2 Role of RAG1 and RAG2 in B-cell development | 19 recombination of Ig genes takes place at the immunoglobulin heavy chain locus (Igh). Typically, the DH to JH recombinations take place first, followed by a recombination of the upstream VH region to the already rearranged DJ segment. The successful recombination of Igh marks the transition to the pre-B cell stage10. The early pre-B cells express a pre-B cell antigen receptor (pre-BCR), consisting of the m-Igh chain and a surrogate light chain (SLC). The SLC is a heterodimer and consists of 2 proteins: λ5 and VpreB. The pre-BCR can oligomerize and trigger downstream signaling in the absence of a specific antigen, so-called tonic pre-BCR signaling, which is crucial for the survival of the pre-B cells at this stage13,14. Subsequently, pre-B cells may undergo 1 or 2 cell divisions and then proceed with the recombination of gene segments encoding for the immunoglobulin light chain (Igl). At this stage the RAG1 and RAG2 are re-expressed and at first, the immunoglobulin kappa chain (Igk) is recombined. If the pre-B cells fail to productively recombine the first and the second allele of Igk, and when they have exhausted all the recombination possibilities, then they proceed with recombination of the immunoglobulin lambda chain (Igl)15. The human Igk is located on chromosome 2 (the mouse Igk is located on chromosome 6), and the human Igl on chromosome 22 ( mouse Igl is located on chromosome 16) The light chain loci consist of VL and JL segments, and the constant region CL but lack D gene segments, in contrast to the Igh locus. Following a successful recombination, an IgM BCR is expressed on the cell surface. Once the recombination has successfully been performed, the RAG1/2 expression is in general suppressed throughout the mature stage of the B cells, though there are instances when RAG1/2 can be re-expressed at immature B cells and mediate secondary rearrangements in Ig loci, so-called receptor editing16. In the process of receptor editing, the functionally unresponsive or the self-reactive BCR may acquire a new specificity, and thus escape the apoptosis. Secondary rearrangements in mature peripheral B cells may also take place, the so-called receptor revision, which further diversifies the repertoire17. Each B-cell expresses a BCR of only one particular specificity. This is achieved by allowing only one functional recombined allele to be expressed. This phenomenon called allelic exclusion, guarantees specificity of immune responses and prevents auto-immune reactions. More details on the mechanism of allelic exclusion are discussed elsewhere in this review. After successful recombination, IgM-expressing immature B cells complete their maturation outside of the BM, they enter the circulation or migrate to the lymph nodes or spleen.
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