturation]]''

Another mechanism that generates antibody diversity occurs in the mature B cell. Following activation with antigen, B cells begin to [[Cell division|proliferate]] 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]], by a process called ''somatic hypermutation'' (SHM). SHM results in approximately one [[nucleotide]] change per variable gene, per cell division.<ref name=diaz/>  As a consequence, any daughter B cells will acquire slight [[amino acid]] differences in the variable domains of their antibody chains. 

Somatic hypermutation serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding [[Chemical affinity|affinity]].<ref>{{cite journal |author=Honjo T, Habu S |title=Origin of immune diversity: genetic variation and selection |journal=Annu Rev Biochem |volume=54 |issue= |pages=803-30 |year=1985 |pmid=3927822}}</ref>  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).<ref name=orguil>{{cite journal |author=Or-Guil M, Wittenbrink N, Weiser AA, Schuchhardt J |title=Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation |journal=Immunol. Rev. |volume=216 |issue= |pages=130-41 |year=2007 |pmid=17367339 |doi=10.1111/j.1600-065X.2007.00507.x}}</ref> 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]].<ref name=orguil/> Thus, B cells expressing higher affinity antibodies for 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 cell]]s.<ref>{{Cite journal | author = Neuberger M, Ehrenstein M, Rada C, Sale J, Batista F, Williams G, Milstein C | title = Memory in the B-cell compartment: antibody affinity maturation  | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10794054  | journal = Philos Trans R Soc Lond B Biol Sci| volume=355| issue=1395| pages=357-60 | year=2000 | pmid=10794054}}</ref>
[[Image:Class switch recombination.png|thumb|250px|right|Mechanism of class switch recombination that allows isotype switching in activated B cells]]

===Class switching===

[[Immunoglobulin class switching|Isotype or class switching]] is a [[biological process]] occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG).<ref name=Market/> 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.<ref>{{cite journal |author=Stavnezer J, Amemiya CT |title=Evolution of isotype switching |journal=Semin. Immunol. |volume=16 |issue=4 |pages=257-75 |year=2004 |pmid=15522624}}</ref> 

Class switching occurs in the heavy chain gene [[Locus (genetics)|locus]] by a mechanism called [[class switch recombination]] (CSR). This mechanism relies on conserved [[nucleotide]] motifs, called ''switch (S) regions'', found in [[DNA]] upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of [[enzyme]]s at two selected S-regions.<ref>{{cite journal |author=Durandy A |title=Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation |journal=Eur. J. Immunol. |volume=33 |issue=8 |pages=2069-73 |year=2003 |pmid=12884279}}</ref><ref>{{cite journal |author=Casali P, Zan H |title=Class switching and Myc translocation: how does DNA break? |journal=Nat. Immunol. |volume=5 |issue=11 |pages=1101-3 |year=2004 |pmid=15496946}}</ref> The variable domain [[exon]] is rejoined through a process called [[non-homologous end joining]] (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.<ref>{{cite journal |author=Lieber MR, Yu K, Raghavan SC |title=Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations |journal=DNA Repair (Amst.) |volume=5 |issue=9-10 |pages=1234-45 |year=2006 |pmid=16793349}}</ref>

