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 - PubMed (original) (raw)

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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

Federico Serana et al. J Transl Med. 2013.

Abstract

T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients' subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV-infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established.

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Figure 1

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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