Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

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Loss of IP3 Receptor–Mediated Ca2+ Release in Mouse B Cells Results in Abnormal B Cell Development and Function

The Journal of Immunology ◽

10.4049/jimmunol.1700109 ◽

2017 ◽

Vol 199 (2) ◽

pp. 570-580 ◽

Cited By ~ 13

Author(s):

Huayuan Tang ◽

Hong Wang ◽

Qingsong Lin ◽

Feifei Fan ◽

Fei Zhang ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Ip3 Receptor ◽

And Function

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Regulation of B-cell development and function by microRNAs

Immunological Reviews ◽

10.1111/imr.12046 ◽

2013 ◽

Vol 253 (1) ◽

pp. 25-39 ◽

Cited By ~ 56

Author(s):

Virginia G de Yébenes ◽

Nahikari Bartolomé-Izquierdo ◽

Almudena R. Ramiro

Keyword(s):

B Cell ◽

Cell Development ◽

B Cell Development ◽

And Function

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Essential Immunoregulatory Role for BCAP in B Cell Development and Function

Journal of Experimental Medicine ◽

10.1084/jem.20011751 ◽

2002 ◽

Vol 195 (5) ◽

pp. 535-545 ◽

Cited By ~ 89

Author(s):

Tetsuo Yamazaki ◽

Kiyoshi Takeda ◽

Kumiko Gotoh ◽

Hiroshi Takeshima ◽

Shizuo Akira ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Receptor ◽

Cell Development ◽

B Cell Development ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Phosphoinositide 3 Kinase ◽

And Function ◽

B Cell Deficiency

BCAP was recently cloned as a binding molecule to phosphoinositide 3-kinase (PI3K). To investigate the role of BCAP, mutant mice deficient in BCAP were generated. While BCAP-deficient mice are viable, they have decreased numbers of mature B cells and B1 B cell deficiency. The mice produce lower titers of serum immunoglobulin (Ig)M and IgG3, and mount attenuated responses to T cell–independent type II antigen. Upon B cell receptor cross-linking, BCAP-deficient B cells exhibit reduced Ca2+ mobilization and poor proliferative responses. These findings demonstrate that BCAP plays a pivotal immunoregulatory role in B cell development and humoral immune responses.

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Germline-activating mutations in PIK3CD compromise B cell development and function

Journal of Experimental Medicine ◽

10.1084/jem.20180010 ◽

2018 ◽

Vol 215 (8) ◽

pp. 2073-2095 ◽

Cited By ~ 33

Author(s):

Danielle T. Avery ◽

Alisa Kane ◽

Tina Nguyen ◽

Anthony Lau ◽

Akira Nguyen ◽

...

Keyword(s):

B Cell ◽

Cytidine Deaminase ◽

Pathogenic Mutation ◽

Gene Signature ◽

Cell Development ◽

B Cell Development ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Class Switch ◽

And Function

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

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Transcriptional control of B cell development and function

Gene ◽

10.1016/j.gene.2003.11.008 ◽

2004 ◽

Vol 327 (1) ◽

pp. 1-23 ◽

Cited By ~ 53

Author(s):

Boris Bartholdy ◽

Patrick Matthias

Keyword(s):

B Cell ◽

Transcriptional Control ◽

Cell Development ◽

B Cell Development ◽

And Function

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Essential Role of Phospholipase Cγ2 in Early B-Cell Development and Myc-Mediated Lymphomagenesis

Molecular and Cellular Biology ◽

10.1128/mcb.00839-06 ◽

2006 ◽

Vol 26 (24) ◽

pp. 9364-9376 ◽

Cited By ~ 22

Author(s):

Renren Wen ◽

Yuhong Chen ◽

Li Bai ◽

Guoping Fu ◽

James Schuman ◽

...

Keyword(s):

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Cell Receptor ◽

Cell Development ◽

B Cell Development ◽

B Cell Receptor ◽

Wild Type ◽

Interleukin 7

ABSTRACT Phospholipase Cγ2 (PLCγ2) is a critical signaling effector of the B-cell receptor (BCR). Here we show that PLCγ2 deficiency impedes early B-cell development, resulting in an increase of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B cells. PLCγ2 deficiency impairs pre-BCR-mediated functions, leading to enhanced interleukin-7 (IL-7) signaling and elevated levels of RAGs in the selected large pre-B cells. Consequently, PLCγ2 deficiency renders large pre-B cells susceptible to transformation, resulting in dramatic acceleration of Myc-induced lymphomagenesis. PLCγ2 −/− Eμ-Myc transgenic mice mainly develop lymphomas of B220+ CD43+ BP-1+ CD24hi pre-BCR+ large pre-B-cell origin, which are uncommon in wild-type Eμ-Myc transgenics. Furthermore, lymphomas from PLCγ2 −/− Eμ-Myc transgenic mice exhibited a loss of p27Kip1 and often displayed alterations in Arf or p53. Thus, PLCγ2 plays an important role in pre-BCR-mediated early B-cell development, and its deficiency leads to markedly increased pools of the most at-risk large pre-B cells, which display hyperresponsiveness to IL-7 and express high levels of RAGs, making them prone to secondary mutations and Myc-induced malignancy.

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Cutting Edge: Essential Role of Phospholipase C-γ2 in B Cell Development and Function

The Journal of Immunology ◽

10.4049/jimmunol.165.4.1738 ◽

2000 ◽

Vol 165 (4) ◽

pp. 1738-1742 ◽

Cited By ~ 110

Author(s):

Ari Hashimoto ◽

Kiyoshi Takeda ◽

Muneo Inaba ◽

Masayuki Sekimata ◽

Tsuneyasu Kaisho ◽

...

Keyword(s):

B Cell ◽

Phospholipase C ◽

Essential Role ◽

Cell Development ◽

B Cell Development ◽

Cutting Edge ◽

And Function

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B cell development is perturbed in bone marrow from c-fos/v-jun doubly transgenic mice

International Immunology ◽

10.1093/intimm/5.2.227 ◽

1993 ◽

Vol 5 (2) ◽

pp. 227-230 ◽

Cited By ~ 8

Author(s):

Kenji Fujita ◽

Nobuhiko Miki ◽

Mariluz P. Mojica ◽

Shintaro Takao ◽

Janyaporn Phuchareon ◽

...

Keyword(s):

Bone Marrow ◽

Transgenic Mice ◽

B Cell ◽

Cell Development ◽

B Cell Development

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Iκb Kinase α Is Essential for Mature B Cell Development and Function

Journal of Experimental Medicine ◽

10.1084/jem.193.4.417 ◽

2001 ◽

Vol 193 (4) ◽

pp. 417-426 ◽

Cited By ~ 147

Author(s):

Tsuneyasu Kaisho ◽

Kiyoshi Takeda ◽

Tohru Tsujimura ◽

Taro Kawai ◽

Fumiko Nomura ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Fetal Liver ◽

Cell Development ◽

B Cell Development ◽

Cytokine Signaling ◽

Iκb Kinase ◽

And Function

IκB kinase (IKK) α and β phosphorylate IκB proteins and activate the transcription factor, nuclear factor (NF)-κB. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKKα is involved in skin and limb morphogenesis, whereas IKKβ is essential for cytokine signaling. To elucidate in vivo roles of IKKα in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKKα-deficient fetal liver cells. The mature B cell population was decreased in IKKα−/− chimeras. IKKα−/− chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKKα−/− B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-κB activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKKα−/− chimeras. Taken together, these results demonstrate that IKKα is critically involved in the prevention of cell death and functional development of mature B cells.

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