Genomic deletion of the whole IgH 3′ regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1895-1898 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Remi Fiancette ◽  
Eric Pinaud ◽  
Véronique Truffinet ◽  
Nadine Cogné ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Heavy Chains ◽  
Class Switch ◽  
Transcriptional Changes

Abstract The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of μ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)μ gene with a downstream CH gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3′ regulatory region (3′RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all CH genes. Although plasma cell numbers are unaffected, we reveal the role of the 3′RR into the transcriptional burst normally associated with plasma cell differentiation. Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3′RR working as a single functional unit.

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 TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

2020 ◽  
Vol 4 (12) ◽  
pp. 2821-2836
Author(s):  
Jennifer Shrimpton ◽  
Matthew A. Care ◽  
Jonathan Carmichael ◽  
Kieran Walker ◽  
Paul Evans ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Immunoglobulin M ◽  
B Cell Differentiation ◽  
Waldenström Macroglobulinemia ◽  
Plasma Cell Differentiation ◽  
Waldenstrom Macroglobulinemia

Abstract Waldenström macroglobulinemia (WM) is a rare malignancy in which clonal B cells infiltrate the bone marrow and give rise to a smaller compartment of neoplastic plasma cells that secrete monoclonal immunoglobulin M paraprotein. Recent studies into underlying mutations in WM have enabled a much greater insight into the pathogenesis of this lymphoma. However, there is considerably less characterization of the way in which WM B cells differentiate and how they respond to immune stimuli. In this study, we assess WM B-cell differentiation using an established in vitro model system. Using T-cell–dependent conditions, we obtained CD138+ plasma cells from WM samples with a frequency similar to experiments performed with B cells from normal donors. Unexpectedly, a proportion of the WM B cells failed to upregulate CD38, a surface marker that is normally associated with plasmablast transition and maintained as the cells proceed with differentiation. In normal B cells, concomitant Toll-like receptor 7 (TLR7) activation and B-cell receptor cross-linking drives proliferation, followed by differentiation at similar efficiency to CD40-mediated stimulation. In contrast, we found that, upon stimulation with TLR7 agonist R848, WM B cells failed to execute the appropriate changes in transcriptional regulators, identifying an uncoupling of TLR signaling from the plasma cell differentiation program. Provision of CD40L was sufficient to overcome this defect. Thus, the limited clonotypic WM plasma cell differentiation observed in vivo may result from a strict requirement for integrated activation.

scholarly journals The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation

2014 ◽  
Vol 211 (11) ◽  
pp. 2169-2181 ◽  
Author(s):  
Sebastian Carotta ◽  
Simon N. Willis ◽  
Jhagvaral Hasbold ◽  
Michael Inouye ◽  
Swee Heng Milon Pang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Terminal Differentiation ◽  
Plasma Cell Differentiation ◽  
Class Switch ◽  
Complex Functions

Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell–promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1–IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation.

Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination

2006 ◽  
Vol 7 (7) ◽  
pp. 773-782 ◽  
Author(s):  
Ulf Klein ◽  
Stefano Casola ◽  
Giorgio Cattoretti ◽  
Qiong Shen ◽  
Marie Lia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Plasma Cell ◽  
Class Switch Recombination ◽  
Plasma Cell Differentiation ◽  
Class Switch

Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2

Blood ◽  
2011 ◽  
Vol 117 (20) ◽  
pp. 5438-5448 ◽  
Author(s):  
Miki Watanabe-Matsui ◽  
Akihiko Muto ◽  
Toshitaka Matsui ◽  
Ari Itoh-Nakadai ◽  
Osamu Nakajima ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Heme Oxygenase ◽  
Plasma Cell ◽  
Heme Oxygenase 1 ◽  
Plasma Cell Differentiation ◽  
Class Switch ◽  
Antibody Class

Abstract Heme binds to proteins to modulate their function, thereby functioning as a signaling molecule in a variety of biologic events. We found that heme bound to Bach2, a transcription factor essential for humoral immunity, including antibody class switch. Heme inhibited the DNA binding activity of Bach2 in vitro and reduced its half-life in B cells. When added to B-cell primary cultures, heme enhanced the transcription of Blimp-1, the master regulator of plasma cells, and skewed plasma cell differentiation toward the IgM isotype, decreasing the IgG levels in vitro. Intraperitoneal injection of heme in mice inhibited the production of antigen-specific IgM when heme was administered simultaneously with the antigen but not when it was administered after antigen exposure, suggesting that heme also modulates the early phase of B-cell responses to antigen. Heme oxygenase-1, which is known to be regulated by heme, was repressed by both Bach2 and Bach1 in B cells. Furthermore, the expression of genes for heme uptake changed in response to B-cell activation and heme administration. Our results reveal a new function for heme as a ligand of Bach2 and as a modulatory signal involved in plasma cell differentiation.

scholarly journals Regulation of Class-Switch Recombination and Plasma Cell Differentiation by Phosphatidylinositol 3-Kinase Signaling

Immunity ◽  
2006 ◽  
Vol 25 (4) ◽  
pp. 545-557 ◽  
Author(s):  
Sidne A. Omori ◽  
Matthew H. Cato ◽  
Amy Anzelon-Mills ◽  
Kamal D. Puri ◽  
Miriam Shapiro-Shelef ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Plasma Cell ◽  
Class Switch Recombination ◽  
Kinase Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Plasma Cell Differentiation ◽  
Class Switch ◽  
Phosphatidylinositol 3

Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3058-3064 ◽  
Author(s):  
Hendrik Poeck ◽  
Moritz Wagner ◽  
Julia Battiany ◽  
Simon Rothenfusser ◽  
Daniela Wellisch ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
B Cell Differentiation ◽  
Immunoglobulin Production ◽  
Plasma Cell Differentiation ◽  
Cpg Oligonucleotides ◽  
T Cell Help

Abstract It has been reported that interferon α (IFN-α) enhances humoral immunity and that dendritic cells of the myeloid lineage promote B-cell differentiation. Here we studied whether the plasmacytoid dendritic cell (PDC), a subset of dendritic cells specialized for the production of IFN-α, is involved in regulating B-cell differentiation and immunoglobulin production. The recently identified class of CpG oligonucleotides (CpG-C) was used to activate both B cells and PDCs via Toll-like receptor 9 (TLR9). The presence of PDCs synergistically enhanced CD86 expression, cytokine production (interleukin 6 [IL-6], tumor necrosis factor α, and IL-10) and plasma cell differentiation of isolated human peripheral blood B cells stimulated through CpG-C and B-cell antigen receptor (BCR) ligation. This stimulation protocol was sufficient to drive purified naive B cells into IgM-producing plasma cells and to trigger IgG synthesis in memory B cells. PDCs contributed to B-cell activation via IFN-α secretion. Up-regulation of TLR9 on B cells was not involved. These results demonstrate that CpG-stimulated PDCs induce plasma cell differentiation in naive and memory B cells in the absence of T-cell help, providing an explanation for the excellent activity of CpG oligonucleotides as a humoral vaccine adjuvant. (Blood. 2004;103:3058-3064)

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