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

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.

Thymic and bone marrow output in individuals with 22q11.2 deletion syndrome

“…Thus, the results obtained from the TREC assay may be used to classify patients based on the status of their immunity, predicting susceptibility to infections. In this study, we found that the TREC levels were significantly lower in individuals with 22q11.2DS compared with healthy controls and tended to decrease with age due to the natural thymic involution, as has been previously shown (6,(22)(23)(24). Furthermore, lower TREC levels were found in 22q11.2DS patients with recurrent infections, regardless of their age, which probably contributes to the immunodeficiency in some patients.…”

T-Cell Abnormalities in Common Variable Immunodeficiency

“…T-cell receptor excision circles (TRECs) and kappadeleting recombination excision circles (KRECs), such as circular DNA segments that persist in T cells and B cells, were recently considered markers of new lymphocyte output [32]. Kamae et al [33] indicated that low TREC and/or KREC levels are useful biomarkers that are associated with the overall survival rate in CVID patients.…”

Limitation of Simultaneous Analysis of T-Cell Receptor and κ-Deleting Recombination Excision Circles Based on Multiplex Real-Time Polymerase Chain Reaction in Common Variable Immunodeficiency Patients

“…TRECs and KRECs are circular episomes of DNA that are formed into differentiating T- and B-cell progenitors during V(D)J rearrangement in the thymus and bone marrow. It is supposed that TREC and KREC measurement could be a valuable marker for lymphocyte neogenesis [6]. …”