Jacobo Abadi, Department of Pediatrics, Division of Pediatric Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York, USA

Liise-anne Pirofski, Department of Medicine, Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

Immunoglobulin (Ig) isotypes are responsible for the biological effector functions of antibody molecules. In humans, there are nine Ig heavy (H) chain and two light (L) chain isotypes which differ in the structure of their carboxy-terminal portion, or constant (C) region. The L chain isotypes, K and are not known to be associated with biological functional differences. There are five H chain isotypes, or classes: IgA, IgD, IgE, IgG and IgM. Based on 95% or greater amino acid homology, IgA and IgG have two and four subclasses, respectively. C region genes are located on chromosome 14, 3' to the JH genes of the human Ig locus: C|jl for IgM, C8 for IgD, Cyl for IgGl, Cy2 for IgG2, Cy.3 for IgG3, Cy4 for IgG4, Cal for IgAl, Ca2 for IgA2, and Ce for IgE. Each one of these genes encodes glycoprotein molecules with four structural components: CH1, hinge, Cn2 and C|,3. The CM1 interaction with the I. chain C region is of importance for the structural integrity of antibody molecules. The Q,2 regions interact through branched chain N-linked carbohydrate moieties which facilitate antibody solubility and secretion. The hinge region enables bivalent variable-region antigen-binding sites to engage two epitopes: it enhances antigen binding and cross-linking, influences steric relationships between Fab sites and Fc regions, and is responsible for antibody molecule flexibility. IgM and IgE have a CH4 region and lack a genetic hinge, although the pentameric structure of IgM facilitates multivalent antigen binding. IgG3 has an extended hinge region encoded by several exons rather than one. IgG4 has a short, inflexible hinge that creates steric hindrance for fixation of complement. Allotypic variants, designated as Km, Am, Mm, and Gm, may exist at any of the H chain C region loci. Such allelic differences may also influence individual isotype levels and produce differences in biological activity. There are two pseudogenes (v|i) in the H chain C region locus and multiple X. light chain pseudogenes.

Complement fixation is a critical isotype function in host defense. The classical pathway is activated by Clq binding to the Cn2 region of cross-linked IgG (IgG3>IgG 1 >IgG2) and to the CH3 region of IgM. Clq binds immune complexes and IgM pentamers with higher avidity than single molecules. Antibody is not required for the activation of the alternative pathway. The CH2 and CH3 regions of antibody molecules are responsible for Fc receptor binding to a large spectrum of host effector cells. Fc receptor binding results in aggregation, phagocytosis and lysis of antibody-coated targets. Unique Fc receptors demonstrate different specificities and affinities for individual isotypes.

Ig class switching, regulated by T and B cell differentiation factors, determines isotype commitment during B cell maturation. Developmental maturation of IgG subclasses results in a delay in the appearance of IgG2 antibodies until age 2 years. In adults, T-independent antigens such as polysaccharides often elicit isotype restricted responses which are predominantly IgM and IgG2. T-dependent antigens such as proteins primarily elicit IgGl and IgG3 antibodies. IgG subclass deficiency, such as the physiologic IgG2 deficiency of infancy and early childhood, is frequently compensated by increased production of alternative IgG subclasses. Isolated isotype or IgG subclass deficiencies usually do not result in increased disease susceptibility, although combined deficiencies may be a risk factor for given infections.

The five major human isotypes are variably distributed. The IgG subclasses constitute 70-75% of the total Ig pool and 50% of these antibodies are located in the intravascular space. IgG antibodies are the predominant isotype of the secondary antibody response and through a transcytosis-mediated process are the only Igs to cross the human placenta. IgM is the predominant isotype in primary antibody responses and is typically secreted as a pentamer. It represents 10% of the Ig pool and is largely (75%) intravascular. IgA constitutes 15-20% of the Ig pool. It provides mucosal immunity and is distributed in saliva, tears and breast milk, and respiratory, genitourinary and intestinal secretions. Secretory IgA, which is predominantly IgA2, is secretcd from the extracellular matrix to the lumen by transcytosis in association with a non-lg protein, the secretory component, which is synthesized by epithelial cells. Dimeric IgA and pentameric IgM are each associated with another non-lg protein called the J chain. Serum IgA is mainly monomeric and of the IgA I subclass. IgD accounts for less than 1 % of human Ig and appears mainly on the surface membrane of circulating B lymphocytes. The long hinge region of IgD may play a role in B cell activation by cross-linking membrane IgD to antigen. Finally, significant levels of scrum IgE are rarely found in nonallergic individuals, although it is present on the surface of basophils and mast cells. It is homocytotropic because of its presence on the surface of mast cells and basophils serving as an antigen-binding molecule. IgE appears in response to helminthic infections and in hypersensitivity reactions, allergy and asthma.

See also: Allotypes, immunoglobin; Idiotype; IgA; IgE; IgG; IgM; Immunoglobulin class switching; Immunoglobulin genes; Immunoglobulin structure.

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