Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4770-4777 ◽  
Author(s):  
Mirjam van der Burg ◽  
Malgorzata Pac ◽  
Magdalena A. Berkowska ◽  
Bozenna Goryluk-Kozakiewicz ◽  
Anna Wakulinska ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Gene Segment ◽  
Cell Receptor ◽  
Nijmegen Breakage Syndrome ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Receptor Repertoire ◽  
Recombination Activating Gene ◽  
Dna Ends

Abstract The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.

scholarly journals B-1 Cell Development: Evidence for an Uncommitted Immunoglobulin (Ig)M+ B Cell Precursor in B-1 Cell Differentiation

1998 ◽  
Vol 187 (8) ◽  
pp. 1325-1334 ◽  
Author(s):  
Stephen H. Clarke ◽  
Larry W. Arnold
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Lineage ◽  
Signal Transduction Pathway ◽  
Cell Receptor ◽  
Cell Development ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Receptor Signal

Murine phosphatidyl choline (PtC)–specific B cells in normal mice belong exclusively to the B-1 subset. Analysis of anti-PtC (VH12 and VH12/Vκ4) transgenic (Tg) mice indicates that exclusion from B-0 (also known as B-2) occurs after immunoglobulin gene rearrangement. This predicts that PtC-specific B-0 cells are generated, but subsequently eliminated by either apoptosis or differentiation to B-1. To investigate the mechanism of exclusion, PtC-specific B cell differentiation was examined in mice expressing the X-linked immunodeficiency (xid) mutation. xid mice lack functional Bruton's tyrosine kinase (Btk), a component of the B cell receptor signal transduction pathway, and are deficient in B-1 cell development. We find in C57BL/ 6.xid mice that VH12 pre-BII cell selection is normal and that PtC-specific B cells undergo modest clonal expansion. However, the majority of splenic PtC-specific B cells in anti-PtC Tg/xid mice are B-0, rather than B-1 as in their non-xid counterparts. These data indicate that PtC-specific B-0 cell generation precedes segregation as predicted, and that Btk function is required for efficient segregation to B-1. Since xid mice exhibit defective B cell differentiation, not programmed cell death, these data are most consistent with an inability of PtC-specific B-0 cells to convert to B-1 and a single B cell lineage.

scholarly journals The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

2017 ◽  
Vol 37 (24) ◽  
Author(s):  
Toru Tamahara ◽  
Kyoko Ochiai ◽  
Akihiko Muto ◽  
Yukinari Kato ◽  
Nicolas Sax ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Class Switch Recombination ◽  
Cyclin D3 ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Class Switch

ABSTRACT The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the Ccnd3 gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.

scholarly journals Increased Frequency of Pre–Pro B Cells in the Bone Marrow of New Zealand Black (NZB) Mice: Implications for aDevelopmental Block in B Cell Differentiation

2002 ◽  
Vol 9 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Zhe-Xiong Lian ◽  
Hiroto Kita ◽  
Tomoyuki Okada ◽  
Tom Hsu ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
New Zealand ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Differentiation Markers ◽  
Cell Stage

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor componentIgα(mb-1). Furthermore, levels of expression of theRug2, λ5andIgβ(B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.

Ikaros Mutation Confers Integrin-Dependent Survival Of Pre-B Cells and Progression To Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1259-1259
Author(s):  
Nilamani Jena ◽  
Ila Joshi ◽  
Toshimi Yoshida ◽  
Xiaoqing Qi ◽  
Jiangwen Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Dna Binding ◽  
B Cell ◽  
Focal Adhesion ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Mapk Signaling ◽  
Dominant Negative ◽  
B Cell Differentiation

Abstract Deletion of the IKAROS DNA-binding domain generates dominant-negative isoforms that interfere with the transcriptional activity of the IKAROS family and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). In this study, we defined the role of the Ikaros family during pre-B cell differentiation, the stage from which human B-ALLs arise, by conditionally inactivating IKAROS DNA binding in the immediate precursors of pre-B cells in mice. We demonstrate a novel niche-dependent phase in early pre-B cell differentiation that supports self-renewal and proliferative expansion. Expression of dominant-negative IKAROS arrests cells in this state by augmenting integrin and MAPK signaling and attenuating pre-B cell receptor signaling and differentiation. Up-regulated genes in Ikaros mutant pre-B cells were highly enriched in pathways involved in focal adhesion and remodeling of the actin cytoskeleton. The mutant pre-B cells had increased β1 integrin-mediated adhesion and elevated levels of activated focal adhesion kinase (FAK), whereas treatment with a small molecule FAK inhibitor greatly reduced pre-B cell stromal adhesion and selectively induced apoptosis in Ikaros mutant but not WT pre-B cells. Transplantation of polyclonal Ikaros mutant pre-B cells into recipient mice resulted in long-latency oligoclonal pre-B-ALL, demonstrating that loss of IKAROS contributes to multistep B-leukemogenesis. The highly proliferative and aberrantly self-renewing phenotype of Ikaros-deficient pre-B cells illuminates mechanisms underlying human IKAROS mutant B-ALL and suggests new therapeutic strategies for treatment of this aggressive leukemia. Disclosures: Van Etten: Bristol Myers Squibb: Consultancy; Deciphera Pharmaceuticals: Consultancy; TEVA Pharmaceuticals: Consultancy, Research Funding.

