2FCB , 3WJJ ,%%s 3WJL
101-475: 2213 14130 ENSG00000072694 ENSMUSG00000026656 P31994 P31995 P08101 NM_001002273 NM_001002274 NM_001002275 NM_001190828 NM_004001 NM_001077189 NM_010187 NP_963857 NP_001070657 NP_034317 Fc fragment of IgG receptor IIb (coded by FCGR2B gene) is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma ( IgG ). FCGR2B participates in
202-413: A dissociation constant ( K D ) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex falls apart into its component molecules , or when a salt splits up into its component ions . The dissociation constant is the inverse of the association constant . In the special case of salts,
303-488: A ligand L binds with a macromolecule M , it can influence binding kinetics of other ligands L binding to the macromolecule. A simplified mechanism can be formulated if the affinity of all binding sites can be considered independent of the number of ligands bound to the macromolecule. This is valid for macromolecules composed of more than one, mostly identical, subunits. It can be then assumed that each of these n subunits are identical, symmetric and that they possess only
404-472: A "sandwich" shape, the immunoglobulin fold , held together by a disulfide bond. 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). IgG can also form hexamers, though no J chain
505-520: 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 B cell ready to respond to antigen. B cell activation follows engagement of
606-600: A Y shape. In humans and most other 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 V L and one constant domain C L , while heavy chains contain one variable domain V H and three to four constant domains C H 1, C H 2, ... Structurally an antibody
707-450: A dissociation constant of roughly 10 M = 1 fM = 0.000001 nM. Ribonuclease inhibitor proteins may also bind to ribonuclease with a similar 10 M affinity. The dissociation constant for a particular ligand–protein interaction can change with solution conditions (e.g., temperature , pH and salt concentration). The effect of different solution conditions is to effectively modify the strength of any intermolecular interactions holding
808-441: A distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of genes 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. The chromosomal region that encodes an antibody
909-542: A given microbe – that is, the ability of the microbe to enter the body and begin to replicate (not necessarily to cause disease) – depends on sustained production of large quantities of antibodies, meaning that effective vaccines ideally elicit persistent high levels of antibody, which relies on long-lived plasma cells. At the same time, many microbes of medical importance have the ability to mutate to escape antibodies elicited by prior infections, and long-lived plasma cells cannot undergo affinity maturation or class switching. This
1010-408: A huge number of antibodies, each with different paratopes , and thus different antigen specificities. The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells. RAG proteins play an important role with V(D)J recombination in cutting DNA at a particular region. Without
1111-442: A low on- and off-rate constant. For the deprotonation of acids , K is known as K a , the acid dissociation constant . Strong acids, such as sulfuric or phosphoric acid , have large dissociation constants; weak acids, such as acetic acid , have small dissociation constants. The symbol K a , used for the acid dissociation constant, can lead to confusion with the association constant , and it may be necessary to see
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#17330853648551212-436: A macromolecule M has three binding sites, K′ 1 describes a ligand being bound to any of the three binding sites. In this example, K′ 2 describes two molecules being bound and K′ 3 three molecules being bound to the macromolecule. The microscopic or individual dissociation constant describes the equilibrium of ligands binding to specific binding sites. Because we assume identical binding sites with no cooperativity,
1313-440: A manifestation of immunological memory. In the course of an immune response, B cells can progressively differentiate into antibody-secreting cells or into memory B cells. Antibody-secreting cells comprise plasmablasts and plasma cells , which differ mainly in the degree to which they secrete antibody, their lifespan, metabolic adaptations, and surface markers. Plasmablasts are rapidly proliferating, short-lived cells produced in
1414-400: A mast cell, triggering its degranulation : the release of molecules stored in its granules. 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. Although The antibody isotype of
1515-444: A part of a virus that is essential for its invasion). More narrowly, an antibody ( Ab ) can refer to the free (secreted) form of these proteins, as opposed to the membrane-bound form found in a B cell receptor. The term immunoglobulin can then refer to both forms. Since they are, broadly speaking, the same protein, the terms are often treated as synonymous. To allow the immune system to recognize millions of different antigens,
1616-460: A particular ligand–protein complex together. Drugs can produce harmful side effects through interactions with proteins for which they were not meant to or designed to interact. Therefore, much pharmaceutical research is aimed at designing drugs that bind to only their target proteins (negative design) with high affinity (typically 0.1–10 nM) or at improving the affinity between a particular drug and its in vivo protein target (positive design). In
