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Figure 1 | Journal of Translational Medicine

Figure 1

From: Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies

Figure 1

New T- and B-cell generation. A) Lymphoid progenitors migrate to the thymus, where they progressively rearrange T-cell receptor (TR) genes. Before the rearrangements of the TR alpha (TRA) locus, the TR delta (TRD) locus, which lies within the TRA locus, must be excised by DNA recombinations. Among them, the δREC–ψJα recombination, which occurs in about 70% of thymocytes [13], leads to the generation of a δREC–ψJα coding joint (CJ) in the chromosome and of a δREC–ψJα signal joint (SJ) in a circle of DNA called TR excision circle (TREC). Maturing thymocytes undergo 3–4 intrathymic divisions, in which TRECs cannot be duplicated; thus, only a fraction (about 1:8–1:16) of the originally TREC+ cells will leave the thymus as TREC+ recent-thymic emigrants (RTE) [6,13,15]. Peripheral proliferation will determine further TREC dilution. B) In the bone marrow, progenitor B cells undergo V(D)J rearrangements of the Ig heavy chain (IGH) locus followed by those of the light chains (IGK and IGL). After successful IGH rearrangements at the Pre-B stage, a VJ recombination on the IGK locus is initiated. If it is not productive, another recombination between the Ig kappa deleting element or like (IGKDEL) and one of the upstream recombination signal sequences (RSS) renders the IGK allele non-functional. In 30%-50% of cases, this occurs through the intronRSS-IGKDEL rearrangement, by which the IGKC exon and its enhancers (iEκ, 3’Eκ) are excised, with the creation of the so-called kappa-deleting recombination excision circles (KRECs). Thus, KRECs carry an intronRSS-IGKDEL SJ, and remain in the cells, but, as they cannot be replicated, they will be diluted during peripheral expansion of mature B cells. Instead, an intronRSS-IGKDEL CJ is formed and stably retained in the genomic DNA [7,8,10], because, due to the enhancer loss, any further rearrangement in the IGK locus is precluded.

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