B cells produced in the bone marrow have cell surface immunoglobulins (Igs) as their antigen receptors (B-cell receptors). When B cells are activated, however, they can differentiate into plasma cells that secrete their Ig receptors as soluble antibodies.
Immunoglobulin structure
Igs are composed of two identical heavy chains and two identical light chains that are held together by disulfide bonding (Figure 1). The light chains can be one of two varieties (κ or λ) that are functionally equivalent. The heavy chains can be one of five functionally distinct types that define five immunoglobulin classes (Table 1). Each Ig chain contains two distinct regions, as listed below.
• An N-terminal variable region is involved in antigen binding and has a variable sequence that accounts for the unique specificity of each B-cell receptor and antibody. The variability is not distributed evenly throughout the domain but is concentrated in hypervariable regions (also called complementarity determining regions), which are the regions that directly interact with antigen.
• A C-terminal constant region is invariant within each class of immunoglobulin but differs significantly between the different heavy-chain classes, accounting for the different functionality of each isotype.
Fig1. Antibody (immunoglobulin) structure. Antibodies are soluble immunoglobulins (Igs) that consist of two identical heavy chains (one of five classes) and two identical light chains (one of two classes). The two heavy chains are held together by disulfide bonds and each light chain is linked to one heavy chain by disulfide bridges. Each chain is composed of globular domains that are maintained by intrachain disulfide bridges. The N-terminal regions are known as variable regions as their sequence varies significantly from one antibody to another. Most of the sequence variation is concentrated in hypervariable regions (also called complementarity determining regions), which are the sequences involved in antigen binding. The constant region of each heavy chain determines the class of the heavy chain and the response to bound antigen (see Table 3.6). Sequences at the bottom of each heavy chain can be recognized by specific receptors (Fc receptors) on the surface of effector cells.
Table1. IMMUNOGLOBULIN ISOTYPES
Light and heavy chains are structurally closely related, being made up of Ig domains, each ∼ 100 amino acids long and held together by an internal disulfide bond. The light chain has two Ig domains, one each for the variable and constant regions; the heavy chain has one variable Ig domain and three constant Ig domains—see the B-cell receptor/Ig structure in Figure 2
Fig2. The immunoglobulin superfamily. The immunoglobulin (Ig) domain is a barrel-like structure held together by a disulfide bond (red dot). As shown here, multiple copies of the Ig domain are found in many proteins with important immune system functions—the pale orange boxes show variable domains. Note that immunoglobulins have essentially the same structure as the B-cell receptor (they differ by lacking membrane-binding sequences near the end of the constant region). TCR, T-cell receptor; β2 M, β2-microglobulin.
Immunoglobulin function
Antibodies can bind to specific receptors at multiple regions of the surface of microbes, forming a surface coat. Once a microbe has been coated with IgM or IgG antibodies the classical pathway of complement activation can be activated, causing lysis of the microbes. Complement can also promote phagocytosis via complement receptors on macrophages and neutrophils. In addition, antibodies have several other important functions as listed below.
• Blocking pathogen entry into cells. Viruses and certain microorganisms that can exist within animal cells enter into the cells by binding to certain preferred receptors on the cell surface. Antibodies can physically block this process (Figure 3A).
• Neutralizing toxins. Antibodies can directly bind and neutralize toxins released by bacteria, inhibiting their enzymatic activity or their ability to bind to cell sur face receptors (Figure 3B).
• Activating effector cells. Many immune system cells express receptors that recognize the invariant domains of Ig molecules. Antibodies bound to the surface of microbes can therefore not only activate complement but also directly activate those immune system cells that carry appropriate Fc receptors. IgG antibodies, for example, promote phagocytic uptake by neutrophils and macrophages and antibody-dependent cell-mediated cytotoxicity by NK cells (Figure 3C). IgE bound to IgE-specific Fc receptors on eosinophils, basophils, and mast cells can trigger the release of powerful pharmacological mediators and activate these cells to kill antibody-coated parasites.
Fig3. Aspects of antibody function. (A) Inhibiting viral infection. Viruses infect cells by first using docking proteins to bind to certain receptors on the plasma membrane of host cells. Antibodies can bind to the viral docking proteins to prevent them binding to host-cell receptors. (B) Neutralizing toxins. Antibodies bind to toxins released from invading microbes and so stop them binding to cell receptors. (C) Activating effector cells. Antibodies can bind and coat the surfaces of microbes and large target cells. Various immune system effector cells (notably macrophages, natural killer cells, neutrophils, eosinophils, and mast cells) carry Fc receptors that enable them to bind to the Fc region on IgA, IgG, or IgE antibodies. Antibody binding to an Fc receptor activates the effector cell and can lead to cell killing by phagocytosis, or release of lytic enzymes, death signals, and so on. (Adapted from Alberts B et al. [2014] Molecular Biology of the Cell, 6th edn. Garland Science. With permission from WW Norton.)
