The classes of immunoglobulins are defined by their heavy-chain C regions, with the different heavy-chain isotypes being encoded by different C-region genes. The heavy-chain C-region genes are present in a cluster 3ʹ to the V, D, and J gene segments. A productively rearranged V-region exon is initially expressed in association with μ and δ CH genes, which are coexpressed in naive B cells by alternative splicing of an mRNA transcript that contains both the μ and δ CH exons. In addition, B cells can express any class of immunoglobulin as a membrane-bound antigen receptor or as a secreted antibody. This is achieved by differential splicing of mRNA to include exons that encode either a hydrophobic membrane anchor or a secretable tailpiece. The antibody that a B cell secretes upon activation thus recognizes the antigen that initially activated the B cell via its antigen receptor. The same V-region exon can subsequently be associated with any one of the other isotypes to direct the production of antibodies of different classes by the process of class switching, which is described in Chapter 10.
Evolution of the adaptive immune response.
The form of adaptive immunity that we have discussed so far in this book depends on the action of the RAG-1/RAG-2 recombinase to generate an enormously diverse clonally distributed repertoire of immunoglobulins and T-cell receptors. This system is found only in the jawed vertebrates, the gnathostomes, which split off from the other vertebrates around 500 million years ago. Adaptive immunity seems to have arisen abruptly in evolution. Even the cartilaginous fishes, the earliest group of jawed fishes to survive to the present day, have organized lymphoid tissue, T-cell receptors and immunoglobulins, and the ability to mount adaptive immune responses. The diversity generated within the vertebrate adaptive immune system was once viewed as unique among animal immune systems. But we now know that organisms as different as insects, echinoderms, and mollusks use a variety of genetic mechanisms to increase their repertoires of pathogen-detecting molecules, although they do not achieve true adaptive immunity. Nearer to home, it has been found that the surviving species of jawless vertebrates, the agnathans—the lampreys and hagfish—have a form of adaptive or ‘anticipatory’ immunity that is based on non-immunoglobulin ‘antibody’-like proteins and involves a system of somatic gene rearrangement that is quite distinct from RAG-dependent V(D)J rearrangement. So we should now view our adaptive immune system as only one solution, albeit the most powerful, to the problem of generating highly diverse systems for pathogen recognition.
5-17 Some invertebrates generate extensive diversity in a repertoire of immunoglobulin-like genes.
Until very recently, it was thought that invertebrate immunity was limited to an innate system that had a very restricted diversity in recognizing pathogens.
This idea was based on the knowledge that innate immunity in vertebrates relied on around 10 distinct Toll-like receptors and a similar number of other receptors that also recognize PAMPs, and also on the assumption that the number of receptors in invertebrates was no greater. Recent studies have, however, uncovered at least two invertebrate examples of extensive diversification of an immunoglobulin superfamily member, which could potentially provide an extended range of recognition of pathogens.