1717-462: A secondary immune response, undergoing class switching, affinity maturation, and differentiating into antibody-secreting cells. Antibodies are central to the immune protection elicited by most vaccines and infections (although other components of the immune system certainly participate and for some diseases are considerably more important than antibodies in generating an immune response, e.g. herpes zoster ). Durable protection from infections caused by
1818-399: A single binding site. Then the concentration of bound ligands [ L ] bound {\displaystyle {\ce {[L]_{bound}}}} becomes In this case, [ L ] bound ≠ [ LM ] {\displaystyle {\ce {[L]}}_{\text{bound}}\neq {\ce {[LM]}}} , but comprises all partially saturated forms of
1919-432: 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
2020-429: A strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis . Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival allowing the average affinity of antibodies to increase over time. The process of generating antibodies with increased binding affinities
2121-437: A substance, in the same way that EC 50 and IC 50 describe the biological activities of substances. Experimentally, the concentration of the molecule complex [AB] is obtained indirectly from the measurement of the concentration of a free molecules, either [A] or [B]. In principle, the total amounts of molecule [A] 0 and [B] 0 added to the reaction are known. They separate into free and bound components according to
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#17330853648552222-522: Is also partitioned into two antigen-binding fragments (Fab), containing one V L , V H , C L , and C H 1 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
2323-511: Is associated with systemic lupus erythematosus , rheumatoid arthritis, Goodpasture's disease, multiple sclerosis and others. FCGR2B may be a target for monoclonal antibody therapy for autoimmune diseases as well as malignancies. This article incorporates text from the United States National Library of Medicine , which is in the public domain . Receptor affinity In chemistry , biochemistry , and pharmacology ,
2424-415: 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 . 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). The different classes of antibody, and thus effector functions, are defined by
2525-448: Is closer to human IgG2 than human IgG1 in terms of its function. The term humoral immunity is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors (fluids) in the form of soluble proteins, as distinct from cell-mediated immunity , which generally describes the responses of T cells (especially cytotoxic T cells). In general, antibodies are considered part of
2626-544: Is compensated for through memory B cells: novel variants of a microbe that still retain structural features of previously encountered antigens can elicit memory B cell responses that adapt to those changes. It has been suggested that long-lived plasma cells secrete B cell receptors with higher affinity than those on the surfaces of memory B cells, but findings are not entirely consistent on this point. Antibodies are heavy (~150 k Da ) proteins of about 10 nm in size, arranged in three globular regions that roughly form
2727-486: Is defined where [ P ] , [ L ] {\displaystyle {\ce {[P], [L]}}} , and [ LP ] {\displaystyle {\ce {[LP]}}} represent molar concentrations of the protein, ligand, and protein–ligand complex, respectively. The dissociation constant has molar units (M) and corresponds to the ligand concentration [ L ] {\displaystyle {\ce {[L]}}} at which half of
2828-483: Is depending on the number of the protons they can give up, we define monoprotic , diprotic and triprotic acids . The first (e.g., acetic acid or ammonium ) have only one dissociable group, the second (e.g., carbonic acid , bicarbonate , glycine ) have two dissociable groups and the third (e.g., phosphoric acid) have three dissociable groups. In the case of multiple p K values they are designated by indices: p K 1 , p K 2 , p K 3 and so on. For amino acids,
2929-426: Is filled last (I, II or III) — and one state (I–II–III). Even when the microscopic dissociation constant is the same for each individual binding event, the macroscopic outcome ( K′ 1 , K′ 2 and K′ 3 ) is not equal. This can be understood intuitively for our example of three possible binding sites. K′ 1 describes the reaction from one state (no ligand bound) to three states (one ligand bound to either of
3030-430: Is highly expressed on basophils and at low levels on monocytes. FCGR2B is co-expressed with the activating FCGRA on circulating myeloid dendritic cells in peripheral blood. Cytokine regulation of the expression is positive in the case of IL-10 and IL-6 and negative in the case of TNF-α , C5a and IFN-γ . FCGR2B is co-expressed with the activating FCGRA on circulating myeloid dendritic cells. The receptor inhibits
3131-507: Is large and contains several distinct gene loci for each domain of the antibody—the chromosome region containing heavy chain genes ( IGH@ ) is found on chromosome 14 , and the loci containing lambda and kappa light chain genes ( IGL@ and IGK@ ) 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
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3232-458: Is present, ensuring that antibody levels to the antigen in question do not fall to 0, provided the plasma cell stays alive. The rate of antibody secretion, however, can be regulated, for example, by the presence of adjuvant molecules that stimulate the immune response such as TLR ligands. Long-lived plasma cells can live for potentially the entire lifetime of the organism. Classically, the survival niches that house long-lived plasma cells reside in
