The Protean Nature of Cells in the B Lymphocyte Lineage

The Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Immunity (Impact Factor: 21.56). 07/2007; 26(6):703-14. DOI: 10.1016/j.immuni.2007.05.013
Source: PubMed


The subdivision of bone marrow (BM) with surface markers and reporter systems and the use of multiple culture and transplantation assays to assess differentiation potential have led to extraordinary progress in defining stages of B lymphopoiesis between the hematopoietic stem cell and B cell receptor (BCR)-expressing lymphocytes. Despite the lack of standard nomenclature and a series of technical issues that still need to be resolved, there seems to be a general consensus regarding the major route to becoming a B cell. Nevertheless, evidence that additional, minor pathways through which B lineage cells are generated exists, and a new appreciation that lymphoid progenitors are protean and able to alter their differentiation potential during embryogenesis and after birth in response to infections suggests that a full understanding of B cell development and how it is regulated has not yet been attained.

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    • "Stages shown include those analyzed in Seita et al. [1]. Pluripotent hematopoietic stem cells (HSC) differentiate in the bone marrow to generate multipotent progenitors (MPP), common lymphoid progenitors (CLP), B lymphoid progenitors (BLP), pre–pro-B cells, and B cell fractions as defined previously by Hardy and colleagues [2]. Although not indicated, lymphoid-primed multipotent progenitors (LMPP) would be present between MPP and CLP. "
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    ABSTRACT: The systematic activation of the B cell–specific transcriptional network drives differentiation of hematopoietic stem cells through B lymphopoiesis. This process requires the ordered expression of the following transcription factors: PU.1, Ikaros, E2A, Stat5, EBF1, Foxo1, and Pax5. Collectively, PU.1, Ikaros and E2A orchestrate early modifications of lineage-specific genes (lineage priming) necessary for the development of all lymphoid cells. Initiation of B lineage specification and commitment requires responsiveness to interleukin-7 mediated by Stat5. E2A, EBF1 and Foxo1 function in concert to activate early genes of the B cell–specific program, V(D)J recombination, and expression of Pax5. Pax5 synergizes with these factors and promotes locus contraction necessary for V(D)J recombination. Together, EBF1 and Pax5 mediate B cell lineage commitment via repression of genes of other hematopoietic lineages. Here, we describe the global network of regulatory circuits and epigenetic mechanisms that initiate and drive early B cell development.
    Molecular Biology of B Cells, 12/2015: pages 35-53; , ISBN: 9780123979339
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    • "B cells at various stages of development may also be phenotyped based on the expression of specific surface markers [69], [70]. dCK KO mice have a partial block at the pro-B (CD43+CD19+) to pre-B cell (CD43−CD19+) transition [36]. "
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    ABSTRACT: Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [18F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.
    PLoS ONE 08/2014; 9(8):e104125. DOI:10.1371/journal.pone.0104125 · 3.23 Impact Factor
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    • "Hardy fraction B+C cells had a lower frequency of cell death in the absence of MyD88 in DCs (Figure 3G). Because survival and growth of fraction B+C cells is mediated by IL-7 (Hardy et al., 2007), those findings suggested stronger IL-7R signaling in DC-Myd88 D mice. Importantly, IL-7R signaling is inhibited by IFN-I. "
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    ABSTRACT: Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
    Immunity 03/2013; 38(3). DOI:10.1016/j.immuni.2012.11.017 · 21.56 Impact Factor
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