==Medical applications==
===Disease diagnosis===
Detection of particular antibodies is a very common form of medical [[Diagnosis|diagnostics]], and applications such as [[serology]] depend on these methods.<ref>{{cite web |url=http://www.elispot-analyzers.de/english/elisa-animation.html |title=Animated depictions of how antibodies are used in [[ELISA]] assays |accessdate=2007-05-08 |format= |work=Cellular Technology Ltd.—Europe}}</ref> For example, in biochemical assays for disease diagnosis,<ref>{{cite web |url= http://www.elispot-analyzers.de/english/elispot-animation.html |title=Animated depictions of how antibodies are used in [[ELISPOT]] assays |accessdate=2007-05-08 |format= |work=Cellular Technology Ltd.—Europe}}</ref> a [[titer]] of antibodies directed against [[Epstein-Barr virus]] or [[Lyme disease]] 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 [[immunology#clinical immunology|clinical immunology]], levels of individual classes of immunoglobulins are measured by [[nephelometry]] (or turbidimetry) to characterize the antibody profile of patient.<ref>{{cite journal |author=Stern P |title=Current possibilities of turbidimetry and nephelometry |journal=Klin Biochem Metab |volume=14 |issue=3 |pages=146-151 |year=2006| url= http://www.clsjep.cz/odkazy/kbm0603-146.pdf}}</ref> Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of [[liver]] damage in patients whom the diagnosis is unclear.<ref name=Rhoades/> For example, elevated IgA indicates alcoholic [[cirrhosis]], elevated IgM indicates [[hepatitis#viral hepatitis|viral hepatitis]] and [[primary biliary cirrhosis]], while IgG is elevated in [[hepatitis#viral hepatitis|viral hepatitis]], [[autoimmune hepatitis]] and cirrhosis. [[Autoimmune disorder]]s can often be traced to antibodies that bind the body's own [[epitope]]s; many can be detected through [[blood test]]s.  Antibodies directed against [[red blood cell]] surface antigens in immune mediated [[hemolytic anemia]] are detected with the [[Coombs test]].<ref name=Dean>{{cite book |last=Dean |first=Laura  |authorlink= |coauthors= |title= Blood Groups and Red Cell Antigens| year= 2005|publisher=National Library of Medicine (US), |location=NCBI Bethesda (MD) |isbn= |chapter= Chapter 4: Hemolytic disease of the newborn |chapterurl= http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=rbcantigen.chapter.ch4}}</ref> The Coombs test is also used for antibody screening in [[blood transfusion]] preparation and also for antibody screening in [[antenatal]] women.<ref name=Dean/>
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example [[ELISA]], [[immunofluorescence]], [[Western blot]], [[immunodiffusion]], and [[immunoelectrophoresis]].

===Disease therapy===
"Targeted" [[monoclonal antibody]] therapy is employed to treat diseases such as [[rheumatoid arthritis]],<ref>{{cite journal |author=Feldmann M, Maini R |title=Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? |journal=Annu Rev Immunol |volume=19 |issue= |pages=163-96 |year=2001 |pmid=11244034}}</ref> [[multiple sclerosis]],<ref>{{cite journal |author=Doggrell S |title=Is natalizumab a breakthrough in the treatment of multiple sclerosis? |journal=Expert Opin Pharmacother |volume=4 |issue=6 |pages=999-1001 |year=2003 |pmid=12783595}}</ref> [[psoriasis]],<ref>{{Cite journal |author=Krueger G, Langley R, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley L, Lebwohl M |title=A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis| journal = [[N Engl J Med]]|volume=356 |issue=6 |pages=580-92 |year=2007 |pmid=17287478}}</ref> and many forms of [[cancer]] including [[non-Hodgkin's lymphoma]],<ref>{{cite journal |author=Plosker G, Figgitt D |title=Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia |journal=Drugs |volume=63 |issue=8 |pages=803-43 |year=2003 |pmid=12662126}}</ref> [[colorectal cancer]], [[head and neck cancer]] and [[breast cancer]].<ref>{{cite journal |author=Vogel C, Cobleigh M, Tripathy D, Gutheil J, Harris L, Fehrenbacher L, Slamon D, Murphy M, Novotny W, Burchmore M, Shak S, Stewart S |title=First-line Herceptin monotherapy in metastatic breast cancer |journal=Oncology |volume=61 Suppl 2 |issue= |pages=37-42 |year=2001 |pmid=11694786}}</ref>
Some immune deficiencies, such as [[X-linked agammaglobulinemia]] and [[hypogammaglobulinemia]], result in partial or complete lack of antibodies.<ref>{{cite journal | author = LeBien TW | title = Fates of human B-cell precursors | journal = Blood | volume = 96 | issue = 1 | pages = 9-23 | year = 2000 | pmid = 10891425 | url = http://bloodjournal.hematologylibrary.org/cgi/content/full/96/1/9 }}</ref> These diseases are often treated by inducing a short term form of [[immunity (medical)|immunity]] called [[passive immunity]]. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal [[blood plasma|serum]], pooled immunoglobulin or monoclonal antibodies, into the affected individual.<ref name=USC>{{cite web | author = Ghaffer A | title = Immunization | work = Immunology - Chapter 14 | publisher = University of South Carolina School of Medicine | url = http://pathmicro.med.sc.edu/ghaffar/immunization.htm | date = 2006-03-26 | accessdate = 2007-06-06}}</ref>

