The transcription factor RelB had been shown to be important for dendritic cell (DC) development, but the type of DC involved was not clear. Here, we report that RelB mRNA is expressed strongly in CD8alpha- DEC-205- DC but only weakly in CD8alpha+ DEC-205+ DC. In addition, CD8alpha+ DEC-205+ DC are present and functional in RelB null mice, the DC deficiency being mainly in the CD8alpha- DEC-205- population. By constructing bone-marrow chimeric mice, we demonstrate that the partial deficiency in RelB null thymic DC is a secondary effect of disrupted thymic architecture. However, the deficiency in splenic CD8alpha- DEC-205- DC is a direct, stem cell intrinsic effect of the RelB mutation. Thus, RelB selectively regulates a myeloid-related DC lineage.

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The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: fi...

In this study, 2 distinct populations of mature dendritic cells (DCs) were identified in the human thymus. The major population is CD11b ؊ , CD11c ؉ , and CD45RO low and does not express myeloidrelated markers. It displays all the characteristics of mature DCs with a typical dendritic morphology, high surface levels of HLA-DR, CD40, CD83, and CD86, and expression of DC-lysosome-associated membrane glycoprotein messenger RNA (mRNA). In addition, CD11b ؊ thymic DCs do not express macrophage inflammatory protein-1␣ (MIP-1␣) mRNA, but express thymus-expressed chemokine (TECK) mRNA and are able to secrete bioactive interleukin 12 (IL-12) upon stimulation. In contrast, the minor and variable thymic DC population is CD11b ؉ , CD11c high , and CD45RO high and comprises CD83 ؉ CD14 ؊ mature and CD83 ؊ CD14 ؉ immature DCs. It expresses macrophage-colony stimulating factor receptor, MIP-1␣ mRNA and high amounts of decysin mRNA after CD40 activation, but does not express TECK and is a weak bioactive IL-12 producer. Also identified were the IL-3R␣ high plasmacytoid cells, which are present in the thymic cortex and medulla. Upon culture with IL-3, granulocyte/macrophage-colony stimulating factor, and CD40 ligand, the plasmacytoid cells can adopt a phenotype resembling that of freshly isolated CD11b ؊ thymic DCs. However, these plasmacytoid-derived DCs fail to secrete bioactive IL-12; therefore, conclusions cannot be made about a direct relation between thymic plasmacytoid cells and CD11b ؊ DCs. Whereas CD11b ؉ thymic DCs appear to be related to tonsillar germinal-center DCs, the major CD11b ؊ IL-12-secreting human thymus DC population has similarities to mouse CD11b ؊ CD8 ؉ DCs. IntroductionDendritic cells (DCs) are professional antigen presenting cells 1 that form a dynamic network throughout most tissues and organs and that are crucial for the immune surveillance of the body. [2][3][4] The current model is that Langerhans cells, immature DCs found in epithelia, are the precursors of mature "interdigitating" DCs, found in the T-cell zones of lymphoid organs. 5 Immature interstitial DCs in various tissues, such as the dermis, move into germinal centers as germinal center DCs (GCDCs). In the lymph nodes, tonsils, and spleen, the mature DCs present the antigen captured in the periphery to naive T cells and induce immunity. The DCs of the thymus have a somewhat different role, namely, to present selfantigens and induce negative selection of potential auto-reactive T-cell clones. 6 Until recently, the interdigitating DCs were considered a single population of mature DCs. However, this laboratory and others showed that distinct DC subsets of different lineage derivation and different functions 7-13 could be distinguished in mouse lymphoid organs. On the one hand, CD8 ϩ DCs, lacking myeloid markers such as CD11b and apparently arising from a lymphoid-committed progenitor, 14 are typically potent interleukin 12 (IL-12)-secreting mature DCs. 10,13,15 CD8 ϩ DCs are present at various levels in all mouse lymphoid organs and constitute...

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The early thymus precursor population of adult mice has the capacity to generate T cells, B cells and dendritic cells (DC). These precursors were injected into the thymus of irradiated recipients in order to follow the kinetics of thymic DC development. The resultant cohort of T-lineage cells developing in the thymus was accompanied by a parallel cohort of DC, present at 10(3)-fold lower frequency. The intrathymic lifespan of these DC was as short as that of T-lineage thymocytes. As the thymic DC matured, some markers characteristic of the original precursor population gradually declined (Ly-5, c-kit, Sca-2) whereas markers characteristic of thymic DC appeared and were maintained (major histocompatibility complex class II, CD11c, NLDC-145 and CD8 alpha). Some thymic DC expressed the early B-cell marker BP-1, and BP-1 mRNA, throughout their maturation. The surface markers on thymic DC could be divided into two groups. Some markers, including class I and class II MHC, CD8 alpha and BP-1, appeared to be integral components of the DC surface. In contrast, other markers, including Thy-1, CD4 and CD8 beta, had probably been picked up from associated thymocytes.

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