NF- B activity marks cells engaged in receptor editing

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 09/2009; 206(8):1803-16. DOI: 10.1084/jem.20082815
Source: PubMed


Because of the extreme diversity in immunoglobulin genes, tolerance mechanisms are necessary to ensure that B cells do not respond to self-antigens. One such tolerance mechanism is called receptor editing. If the B cell receptor (BCR) on an immature B cell recognizes self-antigen, it is down-regulated from the cell surface, and light chain gene rearrangement continues in an attempt to edit the autoreactive specificity. Analysis of a heterozygous mutant mouse in which the NF-kappaB-dependent IkappaB alpha gene was replaced with a lacZ (beta-gal) reporter complementary DNA (cDNA; IkappaB alpha(+/lacZ)) suggests a potential role for NF-kappaB in receptor editing. Sorted beta-gal(+) pre-B cells showed increased levels of various markers of receptor editing. In IkappaB alpha(+/lacZ) reporter mice expressing either innocuous or self-specific knocked in BCRs, beta-gal was preferentially expressed in pre-B cells from the mice with self-specific BCRs. Retroviral-mediated expression of a cDNA encoding an IkappaB alpha superrepressor in primary bone marrow cultures resulted in diminished germline kappa and rearranged lambda transcripts but similar levels of RAG expression as compared with controls. We found that IRF4 transcripts were up-regulated in beta-gal(+) pre-B cells. Because IRF4 is a target of NF-kappaB and is required for receptor editing, we suggest that NF-kappaB could be acting through IRF4 to regulate receptor editing.

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    • "Ibrutinib inhibits B-cell receptor and NF-kB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL [10]. The fact that NF-kB marks cells engaged in receptor editing [56], suggests that CLL B-cells are in constant receptor editing and that ibrutinb may also inhibit chronic activation of tolerance mechanisms. Ibrutinib [57e59] may block the effect of this BCReBCR interaction and inhibit tolerance mechanisms. "
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    ABSTRACT: The fundamental task of the immune system is to protect the individual from infectious organisms without serious injury to self. The essence of acquired immunity is molecular self/non self discrimination. Chronic lymphocytic leukemia is characterized by a global failure of immune system that begins with the failure of immunological tolerance mechanisms (autoimmunity) and finish with the incapacity to response to non-self antigens (immunodeficiency). Immunological tolerance mechanisms are involved in chronic lymphocytic leukemia (CLL) development. During B cell development some self-reactive B cells acquire a special BCR that recognize their own BCR. This self-autoantibody-self BCR interaction promotes survival, differentiation and proliferation of self-reactive B cells. Continuous self-autoantibody-self BCR interaction cross-linking induces an increased rate of surface BCR elimination, CD5+ expression, receptor editing and anergy. Unfortunately, some times this mechanisms increase genomic instability and promote additional genetic damage that immortalize self-reactive B cells and convert them into CLL like clones with the capability of clonal evolution and transformed CLL B cells. This review summarizes the immunological effects of continuous self-autoantibody-self BCR interaction cross-linking in the surface of self-reactive B cells and their role in CLL development.
    Journal of Autoimmunity 11/2014; 56. DOI:10.1016/j.jaut.2014.10.005 · 8.41 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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    • "There are at least two pathways active in Bc not involving the Bc receptor that can result in the CD27lo phenotype. First, TLR9 can activate NF-κB35, which has been shown to be a marker of receptor editing in Bc36. Gene targets of NF-κB that we found to be upregulated in CD27lo cells include IL2RA, BCL2L11, CD80, and AICDA. "
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    ABSTRACT: 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 CD27(lo) subpopulation, which has a lower frequency of antibody-secreting cells (ASC) than CD27(hi) 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 CD27(lo) and proliferating CD27(hi) subpopulations. Our data supported an alternative hypothesis, that CD27(lo) 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 CD27(lo) and CD27(hi) Bc differentiation.
    Scientific Reports 03/2012; 2:345. DOI:10.1038/srep00345 · 5.58 Impact Factor
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