===Prenatal therapy===
{{details|Rho(D) Immune Globulin}}
''Rho(D) Immune Globulin'' antibodies are specific for human Rhesus D (RhD) antigen, also known as [[Rhesus factor]].<ref name= Fung>{{cite journal |author=Fung Kee Fung K, Eason E, Crane J, Armson A, De La Ronde S, Farine D, Keenan-Lindsay L, Leduc L, Reid G, Aerde J, Wilson R, Davies G, Désilets V, Summers A, Wyatt P, Young D |title=Prevention of Rh alloimmunization |journal=J Obstet Gynaecol Can |volume=25 |issue=9 |pages=765-73 |year=2003 |pmid=12970812}}</ref> These anti-RhD antibodies are known under several brand names, including RhoGAM, BayRHo-D, Gamulin Rh, HypRho-D, and WinRho SDF.  Rhesus factor is an [[antigen]] found on [[red blood cell]]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]], delivery trauma or complications during pregnancy, blood from a [[fetus]] 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]], and any subsequent pregnancies, at risk for [[hemolytic disease of the newborn]].<ref>{{cite journal |author=Urbaniak S, Greiss M |title=RhD haemolytic disease of the fetus and the newborn |journal=Blood Rev |volume=14 |issue=1 |pages=44-61 |year=2000 |pmid=10805260}}</ref> Anti-RhD antibodies are administered as part of a [[prenatal care|prenatal treatment regimen]] 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 cell]]s. Therefore, her [[humoral immune system]] will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent baby.  Rho(D) Immune Globulin treatment prevents sensitization that can lead to [[Rh disease]], but does not prevent or treat the underlying disease itself.<ref name= Fung/>

==Research applications==
[[Image:FluorescentCells.jpg|thumb|right|200px|[[Immunofluorescence]] image of the eukaryotic [[cytoskeleton]]. [[Actin]] filaments are shown in red, [[microtubule]]s in green, and the [[cell nucleus|nuclei in blue]].]]

Specific antibodies are produced by injecting an antigen into a [[mammal]], such as a mouse, rat or rabbit for small quantities of antibody, or goat, sheep, or horse for large quantities of antibody.  Blood isolated from these animals contains ''[[polyclonal antibody|polyclonal antibodies]]'' — multiple antibodies that bind to the same antigen — in the [[Blood plasma|serum]], which can now be called [[antiserum]]. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk.<ref>{{cite journal |author=Tini M, Jewell UR, Camenisch G, Chilov D, Gassmann M |title=Generation and application of chicken egg-yolk antibodies |journal=Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. |volume=131 |issue=3 |pages=569-74 |year=2002 |pmid=11867282 |doi=}}</ref> To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting [[lymphocyte]]s are isolated from the animal and [[Biological immortality|immortalized]] by fusing them with a cancer cell line. The fused cells are called [[hybridoma]]s, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by [[dilution cloning]] to generate [[cloning#Cellular cloning|cell clones]] that all produce the same antibody; these antibodies are called ''[[monoclonal antibodies]]''.<ref>{{cite journal |author=Cole SP, Campling BG, Atlaw T, Kozbor D, Roder JC |title=Human monoclonal antibodies |journal=Mol. Cell. Biochem. |volume=62 |issue=2 |pages=109-20 |year=1984 |pmid=6087121 |doi=}}</ref>
Generated polyclonal and monoclonal antibodies are often purified using [[Protein A/G]] or [[Affinity chromatography|antigen-affinity chromatography]].<ref>{{cite journal |author=Kabir S |title=Immunoglobulin purification by affinity chromatography using protein A mimetic ligands prepared by combinatorial chemical synthesis |journal=Immunol Invest |volume=31 |issue=3-4 |pages=263-78 | year = 2002 |pmid=12472184}}</ref>

