Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Sarcoptic mange in three alpacas treated successfully with amitraz

Sarcoptic mange is a serious skin disease in alpacas that can result in high morbidity and even mortality. Three alpacas were presented with sarcoptic mange that had previously failed to respond to repeated topical applications of eprinomectin, and an injection of doramectin. They were moderately to severely pruritic, had extensive lesions of alopecia, erythema, scaling and crusting, and had lost weight. As no drug is currently licensed for the treatment of sarcoptic mange in alpacas in the UK, they were treated with a topical solution of amitraz (50 mL in 10 L) after initial bathing with antibacterial or keratolytic shampoos. The clinical signs completely resolved with no relapse over a 10-month follow-up period. In this small group of alpacas, amitraz was an effective and well-tolerated treatment for sarcoptic mange.Peri Lau, Peter B. Hill, Jan Rybníček and Lynne Stee

Mitotic arrest and JNK-induced proteasomal degradation of FLIP and Mcl-1 are key events in the sensitization of breast tumor cells to TRAIL by antimicrotubule agents

12 páginas, 7 figuras.Breast tumor cells are often resistant to tumor necrosis factor-related apoptosis-inducing ligand (tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO-2 L). Here, we describe the sensitization by microtubule-interfering agents (MIAs) to TRAIL-induced apoptosis in breast tumor cells through a mitotic arrest and c-Jun N-terminal kinase (JNK)-dependent mechanism. MIA treatment resulted in BubR1-dependent mitotic arrest leading to the sustained activation of JNK and the proteasome-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP) and myeloid cell leukemia-1 (Mcl-1) expression. The JNK inhibitor SP600125 abrogated MIA-induced mitotic arrest and downregulation of cFLIP and Mcl-1 and reduced the apoptosis caused by the combination of MIAs and TRAIL. Silencing of cFLIP and Mcl-1 expression by RNA interference resulted in a marked sensitization to TRAIL-induced apoptosis. Furthermore, in FLIP-overexpressing cells, MIA-induced sensitization to TRAIL-activated apoptosis was markedly reduced. In summary, our results show that mitotic arrest imposed by MIAs activates JNK and facilitates TRAIL-induced activation of an apoptotic pathway in breast tumor cells by promoting the proteasome-mediated degradation of cFLIP and Mcl-1.This work was supported by grants from Ministerio de Educación y Ciencia (SAF2006-00633), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD06/0020/0068) and Junta de Andalucía (CTS-211) to ALR. GO-F and TS-P were supported by a contract and fellowship from Ministerio de Ciencia e Innovación, respectively.Peer reviewe

PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development

Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells