Figure 1.

A Basic Overview of Key Elements That Contribute to the Diversity of Naïve and Memory Repertoires. A basic schematic of the germ-line IGH locus is shown (not to scale), consisting of clusters of tandemly arrayed IGH V, D, J, and constant (C) gene segments. For a subset of these segments, multiple alleles are shown, representing population-level ‘allelic diversity’ (see Table 1). During the initial formation of the naïve repertoire, single IGH V, D and J gene segment on one of two chromosomes in a given B cell are somatically recombined; at each of these steps, P and N nucleotides are added at the D–J and V–D junctions (​‘junctional diversity’), respectively. This process, known as V(D)J rearrangement, is the basis for ‘combinatorial diversity’. The recombined V (red), D (orange), and J (maroon) segments will then be transcribed, and following splicing, will be paired with a C gene (gray). The somatic recombination process also occurs at one of two loci encoding the Ab light-chain gene segments [IGK and IGL; except it involves only V (yellow), J (maroon), and C (light gray) gene segments]. Two identical heavy chains and two identical light chains are ultimately paired through disulfide bonds to form a functional Ab; thus, additional diversity in the expressed Ab repertoire comes from ‘heavy- and light-chain pairing’. Together, the V, D, and J segments depicted comprise the variable domain of the heavy chain of a functional antibody, and together with the variable domain of the light chain, encoded by V and J segments, are responsible for Ag binding. The C domains of both heavy and light chains provide structural and/or effector functions of the Ab. As shown here for the heavy chain, the variable domain is partitioned into four framework regions (FRs) and three complementarity-determining regions (CDRs). Following Ag stimulation, ‘somatic hypermutations’ introduce additional variation in the variable domain of the Ab (vertical purple bars), with the aim of improving binding affinity. Mutations that arise via SHM can occur across all FRs and CDRs, but these are most prevalent in CDRs, as illustrated by the hypothetical frequency histogram shown between the unmutated and mutated IG heavy-chain RNA. While the general molecular mechanisms outlined here have long been realized as the primary determinants of diversity within a given expressed Ab repertoire, there is a growing appreciation for the contribution of ‘allelic diversity’ as well, particularly as this pertains to repertoire differences observed between unrelated individuals. Ab, antibody; C, constant; D, diversity; IGH, immunoglobulin heavy-chain locus; IGK, immunoglobulin kappa; IGL, immunoglobulin lambda; J, joining; SHM, somatic hypermutation; V, variable.