Chapter 4
Structure and function of immunoglobulins

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Immunoglobulins are heterodimeric proteins composed of 2 heavy and 2 light chains. They can be separated functionally into variable domains that bind antigens and constant domains that specify effector functions, such as activation of complement or binding to Fc receptors. The variable domains are created by means of a complex series of gene rearrangement events and can then be subjected to somatic hypermutation after exposure to antigen to allow affinity maturation. Each variable domain can be split into 3 regions of sequence variability termed the complementarity-determining regions (CDRs) and 4 regions of relatively constant sequence termed the framework regions. The 3 CDRs of the heavy chain are paired with the 3 CDRs of the light chain to form the antigen-binding site, as classically defined. The constant domains of the heavy chain can be switched to allow altered effector function while maintaining antigen specificity. There are 5 main classes of heavy chain constant domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. IgG can be split into 4 subclasses, IgG1, IgG2, IgG3, and IgG4, each with its own biologic properties, and IgA can similarly be split into IgA1 and IgA2.

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The immunoglobulin domain: The basic immunoglobulin superfamily building block

Immunoglobulins belong to the eponymous immunoglobulin superfamily (IgSF).1, 2, 3 They consist of 2 heavy (H) and 2 light (L) chains (Fig 1), where the L chain can consist of either a κ or a λ chain. Each component chain contains one NH2-terminal variable (V) IgSF domain and 1 or more COOH-terminal constant (C) IgSF domains, each of which consists of 2 sandwiched β-pleated sheets pinned together by a disulfide bridge between 2 conserved cysteine residues.1 Each V or C domain consists of

Immunoglobulin gene organization and rearrangement

Immunoglobulin heavy and light chains are each encoded by a separate multigene family,9, 10 and the individual V and C domains are each encoded by independent elements: V(D)J gene segments for the V domain and individual exons for the C domains. The primary sequence of the V domain is functionally divided into 3 hypervariable intervals termed complementarity-determining regions (CDRs) that are situated between 4 regions of stable sequence termed framework regions (FRs; Fig 1).

H chain C domain structure and function

In general, the C domain of the H chain defines effector function, whereas the paired V domains of the antibody confer antigenic specificity. The H chain constant domain is generally defined as CH1-CH2-CH3 (IgG, IgA, and IgD), with an additional domain (CH4) for IgM and IgE. As described above, the CH1 domain is located within the F(ab) region, whereas the remaining CH domains (CH2-CH3 or CH2-CH4) comprise the Fc fragment. This Fc fragment defines the isotype and subclass of the immunoglobulin.

FcγR

FcRs for immunoglobulin link the humoral immune compartment to the cellular immune compartment. The net result of binding of immunoglobulin to receptor is a function of the receptor, the cell on which it is expressed, and any ancillary signals. Tight regulation of binding to the FcR is necessary to maintain a healthy immune system.

The most extensively studied FcRs are the IgG-binding receptors, termed FcγR. In human subjects 3 classes of FcγR have been identified: I, II, and III. FcγRII and

Immunoglobulin transport

The transport of polymeric immunoglobulin into mucosal secretions is a function of the polymeric immunoglobulin receptor (pIgR). This receptor is found on the basolateral surface of epithelial cells lining the mucosal surface. Membrane-bound pIgR consists of 5 immunoglobulin-like domains (extracellular portion) with a transmembrane and cytoplasmic domain. pIgA (with the J-chain) binds to the pIgR on the epithelial cell. It is then internalized and transcytosed to the apical cell membrane. The

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    Disclosure of potential conflict of interest: H. W. Schroeder receives research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases, the United States Immunodeficiency Network, and NABI Pharmaceuticals and is a councilor for the Henry Kunkel Society. L. Cavacini is a consultant for GTC Biotherapeutics and receives research support from the National Institutes of Health.

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