The total number of antibodies that humans can potentially produce exceeds 1011. Before the sequences of the immunoglobulin genes were known, there were two theories put forward to explain how this level of diversity could be obtained. The germline theory held that all the possible variations were coded for by separate genes, whilst the somatic diversification theory held that immunoglobulin was coded for by a limited number of sequences which were rearranged throughout an individual’s lifetime. The somatic diversification has proved to be essentially correct.
The vast majority of the diversity of an immunoglobulin molecule lies in the variable domain. The variable domain is coded for by a set of gene segments which are randomly selected and rearranged in a process known as somatic recombination. Further diversification is later introduced when the B cell is activated. This consists of point mutations and is known as somatic hypermutation.
The immunoglobulin molecule is made up of a light and heavy chain. The light chain variable domain is coded for by a set of V gene segments (VL) and a set of joining or J gene segments (JL). The heavy chain variable domain is coded for by a set of V gene segments (VH), a set of diversity of D gene segments (DH) and a set of J gene segments (JH).
The somatic recombination process of the light chain involves the random selection of a VL gene segment which is then joined to a randomly selected JL gene segment. This is catalysed by recombination activation genes (RAGs). VL genes are prevented from accidentally joining to other VL gene segments by the use of recombination signalling sequences (RSS) which consist of a heptamer, a 12 or 23 nucleotide spacer and a nonamer. This is the 12/23 rule and it prevents gene segments with a 12 nucleotide spacer being joined to other 12 spacer segments and gene segments with a 23 nucleotide spacer being joined to other 23 spacer segments. This same process prevents J, D and VH gene segments from self joining. The joining process is not precise and introduces further Junctional diversification.
The variable heavy chain is created by a DH gene segment, randomly selected, joining to a JH segment and then the combination joining to a randomly selected VH gene segment. Junctional diversity is introduced during these joins.
Further combinational diversity is introduced by the different combinations of heavy and light chain variable regions that pair to form the antigen binding site.
Finally upon activation, further diversification is introduced in a process known as somatic hypermutation.
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