antibody antibody an antibody (ab), also known as an immunoglobulin (ig), is a large, y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. the antibody recognizes a unique molecule of the pathogen, called an antigen. each tip of the "y" of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (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 it directly (for example, by blocking a part of a virus that is essential for its invasion). each antibody binds to a specific antigen; an interaction similar to a lock and key. to allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety. in contrast, the remainder of the antibody is relatively constant. it only occurs in a few variants, which define the antibody's class or isotype: iga, igd, ige, igg, and igm. the constant region at the trunk of the antibody includes sites involved in interactions with other components of the immune system. the class hence determines the function triggered by an antibody after binding to an antigen, in addition to some structural features. antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. together with b and t cells, antibodies comprise the most important part of the adaptive immune system. they occur in two forms: one that is attached to a b cell, and the other, a soluble form, that is unattached and found in extracellular fluids such as blood plasma. initially, all antibodies are of the first form, attached to the surface of a b cell – these are then referred to as b-cell receptors (bcr). after an antigen binds to a bcr, the b cell activates to proliferate and differentiate into either plasma cells, which secrete soluble antibodies with the same paratope, or memory b cells, which survive in the body to enable long-lasting immunity to the antigen. soluble antibodies are released into the blood and tissue fluids, as well as many secretions. because these fluids were traditionally known as humors, antibody-mediated immunity is sometimes known as, or considered a part of, humoral immunity. the soluble y-shaped units can occur individually as monomers, or in complexes of two to five units. antibodies are glycoproteins belonging to the immunoglobulin superfamily. the terms antibody and immunoglobulin are often used interchangeably, though the term 'antibody' is sometimes reserved for the secreted, soluble form, i.e. excluding b-cell receptors. structure schematic structure of an antibody: two heavy chains (blue, yellow) and the two light chains (green, pink). the antigen binding site is circled. a more accurate depiction of an antibody (3d structure at rcsb pdb). glycans in the fc region are shown in black. antibodies are heavy (~150 kda) proteins of about 10 nm in size, arranged in three globular regions that roughly form a y shape. in humans and most mammals, an antibody unit consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds. each chain is a series of domains: somewhat similar sequences of about 110 amino acids each. these domains are usually represented in simplified schematics as rectangles. light chains consist of one variable domain vl and one constant domain cl, while heavy chains contain one variable domain vh and three to four constant domains ch1, ch2, ... structurally an antibody is also partitioned into two antigen-binding fragments (fab), containing one vl, vh, cl, and ch1 domain each, as well as the crystallisable fragment (fc), forming the trunk of the y shape. in between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes (dimers, trimers, etc.), and to bind effector molecules more easily. in an electrophoresis test of blood proteins, antibodies mostly migrate to the last, gamma globulin fraction. conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols ig and γ. this variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ (gamma) heavy chains which characterize the igg class of antibodies. antigen-binding site the variable domains can also be referred to as the fv region. it is the subregion of fab that binds to an antigen. more specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody. when the protein folds, these regions give rise to three loops of β-strands, localized near one another on the surface of the antibody. these loops are referred to as the complementarity-determining regions (cdrs), since their shape complements that of an antigen. three cdrs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen. typically however only a few residues contribute to most of the binding energy. the existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as polysaccharides in bacterial cell walls, or other sites at some distance apart), as well as to form antibody complexes and larger antigen-antibody complexes. the resulting cross-linking plays a role in activating other parts of the immune system. the structures of cdrs have been clustered and classified by chothia et al. and more recently by north et al. and nikoloudis et al. however, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. to improve antibody structure prediction and to take the strongly correlated cdr loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities. in the framework of the immune network theory, cdrs are also called idiotypes. according to immune network theory, the adaptive immune system is regulated by interactions between idiotypes. fc region main article: fragment crystallizable region the fc region (the trunk of the y shape) is composed of constant domains from the heavy chains. its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody fab region binds to an antigen. effector cells (such as macrophages or natural killer cells) bind via their fc receptors (fcr) to the fc region of an antibody, while the complement system is activated by binding the c1q protein complex. igg or igm can bind to c1q, but iga cannot, therefore iga does not activate the classical complement pathway. another role of the fc region is to selectively distribute different antibody classes across the body. in particular, the neonatal fc receptor (fcrn) binds to the fc region of igg antibodies to transport it across the placenta, from the mother to the fetus. antibodies are glycoproteins, that is, they have carbohydrates (glycans) added to conserved amino acid residues. these conserved glycosylation sites occur in the fc region and influence interactions with effector molecules. protein structure the n-terminus of each chain is situated at the tip. each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily: it is composed of between 7 (for constant domains) and 9 (for variable domains) β-strands, forming two beta sheets in a greek key motif. the sheets create a "sandwich" shape, the immunoglobulin fold, held together by a disulfide bond. antibody complexes some antibodies form complexes that bind to multiple antigen molecules. secreted antibodies can occur as a single y-shaped unit, a monomer. however, some antibody classes also form dimers with two ig units (as with iga), tetramers with four ig units (like teleost fish igm), or pentamers with five ig units (like shark igw or mammalian igm, which occasionally forms hexamers as well, with six units). antibodies also form complexes by binding to antigen: this is called an antigen-antibody complex or immune complex. small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc. multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies. an extreme example is the clumping, or agglutination, of red blood cells with antibodies in the coombs test to determine blood groups: the large clumps become insoluble, leading to visually apparent precipitation. b cell receptors main article: b-cell receptor 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. 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. in humans, the cell surface is bare around the b cell receptors for several hundred nanometers, which further isolates the bcrs from competing influences. classes antibodies can come in different varieties known as isotypes or classes. in placental mammals there are five antibody classes known as iga, igd, ige, igg, and igm, which are further subdivided into subclasses such as iga1, iga2. the prefix "ig" stands for immunoglobulin, while the suffix denotes the type of heavy chain the antibody contains: the heavy chain types α (alpha), γ (gamma), δ (delta), ε (epsilon), μ (mu) give rise to iga, igg, igd, ige, igm, respectively. the distinctive features of each class are determined by the part of the heavy chain within the hinge and fc region. the classes differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table. for example, ige antibodies are responsible for an allergic response consisting of histamine release from mast cells, often a sole contributor to asthma (though other pathways exist as do exist symptoms very similar to yet not technically asthma). the antibody's variable region binds to allergic antigen, for example house dust mite particles, while its fc region (in the ε heavy chains) binds to fc receptor ε on a mast cell, triggering its degranulation: the release of molecules stored in its granules. antibody isotypes of mammals classsubclassesdescription iga2 found in mucosal areas, such as the gut, respiratory tract and urogenital tract, and prevents colonization by pathogens. also found in saliva, tears, and breast milk. igd1 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. ige1 binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. humans and other animals evolved ige to protect against parasitic worms, though in the present, ige is primarily related to allergies and asthma. igg4 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 the fetus. igm 1 expressed on the surface of b cells (monomer) and in a secreted form (pentamer) with very high avidity. eliminates pathogens in the early stages of b cell-mediated (humoral) immunity before there is sufficient igg. the antibody isotype of a b cell changes during cell development and activation. immature b cells, which have never been exposed to an antigen, express only the igm isotype in a cell surface bound form. the b lymphocyte, in this ready-to-respond form, is known as a "naive b lymphocyte." the naive b lymphocyte expresses both surface igm and igd. the co-expression of both of these immunoglobulin isotypes renders the