Structural variation in immunoglobulin constant regions.
Evolution of the adaptive immune response.
Fig. 5.1 Three hypervariable regions are encoded within a single V-region exon. Panel a: the variable region is based on the immunoglobulin (Ig) fold that is supported by framework regions (yellow) composed of nine β sheets and contains three hypervariable (HV) regions (red) that determine its antigen specificity. Panel b: the three HV regions exist as loops of amino acids between the β sheets of B and C, between Cʹ and Cʹʹ, and between F and
G.
Panel c: a complete variable region in a lymphocyte is encoded within a single exon of the full antigen-receptor gene. The three HV regions are interspersed between four framework regions (FRs) made up of the β sheets of the Ig domain.
expression of the isotypes IgM and IgD is regulated, but we postpone describing how isotype switching occurs until Chapter 10, since that process and the affinity maturation of antibodies occurs normally in the context of an immune response. The last part of this chapter briefly examines alternative evolutionary forms of gene rearrangements that give rise to different forms of adaptive immunity in other species.
Primary immunoglobulin gene rearrangement.
Virtually any substance can be the target of an antibody response, and the response to even a single epitope comprises many different antibody molecules, each with a subtly different specificity for the epitope and a unique affinity, or binding strength. The total number of antibody specificities available to an individual is known as the antibody repertoire or immunoglobulin repertoire, and in humans is at least 1011 and probably several orders of magnitude greater. The number of antibody specificities present at any one time is, however, limited by the total number of B cells in an individual, as well as by each individual’s previous encounters with antigens.
Before it was possible to examine the immunoglobulin genes directly, there were two main hypotheses for the origin of this diversity. The germline theory held that there is a separate gene for each different immunoglobulin chain and that the antibody repertoire is largely inherited. In contrast, somatic diversification theories proposed that the observed repertoire is generated from a limited number of inherited V-region sequences that undergo alteration within B cells during the individual’s lifetime. Cloning of the immunoglobulin genes revealed that elements of both theories were correct and that the DNA sequence encoding each variable region is generated by rearrangements of a relatively small group of inherited gene segments. Diversity is further enhanced by the process of somatic hypermutation in mature activated B cells. Thus, the somatic diversification theory was essentially correct, although the germline theory concept of the existence of multiple germline genes also proved true.
5-1 Immunoglobulin genes are rearranged in the progenitors of antibody-producing cells.
Figure 5.1 shows the relationships between a light-chain variable region’s antigen-binding site, its domain structure, and the gene that encodes it. The variable regions of immunoglobulin heavy and light chains are based on the immunoglobulin fold, which is composed of nine β sheets. The anti-body-binding site is formed by three loops of amino acids known as hyper-variable regions HV1, HV2, and HV3, or also CDR1, CDR2, and CDR3 (see Fig. 5.1a). These loops are located between the pairs of β sheets B and C, Cʹ and Cʹʹ, and F and G (see Fig. 5.1b). In a mature B cell, the variable regions for heavy and light chains are encoded by a single exon, but are separated from one another within this coding sequence (see Fig. 5.1c). This exon is the gene’s second exon (exon 2). The first exon of the variable regions encodes the antibody’s leader sequence, which directs the antibody into the endoplasmic reticulum for surface expression or secretion.