Our focus in this chapter has been on the structure of antibodies produced by humans, which is generally similar in most mammalian species, including mice, an important model system for immunology research. However, some mammals have the ability to produce an alternative form of antibody that is based on the ability of a single VH domain to interact with antigen in the absence of a VL domain (Fig. 4.12). It has been known for some time that the serum of camels contained abundant immunoglobulin-like material composed of heavy-chain dimers that lack associated light chains but retain the capacity to bind antigens. These antibodies are called heavy-chain-only IgGs (hcIgGs). This property is shared by other camelids, including llamas and alpacas. These species have retained the genes for the immunoglobulin light chains, and some IgG-like material in their sera remains associated with light chains, and so it is unclear what led to this particular adaptation during their evolution. In camelids, the ability to produce hcIgGs arises from mutations that allow the alternative splicing of the heavy-chain mRNA, with loss of the CH1 exon and thus the joining of the VH directly to the CH2 domain in the protein. Other mutations stabilize this structure in the absence of VL domains.
Cartilaginous fish, in particular the shark, also have an antibody molecule that differs substantially from human or murine antibodies (see Fig. 4.12). Like camelids, the shark also has genes encoding both immunoglobulin heavy and light chains, and does produce immunoglobulins containing both
Fig. 4.12 Camelid and shark antibody can consist of heavy chain only.
in the camelid heavy-chain-only antibody, a splicing event of the mature heavy chain can delete the exon encoding the ch1 region and thereby create an in-frame hinge region linking the Vh1 to the ch2 region. in the shark, the heavy-chainonly ig molecule retains the ch1 region, suggesting that this form of antibody may predate the evolution of light chains. for both, the repertoire of antigen-binding sites involves extensive variations in long cDR3 regions of the Vh domain relative to other types of antibody.
heavy and light chains. But sharks also produce an immunoglobulin new antigen receptor (IgNAR), with heavy-chain-only antibody in which the VH is spliced to the CH1 exon, rather than the CH1 exon being spliced out as in camelids. These differences suggest that hcIgG production by camelids and sharks represents an event of convergent evolution. The ability of camelid VH domains to interact efficiently with antigens is the basis for producing so-called single-chain antibody. The simplification of using only a single domain for antigen recognition has prompted recent interest in single-chain monoclonal antibodies as an alternative to standard monoclonal antibodies, which we will discuss more in Chapter 16.
Summary.