3333-430: Is required. IgA tetramers and pentamers have also been reported. 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
3434-625: Is reversible, and the antibody's affinity towards an antigen is relative rather than absolute. Relatively weak binding also means it is possible for an antibody to cross-react with different antigens of different relative affinities. The main categories of antibody action include the following: More indirectly, an antibody can signal immune cells to present antibody fragments to T cells , or downregulate other immune cells to avoid autoimmunity . Activated B cells differentiate into either antibody-producing cells called plasma cells that secrete soluble antibody or memory cells that survive in
3535-492: Is the binomial coefficient . Then the first equation is proved by applying the binomial rule The dissociation constant is commonly used to describe the affinity between a ligand L {\displaystyle {\ce {L}}} (such as a drug ) and a protein P {\displaystyle {\ce {P}}} ; i.e., how tightly a ligand binds to a particular protein. Ligand–protein affinities are influenced by non-covalent intermolecular interactions between
3636-410: Is the clumping, or agglutination , of red blood cells with antibodies in blood typing to determine blood groups : the large clumps become insoluble, leading to visually apparent precipitation . 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
3737-463: Is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "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
3838-529: 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. 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
3939-427: Is three times bigger than the microscopic dissociation constant K D . The general relationship between both types of dissociation constants for n binding sites is Hence, the ratio of bound ligand to macromolecules becomes where ( n i ) = n ! ( n − i ) ! i ! {\displaystyle {\binom {n}{i}}={\frac {n!}{(n-i)!i!}}}
4040-451: 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 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
4141-416: The adaptive immune system , though this classification can become complicated. For example, natural IgM, which are made by B-1 lineage cells that have properties more similar to innate immune cells than adaptive, refers to IgM antibodies made independently of an immune response that demonstrate polyreactivity- they recognize multiple distinct (unrelated) antigens. These can work with the complement system in
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4242-736: The iota (ι) chain, are found in other vertebrates like sharks ( Chondrichthyes ) and bony fishes ( Teleostei ). In most placental mammals , the structure of antibodies is generally the same. Jawed fish appear to be the most primitive animals that are able to make antibodies similar to those of mammals, although many features of their adaptive immunity appeared somewhat earlier. Cartilaginous fish (such as sharks) produce heavy-chain-only antibodies (i.e., lacking light chains) which moreover feature longer chain pentamers (with five constant units per molecule). Camelids (such as camels, llamas, alpacas) are also notable for producing heavy-chain-only antibodies. The antibody's paratope interacts with
4343-623: The phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes . There are two major forms of FCGR2B existing (FCGR2B1 and FCGR2B2) and they are created by mRNA splicing mechanism, which results in the inclusion (FCGR2B1) or exclusion (FCGR2B2) of the C1 exon sequence. The presence of the C1 exon sequence (in FCGR2B1) results in tethering to the membrane of B cells, whereas its absence (in FCGR2B2) allows fast internalization of
4444-437: 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 phagocytes in a process called opsonization ; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Second, some complement system components form a membrane attack complex to assist antibodies to kill
4545-610: 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. Antibodies can come in different varieties known as isotypes or classes . In humans 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
4646-513: The F V 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
4747-410: The Fc region and influence interactions with effector molecules. 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
4848-486: 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
4949-593: The ITIM-dependent inhibitory mechanism. Ligation of FCGR2B on B cells downregulates antibody production, prevents the membrane organization of BCR and CD19 and promotes apoptosis . Co-ligation of FCGR2B on dendritic cells inhibits maturation and blocks cell activation. The negative regulatory role of the FCGRIIB molecule is not limited to BCR-induced B-cell activation, but is also functional on other B-cell activation pathways mediated by CD40 and IL-4. BCR signaling attenuates
5050-601: The MAP kinase pathway, together with the anti-apoptotic kinase Akt can negatively affect proliferation and survival of the cells. However, FcγRIIB can restrict activation of cells bearing FcγRs by simply competing with them for engagement with immune complexes, as removal of the ITIM retains this activity. FCGR2B regulates B cell activation by increasing the BCR activation threshold and suppressing B cell-mediated antigen presentation to T cells through
5151-491: The V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals . 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
