Development of immunoglobulin λ-chain-positive B cells, but not editing of immunoglobulin κ-chain, depends on NF-κB signals

Immune Disease Institute, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 20). 07/2009; 10(6):647-54. DOI: 10.1038/ni.1732
Source: PubMed


By genetically ablating IkappaB kinase (IKK)-mediated activation of the transcription factor NF-kappaB in the B cell lineage and by analyzing a mouse mutant in which immunoglobulin lambda-chain-positive B cells are generated in the absence of rearrangements in the locus encoding immunoglobulin kappa-chain, we define here two distinct, consecutive phases of early B cell development that differ in their dependence on IKK-mediated NF-kappaB signaling. During the first phase, in which NF-kappaB signaling is dispensable, predominantly kappa-chain-positive B cells are generated, which undergo efficient receptor editing. In the second phase, predominantly lambda-chain-positive B cells are generated whose development is ontogenetically timed to occur after rearrangements of the locus encoding kappa-chain. This second phase of development is dependent on NF-kappaB signals, which can be substituted by transgenic expression of the prosurvival factor Bcl-2.

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Available from: Geert van Loo, Jan 31, 2014
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    • "Receptor editing has a genetic control and has been studied in several models. Pre-B cells expressing IκB show evidence of receptor editing which is consistent with a role for NFκB [48]. PLCγ2 is present in higher quantities in immature B cells, showing increased phosphorylation in response to BCR crosslinking and probably induces the expression of Rag2 in these cells. "
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    ABSTRACT: B lymphocytes are the effectors of humoral immunity, providing defense against pathogens through different functions including antibody production. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. It is here that their antigen receptors (surface immunoglobulin) are assembled. In the context of autoimmune diseases defined by B and/or T cell autoreactive that upon activation lead to chronic tissue inflammation and often irreversible structural and functional damage, B lymphocytes play an essential role by not only producing autoantibodies but also functioning as antigen-presenting cells (APC) and as a source of cytokines. In this paper, we describe B lymphocyte functions in autoimmunity and autoimmune diseases with a special focus on their abnormalities in systemic lupus erythematosus.
    09/2013; 2013(22):827254. DOI:10.1155/2013/827254
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    • "The upregulation of Pim2 maintains the phosphorylation and inactivation of Bad, which promotes increased levels of Bcl2 and associated cell survival (Bednarski et al., 2012; Youle & Strasser, 2008). Cells deficient in Pim2 do not exhibit this early survival window and Pim2-deficient mice have reduced IgLλ-expressing B cells consistent with a defect in the time available to complete IgL chain gene recombination (Bednarski et al., 2012; Derudder et al., 2009). "
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    ABSTRACT: Lymphocytes traverse functionally discrete stages as they develop into mature B and T cells. This development is directed by cues from a variety of different cell surface receptors. To complete development, all lymphocytes must express a functional nonautoreactive heterodimeric antigen receptor. The genes that encode antigen receptor chains are assembled through the process of V(D)J recombination, a reaction that proceeds through DNA double-stranded break (DSB) intermediates. These DSBs are generated by the RAG endonuclease in G1-phase developing lymphocytes and activate ataxia-telangiectasia mutated (ATM), the kinase that orchestrates cellular DSB responses. The canonical DNA damage response includes cell cycle arrest, DNA break repair, and apoptosis of cells when DSBs are not repaired. However, recent studies have demonstrated that ATM activation in response to RAG DSBs also regulates a transcriptional program including many genes with no known function in canonical DNA damage responses. Rather, these genes have activities that would be important for lymphocyte development. Here, these findings and the broader concept that signals initiated by physiologic DNA DSBs provide cues that regulate cell type-specific processes and functions are discussed.
    Advances in Immunology 10/2012; 116:175-204. DOI:10.1016/B978-0-12-394300-2.00006-5 · 5.96 Impact Factor
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    • "NF-κB, has been shown, by our group and others, to be highly expressed at the pre-B stage [30], [31]. We reported a correlation between the expression of both NF-κB and its inhibitor, IκBα, with κGT and light chain gene rearrangements. "
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    ABSTRACT: Regulated expression of miRNAs influences development in a wide variety of contexts. We report here that miR290-5p (100049710) and miR292-5p (100049711) are induced at the pre-B stage of murine B cell development and that they influence assembly of the Igκ light chain gene (243469) by contributing to the activation of germline Igκ transcription (κGT). We found that upon forced over-expression of miR290-5p/292-5p in Abelson Murine Leukemia Virus (AMuLV) transformed pro-B cells, two known activators of κGT, E2A (21423) and NF-κB (19697), show increased chromosomal binding to the kappa intronic enhancer. Conversely, knockdown of miR290-5p/292-5p in AMuLV pro-B cells blunts drug-induced activation of κGT. Furthermore, miR290-5p/292-5p knockdown also diminishes κGT activation, but not Rag1/2 (19373, 19374) expression, in an IL-7 dependent primary pro-B cell culture system. In addition, we identified a deficiency in κGT induction in miR290 cluster knockout mice. We hypothesize that increased expression of miR290-5p and miR292-5p contributes to the induction of κGT at the pre-B stage of B cell development through increased binding of NF-κB and E2A to kappa locus regulatory sequences.
    PLoS ONE 10/2012; 7(8):e43805. DOI:10.1371/journal.pone.0043805 · 3.23 Impact Factor
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