b cell ready to respond to antigen. b cell activation follows engagement of the cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate 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 the other antibody isotypes, ige, iga, or igg, that have defined roles in the immune system. light chain types 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 the iota (ι) chain, are found in other vertebrates like sharks (chondrichthyes) and bony fishes (teleostei). in non-mammalian animals 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. antibody classes not found in mammals classtypesdescription igyfound in birds and reptiles; related to mammalian igg. igwfound in sharks and skates; related to mammalian igd. igt/zfound in teleost fish antibody–antigen interactions the antibody's paratope interacts with 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 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. function further information: immune system antibodies (a) and pathogens (b) free roam in the blood.the antibodies bind to pathogens, and can do so in different formations such as:opsonization,neutralisation, andagglutination.a phagocyte (c) approaches the pathogen, and the fc region (d) of the antibody binds to one of the fc receptors (e) of the phagocyte.phagocytosis occurs as the pathogen is ingested. the main categories of antibody action include the following: neutralisation, in which neutralizing antibodies block parts of the surface of a bacterial cell or virion to render its attack ineffective agglutination, in which antibodies "glue together" foreign cells into clumps that are attractive targets for phagocytosis precipitation, in which antibodies "glue together" serum-soluble antigens, forcing them to precipitate out of solution in clumps that are attractive targets for phagocytosis complement activation (fixation), in which antibodies that are latched onto a foreign cell encourage complement to attack it with a membrane attack complex, which leads to the following: lysis of the foreign cell encouragement of inflammation by chemotactically attracting inflammatory cells 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 the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures. at the prenatal and neonatal stages of life, the presence of antibodies is provided by passive immunization from the mother. early endogenous antibody production varies for different kinds of antibodies, and usually appear within the first years of life. since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. circulating antibodies are produced by clonal b cells that specifically respond to only one antigen (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 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). the secreted mammalian igm has five ig units. each ig unit (labeled 1) has two epitope binding fab regions, so igm is capable of binding up to 10 epitopes. activation of complement 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 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 the bacterium directly (bacteriolysis). activation of effector cells 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 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 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. natural antibodies 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 the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. many natural antibodies are directed against the disaccharide galactose α(1,3)-galactose (α-gal), which is found as a terminal sugar on glycosylated cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut. rejection of xenotransplantated organs is thought to be, in part, the result of natural antibodies circulating in the serum of the recipient binding to α-gal antigens expressed on the donor tissue. immunoglobulin diversity virtually all microbes can trigger an antibody response. successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens. it has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. although a huge repertoire of different antibodies is generated in a single individual, the number of 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. domain variability the complementarity determining regions of the heavy chain are shown in red (pdb: 1igt​) the chromosomal region that encodes an antibody 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 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 the antibody generates a large cavalry of antibodies with a high degree of variability. this combination is called v(d)j recombination discussed below. v(d)j recombination further information: v(d)j recombination simplified overview of v(d)j recombination of immunoglobulin heavy chains 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 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 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 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. somatic hypermutation and affinity maturation further information: somatic hypermutation and affinity maturation following activation with antigen, b cells begin to 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. 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 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 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