scholarly journals Structural diversity of B-cell receptor repertoires along the B-cell differentiation axis in humans and mice

2020 ◽  
Vol 16 (2) ◽  
pp. e1007636 ◽  
Author(s):  
Aleksandr Kovaltsuk ◽  
Matthew I. J. Raybould ◽  
Wing Ki Wong ◽  
Claire Marks ◽  
Sebastian Kelm ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Structural Diversity ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Differentiation

scholarly journals Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals

2013 ◽  
Vol 210 (13) ◽  
pp. 2823-2832 ◽  
Author(s):  
Beate Heizmann ◽  
Philippe Kastner ◽  
Susan Chan
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Differentiation ◽  
B Cell Signaling ◽  
And Migration ◽  
And Function

Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C′ stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C′ and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.

scholarly journals The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response

2013 ◽  
Vol 210 (12) ◽  
pp. 2755-2771 ◽  
Author(s):  
Jin-Shu He ◽  
Michael Meyer-Hermann ◽  
Deng Xiangying ◽  
Lim Yok Zuan ◽  
Leigh Ann Jones ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Germinal Center ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Comprehensive Model ◽  
B Cell Differentiation ◽  
Memory Response ◽  
High Affinity ◽  
Sequential Switching

The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE+ cells in memory responses is particularly unclear. IgE+ B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE+ GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE+ GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE+ GC cells, whereas sequential switching gives rise to IgE+ PCs. We propose a comprehensive model for the generation and memory of IgE responses.

scholarly journals Crosstalk Between Circulating Follicular T Helper Cells and Regulatory B Cells in Children With Extrinsic Atopic Dermatitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinqiu Jiang ◽  
Shi Yan ◽  
Xiaoying Zhou ◽  
Jinghua Zhou ◽  
Xiaoming Bai ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Cell Differentiation ◽  
B Cell ◽  
Critical Role ◽  
Allergic Inflammation ◽  
Cell Receptor ◽  
Dependent Manner ◽  
B Cell Differentiation ◽  
Initial Manifestation ◽  
Tfh Cells

Atopic dermatitis (AD) in early childhood is often the initial manifestation of allergic disease associated with high IgE. Accumulating evidences show that follicular helper T (Tfh) cells play a critical role in promoting B cell differentiation and IgE production, human regulatory B (Breg) cells participate in immunomodulatory processes and inhibition of allergic inflammation. However, the roles and interactions between IL-10-producing Breg cells and Tfh cells in childhood AD are unclear. In this study, we found that the percentage of CD19+IL-10+ Breg cells in children with extrinsic AD was significantly lower than that in age-matched healthy controls, and that it correlated negatively with enhanced CD4+CXCR5+PD-1+ICOS+ circulating Tfh cell responses and increased disease activity; however, there was no significant correlation with serum total IgE levels. A co-culture system revealed that Breg cells from patients with extrinsic AD cannot effectively inhibit differentiation of Tfh cells in an IL-10 dependent manner. Abnormal pSTAT3 signaling induced via Toll-like receptors (TLR), but not the B-cell receptor (BCR) signaling, might contribute to the defect of Breg cells in AD. Taken together, these observations demonstrate an important role for IL-10-producing Breg cells in inhibiting Tfh cell differentiation, and suggest that they may participate in the pathogenesis of AD.

The Human (ΨL+μ−) proB Complex: Cell Surface Expression and Biochemical Structure of a Putative Transducing Receptor

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4336-4346 ◽  
Author(s):  
Bénédicte Lemmers ◽  
Laurent Gauthier ◽  
Valérie Guelpa-Fonlupt ◽  
Michel Fougereau ◽  
Claudine Schiff
Keyword(s):  
Cell Differentiation ◽  
Cell Surface ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Surface Expression ◽  
Leukemic Cells ◽  
Cell Surface Expression ◽  
B Cell Differentiation ◽  
Cell Reactivity

Abstract The surrogate light chain (ΨL) associates with μ and Ig-Igβ chains to form the preB-cell receptor that plays a critical role in early B-cell differentiation. Discrepancies exist in human concerning the existence of ΨL+μ− proB cells and the biochemical structure of such a proB-cell complex remains elusive. Among new antihuman VpreB monoclonal antibodies (MoAbs), 5 of the γκ isotype bound to recombinant and native VpreB protein with high affinity. They recognized 4 discrete epitopes, upon which 2 were in the extra-loop fragment. Such MoAbs detected the ΨL at the cell surface of either preB or on both proB and preB cells. The previously reported SLC1/SLC2 MoAbs recognize a conformational epitope specific for the μ/ΨL association in accordance with their preB-cell reactivity. Using the proB/preB 4G7 MoAb, ΨL cell surface expression was detected on normal bone marrow, not only on CD34−CD19+ preB but also on CD34+CD19+ proB cells. Futhermore, this MoAb identified ΨL+μ− fresh proB leukemic cells of the TEL/AML1 type. Biochemical studies showed that, at the proB stage, the ΨL is associated noncovalently with two proteins of 105 and 130 kD. Triggering of this complex induces intracellular Ca2+ flux, suggesting that the ΨL may be involved in a new receptor at this early step of the B-cell differentiation.

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