The initial Ig rearrangement event occurs at the heavy chain locus located on human chromosome 14 (Fig. 1). The Ig heavy chain locus includes multiple variable (V), diversity (D), joining (J), and constant (C) region gene segments that are separated from one another by introns. The V region genes are located at the 5′ end of the Ig heavy chain locus, and each consists of approximately 300 base pairs. These genes, which are separated by short intron sequences, are organized into families based on sequence homology. There are ~25 human D region genes located 3′ to the V region that are also grouped into families based on sequence homology. Downstream of the D region are six human J region genes. Finally, 10 C region genes representing alternative Ig isotypes are arranged in tandem.

Fig1. REARRANGEMENT AND EXPRESSION OF THE HUMAN IMMUNOGLOBULIN HEAVY CHAIN GENE. The figure shows the Ig heavy chain gene and the signal sequences 3′ of each V region locus, 5′ and 3′ of each D region locus, and 5′ of each J region locus. These consist of heptamer and nonamer sequences separated by either 12 or 23 base pairs. During immunoglobulin (Ig) recombination, a signal sequence of 12 base pairs can only join to another of 23 base pairs (the so-called 12–23 rule). The initial heavy chain gene rearrangements form coding joints between D and J regions as well as signal joints that are ultimately degraded. Subsequently, the joining of the V region gene to the DJ complex occurs. After a successful rearrangement, the VDJ complex, the μ intron, and portions of the constant regions are transcribed. RNA processing and differential splicing results in formation of an mRNA molecule that is then translated. In the example shown, the rearranged VDJ complex and the constant region, with the μ and δ C region genes, is transcribed. After RNA processing and translation, a particular B cell could then express μ protein, δ protein, or both.

The transcription of the unrearranged heavy chain locus occurs prior to actual Ig gene recombination. This results in production of developmentally regulated transcripts of unrearranged Ig genes, referred to as germline or sterile transcripts. Multiple species of sterile transcripts have been described, and some could conceivably encode proteins. A mechanistic link between transcription and Ig gene rearrangement has been hypothesized. For example, transcription could make unrearranged Ig genes accessible to both RNA polymerase and V(D)J recombinase, the germline transcripts could function in the rearrangement reaction, or transcription could alter structural characteristics of DNA, making the recombination signal sequences described below better targets for recombination.

The initial event during heavy chain gene rearrangement occurs by the CLP stage and juxtaposes a D region segment to a J region segment. Although in theory any D region gene can join with equal frequency to any J region gene, there may be preferential utilization of selected D and J region genes at various times during fetal and adult B-cell development. The next recombination event involves the rearrangement of a V region gene to the D–J complex, and this occurs at the pro-B-cell stage of development. The biased usage of J proximal V genes may occur in the newly generated repertoire of neonatal mice and humans. The heavy chain C region remains separated from the rearranged VDJ complex by an intron, and this entire sequence is transcribed. RNA processing subsequently leads to deletion of the intron between the VDJ complex and the most proximal C region genes. After translation, μ heavy chain protein is expressed in the cytoplasm of pre-B cells (see Fig. 1).

The E2A encoded transcription factors are particularly important for Ig gene recombination and mediate their effects via binding to specific promoter sequences located 5′ of each heavy chain V region and enhancer regions located 3′ of the J region genes and downstream from the CH region genes (see Fig. 1). Before Ig gene rearrangement, E12 and E47 proteins may be in an inactive state owing to their heterodimeric association with another protein known as Id. Successful transition from the pro-B to pre-B-cell stage is dependent on cessation of Id expression, a conclusion consistent with the fact that mice expressing an Id transgene have a complete block in B-cell differentiation.

Each pro-B cell has two Ig heavy chain genes, but only one of these encodes heavy chain protein in any given cell. This phenomenon is known as allelic exclusion. One theory for how this occurs is that functional Ig rearrangements are rare, so the chance that two functional rearrangements will occur in an individual cell is extremely low. Alternatively, the expression of heavy chain protein from a successfully rearranged allele may inhibit rearrangements at the other heavy chain allele.

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