Immunoglobulins are oligomeric glycoproteins composed of heavy (H) or light (L) chains, designations based on their rate of migration during SDS-polyacrylamide gel electrophoresis. Human immunoglobulins can be grouped into five classes abbreviated as IgA, IgD, IgE, IgG, and IgM (Table 1). The most abundant of the five, IgG, consists of two identical light chains (23 kDa) linked together by a network of disulfide bonds to each other as well as two identical heavy chains (53-75 kDa). The respective biologic functions of each class are summarized in Table2.
Table1. Properties of Human Immunoglobulins
Table2. Major Functions of Immunoglobulins
Each class of immunoglobulin contains a different H chain isoform: α (IgA), δ (IgD), ε (IgE), γ (IgG), and μ (IgM). The γ-type H chains of IgG are organized into an amino-terminal variable region (VH ) and three constant regions (CH 1, CH 2, CH 3). The μ and ε chains each have four CH domains rather than the usual three. Some immunoglobulins such as IgG exist only as the basic tetramer, with the various chains arranged in the Y-shaped configuration shown in Figure 1. Others such as IgA and IgM can form higher oligomers comprised of two, three (IgA), or five (IgM) copies of the core tetrameric unit (Figure 2).
Fig1. Structure of IgG. The molecule consists of two light (L) chains and two heavy (H) chains. Each light chain consists of a variable (VL ) and a constant (CL ) region. Each heavy chain consists of a variable region (VH ) and a constant region that is divided into three domains (CH 1, CH 2, and CH 3). The CH 2 domain contains the complement-binding site and the CH 3 domain contains a site that attaches to receptors on neutrophils and macrophages. The antigen-binding site is formed by the hypervariable regions of both the light and heavy chains, which are located in the variable regions of these chains. The light and heavy chains are linked by disulfide bonds, and the heavy chains are also linked to each other by disulfide bonds. (Reproduced with permission from Parslow TG, Stites DP, Terr AI, et al: Medical Immunology, 10th ed. New York, NY: McGraw Hill; 2001.)
Fig2. Schematic representation of serum IgA, secretory IgA, and IgM. Both IgA and IgM have a J chain, but only secretory IgA has a secretory component. Polypeptide chains are represented by thick lines; disulfide bonds linking different polypeptide chains are represented by thin lines. (Reproduced with permission from Parslow TG, Stites DP, Terr AI, et al: Medical Immunology, 10th ed. New York, NY: McGraw Hill; 2001.)
The IgG light chain can be subdivided into a C-terminal constant region (CL ) and amino-terminal variable region (VL ). There are two general types of light chains, kappa (κ) and lambda (λ), which differ in the structure of their CL regions. A given immunoglobulin molecule always contains either two κ or two λ light chains—never a mixture of a κ and a λ, with the former predominating in humans.
Each IgG molecule binds to its target molecules, or antigens, at a specific site, or epitope (sometimes called an antigenic determinant). Typical epitopes may consist of a short polysaccharide or amino acid sequence, or a specific three-dimensional arrangement of amino acids or sugars drawn from disparate parts of the antigen’s primary sequence. Each IgG molecule contains two identical antigen binding sites, which are located near the tips of the Y, making this immunoglobulin bivalent— able to bind two antigen molecules simultaneously. These antigen binding sites are comprised of VH and VL domains arranged together as two antiparallel sheets.
Because the region between the CH 1 and CH 2 domains can be readily cleaved by pepsin or papain (see Figure 1), it is referred to as the hinge region. The hinge region confers flexibility to the Fab arms, which facilitates binding to separate antigen molecules. If IgGs recognizing more than one epitope are present, large antibody-antigen clusters can form which are readily recognized and disposed by phagocytic leukocytes. Cluster formation is often demonstrated in the laboratory by the formation of erythrocyte rosettes.