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#17330853648555252-469: The absence of FcγRIIB is impaired and this may result in lower stringency in selection for entry into the germinal center reaction. FCGR2B is present on non-leukocyte cells including airway smooth muscle and liver sinusoidal endothelial cells, where small immune complexes are internalized inhibiting the pro-inflammatory signalling. FCGR2B is one of the genes thought to influence susceptibility to several autoimmune diseases in humans. Its decreased function
5353-450: The adaptive immune system is regulated by interactions between idiotypes. 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
5454-410: The antibody (also known as effector functions), in addition to some other structural features. Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Between species, while classes and subclasses of antibodies may be shared (at least in name), their functions and distribution throughout the body may be different. For example, mouse IgG1
5555-683: The antibody generates a large cavalry of antibodies with a high degree of variability. This combination is called V(D)J recombination discussed below. 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 (subgenes). 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 . Multiple copies of
5656-556: The antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants. Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example electrostatic forces , hydrogen bonds , hydrophobic interactions , and van der Waals forces . This means binding between antibody and antigen
5757-421: The antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is much less variable; in humans, antibodies occur in five classes , sometimes called isotypes : IgA , IgD , IgE , IgG , and IgM . Human IgG and IgA antibodies are also divided into discrete subclasses (IgG1, IgG2, IgG3, IgG4; IgA1 and IgA2). The class refers to the functions triggered by
5858-404: The antigen-containing immune complexes which are essential for the germinal centre response. It has been shown that in the absence of FcγRIIB on FDCs, the germinal centers are more diverse but populated by low affinity B cells with low levels of somatic hypermutation . The mechanisms underlying this are incompletely understood, but it is noted that the ability of FDCs to retain immune complexes in
5959-401: The bacterium directly (bacteriolysis). To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate . 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
6060-434: 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 (an example is a virus capsid protein fragment). Antibodies contribute to immunity 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
6161-424: 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
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#17330853648556262-477: The bone marrow, though it cannot be assumed that any given plasma cell in the bone marrow will be long-lived. However, other work indicates that survival niches can readily be established within the mucosal tissues- though the classes of antibodies involved show a different hierarchy from those in the bone marrow. B cells can also differentiate into memory B cells which can persist for decades similarly to long-lived plasma cells. These cells can be rapidly recalled in
6363-430: The cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody-producing cell called a plasma cell . In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane -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
6464-423: The classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Antibodies are produced exclusively by B cells in response to antigens where initially, antibodies are formed as membrane-bound receptors, but upon activation by antigens and helper T cells, B cells differentiate to produce soluble antibodies. Many natural antibodies are directed against
6565-563: The complex A x B y , respectively. One reason for the popularity of the dissociation constant in biochemistry and pharmacology is that in the frequently encountered case where x = y = 1, K D has a simple physical interpretation: when [A] = K D , then [B] = [AB] or, equivalently, [ AB ] [ B ] + [ AB ] = 1 2 {\displaystyle {\tfrac {[{\ce {AB}}]}{{[{\ce {B}}]}+[{\ce {AB}}]}}={\tfrac {1}{2}}} . That is, K D , which has
6666-403: The constant (C) regions of the immunoglobulin heavy chain. Initially, naive 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 an IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from
6767-413: The dimensions of concentration, equals the concentration of free A at which half of the total molecules of B are associated with A. This simple interpretation does not apply for higher values of x or y . It also presumes the absence of competing reactions, though the derivation can be extended to explicitly allow for and describe competitive binding. It is useful as a quick description of the binding of
6868-410: The disaccharide galactose 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. These antibodies undergo quality checks in the endoplasmic reticulum (ER), which contains proteins that assist in proper folding and assembly. Rejection of xenotransplantated organs
6969-426: The dissociation constant can also be called an ionization constant . For a general reaction: in which a complex A x B y {\displaystyle {\ce {A}}_{x}{\ce {B}}_{y}} breaks down into x A subunits and y B subunits, the dissociation constant is defined as where [A], [B], and [A x B y ] are the equilibrium concentrations of A, B, and
