Bad(Ff) To The Bone: Misbehaving B Cells In Cgvhd

In this issue of Blood, Jia et al(1) investigate the role of B-cell activating factor (BAFF) in skewing the B-cell pool in chronic graft-versus-host disease (cGVHD) in a major histocompatibility mismatch mouse model. They found a previously unknown mechanism by which BAFF elevations lead to B-cell dysregulation in cGVHD. The investigators first confirm that BAFF levels are increased in the model, as has been described in preclinical models and clinical graft-versus-host-disease (GVHD).(2,3) This elevation is due in part to increased production by recipient fibroblastic reticular cells early after hematopoietic stem cell transplantation (HSCT), and, subsequently by donor hematopoietic cells, including alloreactive CD4(+) T follicular helper (T-FH)-like cells that are increased in the cGVHD setting.(4) Using BAFF-knockout and BAFF-transgenic mice, the investigators then show that BAFF increases an extrafollicular GL7(+) B-cell subset(5) by inducing its NOTCH2 upregulation. The latter occurs as a result of high BAFF levels, in concert with in vivo alloantigen stimulation. This particular mouse B-cell subset is likely the functional counterpart of the CD27(+) circulating B-cell subset that is elevated in patients with cGVHD and is capable of sustained immunoglobulinGproduction.(3) Unlike other B-cell subsets, GL7(+) B cells appear to persist and resist activation-induced death that leads to the profound general B-cell lymphopenia that is characteristic of cGVHD.