===Use===
In research, purified antibodies are used in many applications. They are most commonly used to identify and locate [[intracellular]] and [[extracellular]] proteins. Antibodies are used in [[flow cytometry]] to differentiate cell types by the proteins they express; different types of cell express different combinations of [[cluster of differentiation]] molecules on their surface, and produce different intracellular and secretable proteins.<ref name=Stecher>{{cite journal |author=Brehm-Stecher B, Johnson E |title=Single-cell microbiology: tools, technologies, and applications |url=http://mmbr.asm.org/cgi/content/full/68/3/538?view=long&pmid=15353569 |journal=Microbiol Mol Biol Rev |volume=68 |issue=3 |pages=538-59 |year=2004 |pmid=15353569}}</ref> They are also used in [[immunoprecipitation]] to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a [[cell lysate]],<ref>{{cite journal |author=Williams N |title=Immunoprecipitation procedures |journal=Methods Cell Biol |volume=62 |issue= |pages=449-53 |year=2000 |pmid=10503210}}</ref> in [[Western blot]] analyses to identify proteins separated by  [[electrophoresis]],<ref>{{cite journal |author=Kurien B, Scofield R |title=Western blotting |journal=Methods |volume=38 |issue=4 |pages=283-93 |year=2006 |pmid=16483794}}</ref> and in [[immunohistochemistry]] or [[immunofluorescence]] to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a [[microscope]].<ref>{{cite journal |author=Scanziani E |title=Immunohistochemical staining of fixed tissues |journal=Methods Mol Biol |volume=104 |issue= |pages=133-40 |year= |pmid=9711649}}</ref><ref name=Stecher/> Proteins can also be detected and quantified with antibodies, using ELISA and [[ELISPOT]] techniques.<ref>{{cite journal |author=Reen DJ.|title=Enzyme-linked immunosorbent assay (ELISA).|journal=Methods Mol Biol.|volume=32 |issue= |pages=461-6 |year= 1994|pmid=7951745}}</ref><ref>{{cite journal |author=Kalyuzhny AE |title=Chemistry and biology of the ELISPOT assay|journal=Methods Mol Biol.|volume=302 |issue= |pages=15-31 |year= 2005|pmid=15937343}}</ref>

==History==
{{see also|History of immunology}}
The study of antibodies began in 1890 when [[Emil von Behring]] and [[Shibasaburo Kitasato]] described antibody activity against [[diphtheria]] and [[tetanus toxin]]s. Behring and Kitasato put forward the theory of [[humoral immunity]], proposing that a mediator in serum could react with a foreign antigen.<ref>{{cite web  | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1901/behring-bio.html | title = Emil von Behring - Biography | accessdate = 2007-06-05 | format = | work = }}</ref><ref>{{cite journal | author = AGN | title = The Late Baron Shibasaburo Kitasato | journal = Canadian Medical Association Journal | year = 1931 | volume = | pages = 206 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=382621_prizes/medicine/laureates/1901/behring-bio.html }}</ref>  Their 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]]s – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies.<ref>{{cite journal |author=Winau F, Westphal O, Winau R |title=Paul Ehrlich--in search of the magic bullet |journal=Microbes Infect. |volume=6 |issue=8 |pages=786-9 |year=2004 |pmid=15207826 |doi=10.1016/j.micinf.2004.04.003}}</ref> Other researchers believed that antibodies existed freely in the blood and, in 1904, [[Almroth Wright]] suggested that soluble antibodies coated [[bacteria]] to label them for [[phagocytosis]] and killing; a process that he named [[opsonin]]ization.<ref>{{cite journal |author=Silverstein AM |title=Cellular versus humoral immunology: a century-long dispute |journal=Nat. Immunol. |volume=4 |issue=5 |pages=425-8 |year=2003 |pmid=12719732 |doi=10.1038/ni0503-425}}</ref>

In the 1920s, [[Michael Heidelberger]] and [[Oswald Avery]] observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein.<ref>{{cite journal |author=Van Epps HL |title=Michael Heidelberger and the demystification of antibodies |journal=J. Exp. Med. |volume=203 |issue=1 |pages=5 |year=2006 |pmid=16523537 |url=http://www.jem.org/cgi/reprint/203/1/5.pdf}}</ref> The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack.<ref>{{cite book |last= Marrack | first = JR | title = Chemistry of antigens and antibodies | edition = 2nd ed. | year = 1938 | publisher = His Majesty's Stationery Office | location = London | isbn= | oclc=3220539}}</ref> The next major advance was in the 1940s, when [[Linus Pauling]] 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.<ref>{{cite web |url=http://profiles.nlm.nih.gov/MM/Views/Exhibit/narrative/specificity.html |title=The Linus Pauling Papers: How Antibodies and Enzymes Work |accessdate=2007-06-05}}</ref> In 1948, Astrid Fagreaus discovered that B cells, in the form of [[plasma cell]]s, were responsible for generating antibodies.<ref>{{cite journal | author = Silverstein AM | title = Labeled antigens and antibodies: the evolution of magic markers and magic bullets | journal = Nat. Immunol. | volume = 5 | issue = 12 | pages = 1211-7 | year = 2004 | pmid = 15549122 | url = http://users.path.ox.ac.uk/~seminars/halelibrary/Paper%2018.pdf | doi = 10.1038/ni1140}}</ref>