7070-414: The diversity of the antibody pool and impacts the antibody's antigen-binding affinity . 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
7171-583: The earliest phases of an immune response to help facilitate clearance of the offending antigen and delivery of the resulting immune complexes to the lymph nodes or spleen for initiation of an immune response. Hence in this capacity, the function of antibodies is more akin to that of innate immunity than adaptive. Nonetheless, in general antibodies are regarded as part of the adaptive immune system because they demonstrate exceptional specificity (with some exception), are produced through genetic rearrangements (rather than being encoded directly in germline ), and are
7272-602: The early phases of the immune response (classically described as arising extrafollicularly rather than from the germinal center ) which have the potential to differentiate further into plasma cells. The literature is sloppy at times and often describes plasmablasts as just short-lived plasma cells- formally this is incorrect. Plasma cells, in contrast, do not divide (they are terminally differentiated ), and rely on survival niches comprising specific cell types and cytokines to persist. Plasma cells will secrete huge quantities of antibody regardless of whether or not their cognate antigen
7373-486: The functions of activating FcγRs, such as phagocytosis and pro-inflammatory cytokine release, mainly by clustering of FCGR2B with different activating FCGR receptors or with the BCR by immune complexes. The phosphorylated ITIM of FcγRIIB recruits the inositol phosphatases SHIP1 and SHIP2 , which inhibit Ras activation, downregulate MAPK activity and reduce PLCγ function and lead to decreased activation of PKC. Inhibition of
7474-414: 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. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. This serves to increase
7575-846: 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 though, 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 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
7676-769: The invading microbe. The activation of natural killer cells by antibodies initiates a cytotoxic mechanism known as antibody-dependent cell-mediated cytotoxicity (ADCC) – this process may explain the efficacy of monoclonal antibodies used in biological therapies against cancer . The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens. Humans and higher primates also produce "natural antibodies" that 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
7777-459: 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. The variable domains can also be referred to as
7878-444: The ligand is, or the higher the affinity between ligand and protein. For example, a ligand with a nanomolar (nM) dissociation constant binds more tightly to a particular protein than a ligand with a micromolar (μM) dissociation constant. Sub-picomolar dissociation constants as a result of non-covalent binding interactions between two molecules are rare. Nevertheless, there are some important exceptions. Biotin and avidin bind with
7979-420: The macromolecule: where the saturation occurs stepwise For the derivation of the general binding equation a saturation function r {\displaystyle r} is defined as the quotient from the portion of bound ligand to the total amount of the macromolecule: K′ n are so-called macroscopic or apparent dissociation constants and can result from multiple individual reactions. For example, if
8080-448: The mass conservation principle: To track the concentration of the complex [AB], one substitutes the concentration of the free molecules ([A] or [B]), of the respective conservation equations, by the definition of the dissociation constant, This yields the concentration of the complex related to the concentration of either one of the free molecules Many biological proteins and enzymes can possess more than one binding site. Usually, when
8181-709: The microscopic dissociation constant must be equal for every binding site and can be abbreviated simply as K D . In our example, K′ 1 is the amalgamation of a ligand binding to either of the three possible binding sites (I, II and III), hence three microscopic dissociation constants and three distinct states of the ligand–macromolecule complex. For K′ 2 there are six different microscopic dissociation constants (I–II, I–III, II–I, II–III, III–I, III–II) but only three distinct states (it does not matter whether you bind pocket I first and then II or II first and then I). For K′ 3 there are three different dissociation constants — there are only three possibilities for which pocket
8282-557: The other antibody isotypes, IgE, IgA, or IgG, that have defined roles in the immune system. In mammals there are two types of immunoglobulin light chain , which are called lambda (λ) and kappa (κ). However, there is no known functional difference between them, and both can occur with any of the five major types of heavy chains. Each antibody contains two identical light chains: both κ or both λ. Proportions of κ and λ types vary by species and can be used to detect abnormal proliferation of B cell clones. Other types of light chains, such as
8383-480: The p K 1 constant refers to its carboxyl (–COOH) group, p K 2 refers to its amino (–NH 2 ) group and the p K 3 is the p K value of its side chain . The dissociation constant of water is denoted K w : The concentration of water, [H 2 O], is omitted by convention, which means that the value of K w differs from the value of K eq that would be computed using that concentration. The value of K w varies with temperature, as shown in
