Antibodies the different subclasses belonging to the same class are tion.Once a b lvmphocyte is committed to antibod encoded by different exons,they show greater sequence secretion,the combination of its variable region genes will oeloeheireonantregorsandehibtacommoa comp cis (humans15:mice=19).In humans,there is one will be assembled to variable region genes.so that the firs Ck locus and four C loci (CI to CA4),which comprise isotype to beexpressed at the B-lymphocyte surface is IgM four A subclasses. the H-chain Even though membrane-bound and secreted IgM have th to the antibody molecule.and each antibody isotype has u chain that is 21 amino acids longer than that of the secreted form;most of the extra residu s are uncharged and mmune systen ch e o m are h drophobic,enabling anchorage of the ne le binding al Fe ulation.B cells proliferate,differenti facilitates transport of maternal IgG into the fetus.On the ate and may recombine another constant exon(Cy.Ca or other hand.antibodies of the IgE isotype bind to specific Ce).giving rise to IgG,IgAor IgE antibodies.This process, called sotype switching or h g city to the property,IgE antibodies play an important role in allergic function.It is remarkable that antibodies of different disorders and parasitic infection Consequently, the variable region isotypi antibody response Isotype switching usu econdar thtprto to the iing by immunization or following infection.Different cytokines functionierenta to unc ons,an m response g s rise in all and IgG2 antibody production is triggered in response to there is no class switching for the Lchain. carbohydrate antigens. With successive exposures to the antigen,the isotype and the magnitude Cellular Origin The human bod Tand B ohcooiiciphetamantpeaid he imm h the h response to antgen)use f the r bone marrow,migrate to secondary lymphoid organs decline progressively.A second exposure to the same (spleen,lymph nodes.Peye tonsi appendix) namn led boostin anc fron ized by the uniqueness of its variable regions and the pairing of its H and L chains.This Persistence of memory lymphocytes for many years combinatorial diversity generates a repertoire of lympho provides the ecipient with a pe tential long-lasting protec- cytes bea ainst the inva It is this immunologic memory the B-cell clone is activated and divides rapidly.thus ondary expanding the antigen-specific clone. higher affinity for the immunogen than the primary IgM. ocyte switched cell will evolve to a plasma cellor toa into ant ng a unique imn in recep of the same antigen-bindin ence of T cells and usually involves both memc ry R the lymphocyte progeny after cell activation and prolifera cells and memory Tcells.This increase in affinity enhances 2 ENCYCLOPEDIA OF LIFE SCIENCES/62001 N els netthe different subclasses belonging to the same class are encoded by different exons, they show greater sequence homology in their constant regions and exhibit a common overall molecular structure. The L chain comprises two isotypes (k and l) and the k/l ratio varies in different species (humans 5 1.5; mice 5 19). In humans, there is one Ck locus and four Cl loci (Cl1 to Cl4), which comprise four l subclasses. At the functional level, differences in the H-chain constant regions of the isotypes confer distinct properties to the antibody molecule, and each antibody isotype has been adapted to function in a different compartment of the immune system. It is the H-chain isotype that determines the locations of the antibody and its half-life in vivo. For example, binding of IgG isotypes to placental Fc receptors facilitates transport of maternal IgG into the fetus. On the other hand, antibodies of the IgE isotype bind to specific receptors on mast cells and basophils and, upon cross￾linking by antigen, induce release of mediators and cytokine production by these cells. Because of this unique property, IgE antibodies play an important role in allergic disorders and parasitic infections. Consequently, the isotypic composition of an antibody response imparts the tissue distribution of the immunoglobulins produced and their biological functions, each isotype contributing distinctively to protection against pathogens. IgG sub￾classes, for example, exhibit distinct structures and effector functions, and are differentially expressed in response to specific stimuli. In humans, IgG1 predominates in antiviral responses; specific IgG4 levels rise in allergic responses; and IgG2 antibody production is triggered in response to carbohydrate antigens. Cellular Origin The human body contains approximately 2
1012 T and B lymphocytes. Unlike T lymphocytes, which must migrate through the thymus, B lymphocytes originate from the bone marrow, migrate to secondary lymphoid organs (spleen, lymph nodes, Peyer patches, tonsils, appendix) and produce immunoglobulins. Each B lymphocyte, or B￾cell clone, is committed to the synthesis of one antibody specificity characterized by the uniqueness of its variable regions and the pairing of its H and L chains. This combinatorial diversity generates a repertoire of lympho￾cytes bearing receptors that can recognize virtually all possible antigens. Upon interaction with its target antigen, the B-cell clone is activated and divides rapidly, thus expanding the antigen-specific clone. The progeny of the stimulated B lymphocyte eventually differentiate into antibody-secreting cells, called plasma cells. The membrane of the B lymphocyte bears antibodies of the same antigen-binding specificity as those secreted by the lymphocyte progeny after cell activation and prolifera￾tion. Once a B lymphocyte is committed to antibody secretion, the combination of its variable region genes will be expressed by all members of the progeny. At early stages of B-cell development, it is the Cm exon, which lies closest to the immunoglobulin H-chain variable region locus, that will be assembled to variable region genes, so that the first isotype to be expressed at the B-lymphocyte surface is IgM. Even though membrane-bound and secreted IgM have the same specificity, the two forms produced by the cell clone are not completely identical. Membrane-bound IgM has a m chain that is 21 amino acids longer than that of the secreted form; most of the extra residues are uncharged and some of them are hydrophobic, enabling anchorage of the m chain in the membrane. With antigen stimulation, B cells proliferate, differenti￾ate and may recombine another constant exon (Cg, Ca or Ce), giving rise to IgG, IgA or IgE antibodies. This process, called isotype switching or class switching, enables antibodies of a given specificity to acquire a different constant region and, hence, to change their effector function. It is remarkable that antibodies of different isotypes can express exactly the same variable region. Isotype switching usually takes place during the secondary immune response, i.e. following several rounds of exposure of the antigen to the immune system by deliberate immunization or following infection. Different cytokines preferentially induce switching to different isotypes by making the switch recombination sites that lie 5’ to each H￾chain constant exon accessible to switch recombinases. As the k and l exons are located on different chromosomes, there is no class switching for the L chain. With successive exposures to the antigen, the isotype and the magnitude and affinity of the antibody response change. Following initial antigen injection, termed prim￾ing, the recipient mounts a primary immune response, which is influenced by the nature of the antigen, the dose injected, the route of injection, the adjuvant (a preparation that enhances the immune response to an antigen) used and the genetic make-up of the immunized host. After reaching a plateau, the amount of the primary IgM produced will decline progressively. A second exposure to the same antigen, called boosting, triggers a secondary immune (anamnestic) response that differs in several respects from the primary response. It is produced more rapidly, its magnitude is higher, and it persists for longer time periods. Persistence of memory lymphocytes for many years provides the recipient with a potential long-lasting protec￾tion against the invader. It is this immunological memory that allows successful vaccination and prevention against pathogens. Secondary antibodies are dominated by IgG of higher affinity for the immunogen than the primary IgM. The isotype-switched cell will evolve to a plasma cell or to a memory cell expressing a unique immunoglobulin recep￾tor. The secondary immune response depends on the presence of T cells and usually involves both memory B cells and memory T cells. This increase in affinity enhances Antibodies 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net