Figure 24–27 Ig domains. (A) The light and heavy chains in an Ig protein are each folded into similar repeating domains. The variable domains (shaded in blue) of the light and heavy chains (VL and Vh) make up the antigen-binding sites, while the constant domains (shaded in gray) of the heavy chains (mainly ch2 and ch3) determine the other biological properties of the protein. The heavy chains of IgM and Ige do not have a hinge region and have an extra constant domain (ch4). hydrophobic interactions between domains on adjacent chains help hold the chains together in the Ig molecule: VL binds to Vh, cL binds to ch1, and so on. (B) X-ray crystallography-based structures of the Ig domains of a light chain (Movie 24.5). Both the variable and constant domains have a similar overall structure, consisting of two β sheets joined by a disulfide bond (red). Note that all the hypervariable regions (black) form loops at the far end of the variable domain, where they come together to form part of the antigen-binding site. All Igs are glycosylated on their ch2 domains (not shown); the attached oligosaccharide chains vary from Ig to Ig and can greatly influence the biological properties of the protein, largely by affecting its binding to Fc receptors on immune cells.
antigenic determinant, albeit with low affinity—Ka ≈ 105–107 liters/mole. After stimulation by antigen and helper T cells, B cells can switch from making IgM and IgD to making other classes of Ig—a process called class switching. In addition, the binding affinity of these Igs for their antigen progressively increases over time—a process called affinity maturation. Thus, antigen stimulation generates a secondary Ig repertoire, with a greatly increased affinity (Ka up to 1011 liters/mole) and diversity of both Ig classes and antigen-binding sites.
How can each of us make so many different Igs? The problem is not quite as formidable as it might first appear. Recall that the variable regions of the Ig light and heavy chains usually combine to form the antigen-binding site. Thus, if we had 1000 genes encoding light chains and 1000 genes encoding heavy chains, we could, in principle, combine their products in 1000 × 1000 different ways to make 106 different antigen-binding sites. Nonetheless, we have evolved special genetic mechanisms to enable our B cells to generate an almost unlimited number of different light and heavy chains in a remarkably economical way. We do so in two steps. First, before antigen stimulation, developing B cells join together separate gene segments in DNA to create the genes that encode the primary repertoire of low-affinity IgM and IgD proteins. Second, after antigen stimulation, the assembled Ig genes can undergo two further changes—mutations that can increase the affinity of their antigen-binding site and DNA rearrangements that switch the class of Ig made. Together, these changes produce the secondary repertoire of high-affinity IgG, IgE, and IgA proteins.
We produce our primary Ig repertoire by joining separate Ig gene segments together during B cell development. Each type of Ig chain—κ light chains, λ light chains, and heavy chains—is encoded by a separate locus on a separate chromosome. Each locus contains a large number of gene segments encoding the V region of an Ig chain, and one or more gene segments encoding the C region. During the development of a B cell in the bone marrow, a complete coding sequence for each of the two Ig chains to be synthesized is assembled by site-specific genetic recombination (discussed in Chapter 5). Once a V-region coding sequence is assembled next to a C-region sequence, it can then be co-transcribed and the resulting RNA transcript processed to produce an mRNA molecule that codes for the complete Ig polypeptide chain.