Brief Report TRANSPLANTATION Impact of acute and chronic graft-versus-host disease on human B-cell generation and replication

One of the main of concerns in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the profound and long-lasting immunodeficiency leaving patients highly susceptible to multiple infections. Accordingly, a low B-cell recovery after allo-HSCT has been associated with high infection rate. B-cell reconstitution is a slow process characterized by a relative increase of the percentage of naı̈ve B cells and a recovery of memory B-cell counts that lags long behind. Several factors, such as stem cell source and composition, can affect post-HSCT B-cell recovery with graft-versus-host disease (GVHD) having the strongest influence. Indeed, B-cell lymphopoiesis is highly dependent on the marrow microenvironment, susceptible to damage by the conditioning regimen and side effects of GVHD and/or its treatment. Moreover, alteration of B-cell homeostasis in chronic GVHD (cGVHD) patients associated with high BAFF levels leads to a significantly higher BAFF/B-cell ratio that could promote survival of CD27 autoreactive B-cell clones involved in cGVHD pathogenesis. However, the direct evidence in vivo of an increased B-cell replication in patients with cGVHD is still lacking, and it remains to be clarified whether acute GVHD (aGVHD)may have a persistent impact on B-cell neogenesis. It is now possible to measure the bone marrow (BM) B-cell output using real-time polymerase chain reaction (PCR) for quantification of k-deleting recombination excision circles (KRECs), which are generated in the BMduring B-cell development. The coding joint (Cj) of this rearrangement is duplicated during each cell division, whereas the signal joint KREC (sjKREC) remains stable as episomal DNA. Measuring the ratio between Cj and sjKREC directly reflects themean number of divisions achieved by B cells after the occurrence of the recombination event, thus providing a unique way to quantify the in vivo replicative history of mature B lymphocytes. Here, we analyzed the impact of aGVHD and cGVHD on B-cell reconstitution post allo-HSCT in a cohort of 243 consecutive alloHSCT–treated patients.We showed a clear separate impact of aGVHD andcGVHDonB-cell neogenesis and, incGVHDpatients, a correlation between BAFF/CD19 B-cell ratio and B-cell divisions in vivo.