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]] and Joseph Gally of the antibody [[light chain]],<ref>{{cite journal |author=Edelman GM, Gally JA |title=The nature of Bence-Jones proteins. Chemical similarities to polypetide chains of myeloma globulins and normal gamma-globulins |journal=J. Exp. Med. |volume=116 |issue= |pages = 207-27 |year=1962 |pmid=13889153 |doi=}}</ref> and their realization that this protein was the same as the [[Bence-Jones protein]] described in 1845 by [[Henry Bence Jones]].<ref>{{cite journal |author=Stevens FJ, Solomon A, Schiffer M |title=Bence Jones proteins: a powerful tool for the fundamental study of protein chemistry and pathophysiology |journal=Biochemistry |volume=30 |issue=28 |pages=6803-5 |year=1991 |pmid=2069946 |doi=}}</ref> Edelman went on to discover that antibodies are composed of [[disulphide bond]]-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by [[Rodney Porter]].<ref name=edel>{{cite journal |author=Raju TN |title=The Nobel chronicles. 1972: Gerald M Edelman (b 1929) and Rodney R Porter (1917-85) |journal=Lancet |volume=354 |issue=9183 |pages=1040 |year=1999 |pmid=10501404 |doi=}}</ref>  Together, these scientists deduced the structure and complete [[amino acid]] sequence of IgG, a feat for which they were jointly awarded the 1972 [[Nobel prize]] in [[Physiology]] or [[Medicine]].<ref name=edel/> 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]]) <ref>{{cite journal |author=Tomasi TB |title=The discovery of secretory IgA and the mucosal immune system |journal=Immunol. Today |volume=13 |issue=10 |pages=416-8 |year=1992 |pmid=1343085 |doi=}}</ref> and David Rowe and John Fahey identified IgD,<ref>{{cite journal |author=Preud'homme JL, Petit I, Barra A, Morel F, Lecron JC, Lelièvre E |title=Structural and functional properties of membrane and secreted IgD |journal=Mol. Immunol. |volume=37 |issue=15 |pages=871-87 |year=2000 |pmid=11282392 |doi=}}</ref> and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions.<ref>{{cite journal |author=Johansson SG |title=The discovery of immunoglobulin E |journal=Allergy and asthma proceedings : the official journal of regional and state allergy societies |volume=27 |issue=2 Suppl 1 |pages=S3-6 |year=2006 |pmid=16722325}}</ref>

Genetic studies revealed the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was identified by [[Susumu Tonegawa]] in 1976.<ref>{{cite journal |author=Hozumi N, Tonegawa S |title=Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions |url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=824647| journal=Proc. Natl. Acad. Sci. U.S.A. |volume=73 |issue=10 |pages=3628-32 |year=1976 |pmid=824647 |doi=}}</ref>

==See also==
<div style="-moz-column-count:3; column-count:3;">
* [[Anti-mitochondrial antibodies]]
* [[Anti-nuclear antibodies]]
* [[ELISA]]
* [[Humoral immunity]]
* [[Immunology]]
* [[Immunosuppressive drug]]
* [[Monoclonal antibody]]
* [[Nanobodies]]
* [[Secondary antibodies]]
</div>

==References==
{{reflist|2}}

==External links==
*[http://www.path.cam.ac.uk/~mrc7/mikeimages.html Mike's Immunoglobulin Structure/Function Page] at University of Cambridge
*[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb21_1.html Antibodies as the PDB molecule of the month] Discussion of the structure of antibodies at [[Protein Data Bank]]
*[http://pathmicro.med.sc.edu/mayer/IgStruct2000.htm  Microbiology and Immunology On-line Textbook] at University of South Carolina
*[http://users.path.ox.ac.uk/~scobbold/tig/new1/mabth.html A hundred years of antibody therapy] History and applications of antibodies in the treatment of disease at University of Oxford
*[http://www.cellsalive.com/antibody.htm How Lymphocytes Produce Antibody] from Cells Alive!
*[http://www.ii.bham.ac.uk/clinicalimmunology/CISimagelibrary/ Antibody applications] Fluorescent antibody image library, University of Birmingham
*[http://www.antibodypatterns.com/ Images produced using antibodies] at antibodypatterns.com 

{{immune_system}}
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{{Immune_proteins}}


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