IntroductionB cell-activating factor belonging to the TNF family (BAFF) has emerged as an important regulator of B-cell homeostasis and survival: it acts alone or in combination with B-cell receptor (BCR), IL-4, or CD40 ligands. 1-4 BAFF binds 3 different TNF receptors: BCMA (B-cell maturation), 5,6 TACI (transmembrane activator and CAML interactor), 7 and BAFF-R/BR3 (BLys receptor 3). 8 A highly similar homolog (called "a proliferation-inducing ligand" or APRIL) 1 also binds TACI and BCMA but not BAFF-R. 9 BCMA, TACI, and BAFF-R are mostly found on B lymphocytes, [10][11][12] whereas BAFF-R is also present on a subset of T cells. 11,13 Accordingly, BAFF produced by antigen-presenting cells provides T-cell costimulation. 13 The BAFF/BAFF-R pair is essential for survival of immature T2, B2, and marginal zone (MZ) B cells, [14][15][16] but not for that of B1 cells, 17,18 whereas TACI exerts a negative control over 20 BCMA has no obvious effect on mature B-cell survival, but is important for long-term plasma cell biology 10,12 and antigen presentation. 21 BAFF-or BAFF-R-deficient mice form only rudimentary germinal centers (GCs) and produce low levels of IgG in response to T-dependent (TD) antigens. 22,23 In contrast, TACI-deficient mice display an impaired response to type II T cell-independent antigens, suggesting that TACI is required for B1 cell survival. 24 BAFF-R and TACI provide signals for isotype switching toward IgG and IgE, but the switch to IgA is mainly controlled by TACI. 17,25 Many BAFF transgenic mice show signs of autoimmunelike diseases, 2,26 whereas aged APRIL-transgenic mice display a progressive expansion of B1 cells infiltrating the peritoneum and lymphoid organs. 27 These various observations support a major role for the TACI/APRIL and BAFF-R/BAFF pairs in B1 and B2 cell physiology, respectively.Like CD40L, BAFF mainly promotes NF-B and MAPK activation. 28,29 Triggering BAFF-R results in activation of NF-B2 and NF-B1 pathways, whereas triggering BCMA and TACI only activate the NF-B1 pathway. 7,9,28,30,31 Different sets of MAPK and transcription factors are activated downstream from BCMA, TACI, and BAFF-R. 29,32,33 In particular, it has been shown that p38MAPK but not ERK is stimulated early after BAFF-R triggering. 34 Lymphocyte recirculation, which is essential for maintaining an effective immune system, is tightly regulated by the expression of adhesion molecules, chemoattractant receptors, and environmental cytokines. 35,36 Trafficking of human naive and memory B cells is mainly orchestrated by CXCR4/CXCL12, CXCR5/CXCL13, and CCR7/CCL21 (or CCL19) pairs. 37,38 The efficiency of the humoral response depends on the chemotactic response of mature B cells that is modulated by BCR-and IL-4-receptor triggering and CD40/CD40L interactions. 37,[39][40][41][42] In particular, BCR triggering enhances the chemotactic response of naive B cells to CCL21 but decreases that to CXCL13. In contrast, CD40L enhances the migration of memory B cells to CXCL13 without modifying that of CXCL12, CCL21, or CCL19. ...

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Toxic epidermal necrolysis (TEN) is characterized by an acute detachment and destruction of keratinocytes, affecting large areas of the skin. It is often related to adverse drug reactions. Previous studies have shown that effector CD8+ T cells, which accumulate in the blister fluid, are functionally cytotoxic and act through a classical perforin/granzyme B pathway. It has recently been shown that these cytotoxic T cells also secrete granulysin peptide, which is lethal to keratinocytes. These cytotoxic T cells exert their killer activity against autologous keratinocytes in the presence of the drug. However, they are unlikely to be the only effectors of TEN. We therefore searched for soluble death factors in the blister fluids that might kill keratinocytes. We found that the amounts of interferon-γ, TRAIL and TNF-α proteins were significantly greater in TEN blister fluids than in all controls (normal sera, TEN sera, burns and Eosinophilic pustular folliculitis blister fluids) and TNF-like weak inducer of apoptosis (TWEAK) amounts are also greater in all controls except burns. We showed that these proteins acted in synergy to induce the death of keratinocytes in vitro. We also found that TRAIL and TWEAK were secreted by CD1a+ and CD14+ cells present in the blister fluids. Thus, in addition to MHC class I-restricted cytotoxic T lymphocytes (CTLs), which lyse keratinocytes, ligands secreted by non-lymphoid cells capable of inducing keratinocyte death in an MHC class I-independent manner, also seem to be present in the blister fluids of patients with TEN.

Background: BCMA (B-cell maturation) belongs to the tumour necrosis factor receptor gene family, and is specifically expressed in mature B lymphocytes. Antisense BCMA RNA is produced by transcription from the same locus and has typical mRNA features, e.g, polyadenylation, splicing, Kozak consensus sequence and an ORF (p12). To investigate the function of antisense BCMA RNA, we expressed BCMA in cell lines, in the presence of antisense p12 or a mutant lacking the initiation ATG codon (p12-ATG).