8484-584: The pathogen in cells that recognize their Fc region. Those cells that recognize coated pathogens have Fc receptors, which, as the name suggests, interact 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 cells and neutrophils will degranulate , natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of
8585-455: The pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway . Antibodies will also trigger vasoactive amine degranulation to contribute to immunity against certain types of antigens (helminths, allergens). Antibodies that bind to surface antigens (for example, on bacteria) will attract the first component of the complement cascade with their Fc region and initiate activation of
8686-599: The placenta, from the mother to the fetus. In addition to this, binding to FcRn endows IgG with an exceptionally long half-life relative to other plasma proteins of 3-4 weeks. IgG3 in most cases (depending on allotype) has mutations at the FcRn binding site which lower affinity for FcRn, which are thought to have evolved to limit the highly inflammatory effects of this subclass. Antibodies are glycoproteins , that is, they have carbohydrates (glycans) added to conserved amino acid residues. These conserved glycosylation sites occur in
8787-437: The presence of these proteins, V(D)J recombination would not occur. 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. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells,
8888-565: The pro-apoptotic signaling induced by aggregation of FcγRIIB through immune complexes, allowing for FcγRIIB to effectively tune the affinity threshold for antigen in immune responses and selectively promote retention and survival of high-affinity B cells. The transmembrane region of FcγRIIB also appears to be functionally important. Multiple epidemiological studies link polymorphisms in the transmembrane domain of FcγRIIB to autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis . Mutagenesis studies confirm that lesioning
8989-403: The proteins are occupied at equilibrium, i.e., the concentration of ligand at which the concentration of protein with ligand bound [ LP ] {\displaystyle {\ce {[LP]}}} equals the concentration of protein with no ligand bound [ P ] {\displaystyle {\ce {[P]}}} . The smaller the dissociation constant, the more tightly bound
9090-512: The reaction or the equilibrium expression to know which is meant. Acid dissociation constants are sometimes expressed by p K a , which is defined by This p K {\displaystyle \mathrm {p} K} notation is seen in other contexts as well; it is mainly used for covalent dissociations (i.e., reactions in which chemical bonds are made or broken) since such dissociation constants can vary greatly. A molecule can have several acid dissociation constants. In this regard, that
9191-613: The receptor in myeloid cells . Both forms contain the Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) in their cytoplasmic regions. The extracellular domains are 95% identical to the domains of FCGR2A and almost completely identical to the FCGR2C (the other members of CD32 family). It is the only inhibitory type I FcγR in humans and mice. FCGR2B1 is highly expressed by B cells, and its mRNA has also been identified at lower levels on monocytes . FCGR2B2
9292-437: 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
9393-405: The specific case of antibodies (Ab) binding to antigen (Ag), usually the term affinity constant refers to the association constant. This chemical equilibrium is also the ratio of the on-rate ( k forward or k a ) and off-rate ( k back or k d ) constants. Two antibodies can have the same affinity, but one may have both a high on- and off-rate constant, while the other may have both
9494-444: 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
9595-631: The table below. This variation must be taken into account when making precise measurements of quantities such as pH. Antibody An antibody ( Ab ) or immunoglobulin ( Ig ) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses , including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens . Antigen literally means "antibody generator", as it
9696-440: 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
9797-431: The three binding sides). The apparent K′ 1 would therefore be three times smaller than the individual K D . K′ 2 describes the reaction from three states (one ligand bound) to three states (two ligands bound); therefore, K′ 2 would be equal to K D . K′ 3 describes the reaction from three states (two ligands bound) to one state (three ligands bound); hence, the apparent dissociation constant K′ 3
9898-406: The transmembrane region impairs the ability of FcγRIIB to attenuate B cell signaling. Multiple mechanisms are proposed to account for this, relating to the ability of FcγRIIB to co-localize with the BCR, colocalize with activating FcγRs (in non-B cells), prevent its colocalization with the activating receptor CD19 . FCGR2B expression on follicular dendritic cells ( FDCs ) is important for capturing
9999-428: The two molecules such as hydrogen bonding , electrostatic interactions , hydrophobic and van der Waals forces . Affinities can also be affected by high concentrations of other macromolecules, which causes macromolecular crowding . The formation of a ligand–protein complex LP {\displaystyle {\ce {LP}}} can be described by a two-state process the corresponding dissociation constant
10100-430: 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,
10201-412: The variable domains are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity-determining regions (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
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