Fig. 8.5 A productively rearranged immunoglobulin gene is immediately expressed as a protein by the developing B cell. In early pro-B cells, heavy-chain gene rearrangement is initiated with D to JH rearrangements. As shown in the top panels, no functional μ protein is expressed, although transcription occurs (red arrow). In late pro-B cells, VH to DJH rearrangement occurs on one chromosome first. If no functional H-chain is produced, VH to DJH rearrangement occurs on the second chromosome. As soon as a productive heavy-chain gene rearrangement takes place, μ chains are expressed by the cell in a complex with two other chains, λ5 and VpreB, which together make up a surrogate light chain. The whole immunoglobulin-like complex is known as the pre-B-cell receptor (center panels). It is associated with two other protein chains, Igα and Igβ, which signal the B cell to halt heavy-chain gene rearrangement; this drives the transition to the large pre-B-cell stage by inducing proliferation. Failure to produce a functional H-chain leading to a pre-B-cell receptor signal leads to cell death. The progeny of large pre-B cells stop dividing and become small pre-B cells, in which light-chain gene rearrangements commence. Vκ–Jκ rearrangement (see Section 5-2) occurs first, and if unsuccessful, Vλ to Jλ rearrangement occurs next. Successful light-chain gene rearrangement results in the production of a light chain that binds the μ chain to form a complete IgM molecule, which is expressed together with Igα and Igβ at the cell surface, as shown in the bottom panels. Signaling via this surface receptor complex is thought to trigger the cessation of light-chain gene rearrangement. Failure to produce a functional L chain leads to cell death.
To produce a complete immunoglobulin heavy chain, the late pro-B cell now proceeds with a rearrangement of a VH gene segment to a DJH sequence. In contrast to D to JH rearrangement, VH to DJH rearrangement occurs first on only one chromosome. A successful rearrangement leads to the production of intact μheavy chains, after which VH to DJH rearrangement ceases and the cell becomes a pre-B cell. Pro-B cells that do not produce a μ chain are eliminated, as they fail to receive an important survival signal mediated by the pre-B-cell receptor (see Section 8-3). At least 45% of pro-B cells are lost at this stage. In at least two out of three cases, the first VH to DJH rearrangement is nonproductive as each amino acid is encoded by a triplet of nucleotides. When this initial rearrangement is out of frame, rearrangement then occurs on the other chromosome, again with a theoretical two in three chance of failure. A rough estimate of the chance of generating a pre-B cell is thus 55% [1/3 + (2/3 × 1/3) = 0.55]. The actual frequency is somewhat lower, because the V gene segment repertoire contains pseudogenes that can rearrange yet have major defects that prevent the expression of a functional protein. An initial nonproductive rearrangement does not automatically lead to pro-B cell elimination, as it is possible for most loci to undergo successive rearrangements on the same chromosome, and where that fails, the locus on the other chromosome will rearrange.