TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

Upon activation by antigen, B cells form germinal centers where they clonally expand and introduce affinity-enhancing mutations into their B cell receptor genes. Somatic mutagenesis and class switch recombination in germinal center B cells are initiated by the activation-induced cytidine deaminase (AID). Upon germinal center exit, B cells differentiate into antibody-secreting plasma cells. Germinal center maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of TET proteins, enzymes that facilitate DNA demethylation and promote a permissive chromatin state by oxidizing 5-methylcytosine, in antibody-mediated immunity. Using a conditional gene ablation strategy, we show that TET2 and TET3 guide the transition of germinal center B cells to antibody-secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double-deficient germinal center B cells show defects in class switch recombination. However, TET2/TET3 double-deficiency does not prevent the generation and selection of high-affinity germinal center B cells. Rather, combined TET2 and TET3 loss-of-function in germinal center B cells favors C-to-T and G-to-A transition mutagenesis, a finding that may be of significance for understanding the etiology of B cell lymphomas evolving in conditions of reduced TET function

Featured graphic. City networks in the United States: A comparison of four models

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Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and I{kappa}B kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-κB signals beyond the control of cell survival in these subsets. When canonical NF-κB signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness

Oiling global capital accumulation : analyzing the principles, practices and geographical distribution of Islamic financial services

This article focuses on the Islamic financial services (IFS) sector, which originated in the Middle East, but is now rapidly becoming a global sector. First, Islamic economic ideology is discussed, which resulted in the foundation of IFS firms after the 1973 oil crisis, and then an overview of the most common IFS is provided. The third part discusses the global distribution of IFS firms and Shari'a compliant assets. The Middle East is at the apex of the IFS sector, with the Islamized economies of Iran and Pakistan and prime hubs such as Manama and Dubai. Outside the Middle East, Malaysia is identified as an important growing market for IFS, while outside the Muslim world, London is increasingly profiling itself as a global IFS hub

Global-local dynamics in the transformation of the Jakarta Metropolitan Area into a global city-region

This paper investigates the way in which factors at the global and local level interact in the emergence and development of “global city-regions”, which are deemed to be the contemporary growth machines of the global economy. To this end, this paper takes the Jakarta metropolitan area (JMA) as a case to investigate its evolution in the context of the intertwined dynamics of foreign direct investment (FDI) inflow and state intervention over the past three decades. The findings indicate that from a macro-level perspective the JMA has maintained its position as the country’s hotspot for manufacturing investment embedded in East Asian production networks. In addition, we find that the national state has continuously privileged the JMA as the main grounds for national economic development in spite of the country’s shifting political system. We reveal how the nexus between “global” forces (incoming FDI) and “local” conditions (the state’s strategic intervention) has led to the development and restructuring of the JMA as a global city-region

Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat

Knockout of the ubiquitously expressed miRNA-17~92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17~92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17~92:Bim interactions to the complex miR-17~92 knockout phenotype, we used a system of conditional mutagenesis of the nine Bim 3' UTR miR-17~92 seed matches. Blocking miR-17~92:Bim interactions early in development phenocopied the lethal lung phenotype of miR-17~92 ablation and generated a skeletal kinky tail. In the hematopoietic system, instead of causing the predicted B cell developmental block, it produced a selective inability of B cells to resist cellular stress; and prevented B and T cell hyperplasia caused by Bim haploinsufficiency. Thus, the interaction of miR-17~92 with a single target is essential for life, and BIM regulation by miRNAs serves as a rheostat controlling cell survival in specific physiological contexts

Similar NF-κB Gene Signatures in TNF-α Treated Human Endothelial Cells and Breast Tumor Biopsies

BACKGROUND: Endothelial dysfunction has been implicated in the pathogenesis of diverse pathologies ranging from vascular and immune diseases to cancer. TNF-α is one of the mediators of endothelial dysfunction through the activation of transcription factors, including NF-κB. While HUVEC (macrovascular cells) have been largely used in the past, here, we documented an NF-κB gene signature in TNFα-stimulated microvascular endothelial cells HMEC often used in tumor angiogenesis studies. METHODOLOGY/PRINCIPAL FINDINGS: We measured mRNA expression of 55 NF-κB related genes using quantitative RT-PCR in HUVEC and HMEC. Our study identified twenty genes markedly up-regulated in response to TNFα, including adhesion molecules, cytokines, chemokines, and apoptosis regulators, some of them being identified as TNF-α-inducible genes for the first time in endothelial cells (two apoptosis regulators, TNFAIP3 and TNFRSF10B/Trail R2 (DR5), the chemokines GM-CSF/CSF2 and MCF/CSF1, and CD40 and TNF-α itself, as well as NF-κB components (RELB, NFKB1 or 50/p105 and NFKB2 or p52/p100). For eight genes, the fold induction was much higher in HMEC, as compared to HUVEC. Most importantly, our study described for the first time a connection between NF-κB activation and the induction of most, if not all, of these genes in HMEC as evaluated by pharmacological inhibition and RelA expression knock-down by RNA interference. Moreover, since TNF-α is highly expressed in tumors, we further applied the NF-κB gene signature documented in TNFα-stimulated endothelial cells to human breast tumors. We found a significant positive correlation between TNF and the majority (85 %) of the identified endothelial TNF-induced genes in a well-defined series of 96 (48 ERα positive and 48 ERα negative) breast tumors. CONCLUSION/SIGNIFICANCE: Taken together these data suggest the potential use of this NF-κB gene signature in analyzing the role of TNF-α in the endothelial dysfunction, as well as in breast tumors independently of the presence of ERα

Functionally Distinct Subpopulations of CpG-Activated Memory B Cells

During the human B cell (Bc) recall response, rapid cell division results in multiple Bc subpopulations. The TLR-9 agonist CpG oligodeoxynucleotide, combined with cytokines, causes Bc activation and division in vitro and increased CD27 surface expression in a sub-population of Bc. We hypothesized that the proliferating CD27lo subpopulation, which has a lower frequency of antibody-secreting cells (ASC) than CD27hi plasmablasts, provides alternative functions such as cytokine secretion, costimulation, or antigen presentation. We performed genome-wide transcriptional analysis of CpG activated Bc sorted into undivided, proliferating CD27lo and proliferating CD27hi subpopulations. Our data supported an alternative hypothesis, that CD27lo cells are a transient pre-plasmablast population, expressing genes associated with Bc receptor editing. Undivided cells had an active transcriptional program of non-ASC B cell functions, including cytokine secretion and costimulation, suggesting a link between innate and adaptive Bc responses. Transcriptome analysis suggested a gene regulatory network for CD27lo and CD27hi Bc differentiation