A hypomorphic IgH-chain allele affects development of B-cell subsets and favours receptor editing

Brenner, Sven; Drewel, Diana; Steinbart, Thomas; Weisel, Florian; Härtel, Eric; Pötzsch, Sonja; Welzel, Heike; Brandl, Andreas; Yu, Philipp; Mudde, Geert C.; Schweizer, Astrid; Nitschke, Lars; Winkler, Thomas

doi:10.1038/emboj.2011.168

Cited by 9 publications

(13 citation statements)

References 46 publications

(64 reference statements)

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“…Taken as a whole, our data support a model, first suggested by Nemazee (11) and later on confirmed by studies from other investigators (10,56,57), in which a threshold of tonic BCR signaling is required to prevent receptor editing and lead to positive selection of immature B cells. Behrens and coworkers extended this model, suggesting that autoreactive immature B cells undergo editing because they lack tonic BCR signaling and not because they experience antigen-induced BCR signaling (28).…”

Section: Discussionsupporting

confidence: 76%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Newly generated immature B cells are selected to enter the peripheral mature B-cell pool only if they do not bind (or bind limited amount of) self-antigen. We previously suggested that this selection relies on basal extracellular signal-regulated kinase (Erk) activation mediated by tonic B-cell antigen receptor (BCR) signaling and that this signal can be replaced by an active rat sarcoma (Ras), which are small GTPase proteins. In this study we compared the activity of Ras and Erk in nonautoreactive and autoreactive immature B cells and investigated whether activation of Ras can break tolerance. Our results demonstrate lower levels of active Erk and Ras in autoreactive immature B cells, although this is evident only when these cells display medium/high avidity for self-antigen. Basal activation of Erk in immature B cells is proportional to surface IgM and dependent on sarcoma family kinases, whereas it is independent of B-cell activating factor, IFN, and Tolllike receptor signaling. Ectopic expression of the constitutively active mutant Ras form N-RasD12 in autoreactive cells raises active Erk, halts receptor editing via PI3 kinase, and promotes differentiation via Erk, breaking central tolerance. Moreover, when B cells coexpress autoreactive and nonautoreactive BCRs, N-RasD12 leads also to a break in peripheral tolerance with the production of autoantibodies. Our findings indicate that in immature B cells, basal activation of Ras and Erk are controlled by tonic BCR signaling, and that positive changes in Ras activity can lead to a break in both central and peripheral B-cell tolerance.Src | BAFF

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Section: Discussionsupporting

confidence: 76%

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Teodorovic

Babolin

Rowland

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Besides a minor decrease in mature splenic B cells, we detected a strong reduction in peritoneal B1 cells in Akt1 Tg mice, which seems to reflect the enhanced sensitivity of B1 cells against altered BCR signals [34,35]. Interestingly, the decline of peritoneal B1 cells in younger Akt1 Tg mice was mainly due to a loss of B1b cells.…”

Section: Discussionmentioning

confidence: 67%

“…Since PI3K signaling has been proposed to regulate class switching [15,33], it is feasible that Akt1-mediated alterations in the expression levels of NF-κB, NFAT, and STAT5 influence the activity of activation-induced cytidine deaminase and other enzymes or of transcription factors involved in class switching. Further studies will also be needed to clarify whether besides altered BCR signaling, an altered in vivo migratory response or a survival advantage of Akt1 Tg B cells might contribute to the enhanced Ig production of Akt1 Tg B cells.Besides a minor decrease in mature splenic B cells, we detected a strong reduction in peritoneal B1 cells in Akt1 Tg mice, which seems to reflect the enhanced sensitivity of B1 cells against altered BCR signals [34,35]. Interestingly, the decline of peritoneal B1 cells in younger Akt1 Tg mice was mainly due to a loss of B1b cells.…”

mentioning

confidence: 67%

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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Ligation of the BCR induces a complex signaling network that involves activation ofAkt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca 2+ -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homozygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.Keywords: B cell r NFAT r PKB/Akt r SDF1α r STAT5 IntroductionIn the BM B-cell progenitors develop through defined stages of differentiation to immature B cells giving rise to follicular B2 (FO) B cells, marginal zone (MZ), and B1 B cells. These processes are controlled by the signal intensity arising from the pre-BCR or mature BCR, which activate similar sets of signaling molecules. The most proximal signaling events upon BCR ligation include Correspondence: Prof. Ursula H. Bommhardt e-mail: ursula.bommhardt@med.ovgu.de activation of the protein tyrosine kinases Lyn and Syk. A prominent substrate of Syk is the adaptor protein SLP65/BLNK, which recruits Bruton's tyrosine kinase, phospholipase Cγ2, and further signal proteins into supramolecular complexes that trigger the activation of multiple signaling pathways. Activated phospholipase Cγ2 cleaves the membrane lipid phosphatidylinositol-4, 5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3), two second messengers affecting the * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the surv...

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“…Weak BCR signaling leads to MZ B cell development, whereas strong signaling is required for FO B cells. Although previous reports clearly showed that the intracellular and surface Igm H chain expression affects B cell subset differentiation (24,36), Akirin2 was dispensable for the direct control of Igm H chain expression. Given that Akirin2 is required for upregulation of a set of NF-kB-dependent genes, it is theoretically possible that Akirin2-dependent genes are critical for the cell fate decision of FO and MZ B cells.…”

Section: Discussionmentioning

confidence: 78%

Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

Tartey

Matsushita

Imamura

et al. 2015

The Journal of Immunology

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Akirin2, an evolutionarily conserved nuclear protein, is an important factor regulating inflammatory gene transcription in mammalian innate immune cells by bridging the NF-κB and SWI/SNF complexes. Although Akirin is critical for Drosophila immune responses, which totally rely on innate immunity, the mammalian NF-κB system is critical not only for the innate but also for the acquired immune system. Therefore, we investigated the role of mouse Akirin2 in acquired immune cells by ablating Akirin2 function in B lymphocytes. B cell–specific Akirin2-deficient (Cd19Cre/+Akirin2fl/fl) mice showed profound decrease in the splenic follicular (FO) and peritoneal B-1, but not splenic marginal zone (MZ), B cell numbers. However, both Akirin2-deficient FO and MZ B cells showed severe proliferation defect and are prone to undergo apoptosis in response to TLR ligands, CD40, and BCR stimulation. Furthermore, B cell cycling was defective in the absence of Akirin2 owing to impaired expression of genes encoding cyclin D and c-Myc. Additionally, Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells. Cd19Cre/+Akirin2fl/fl mice showed impaired in vivo immune responses to T-dependent and -independent Ags. Collectively, these results demonstrate that Akirin2 is critical for the mitogen-induced B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex, further emphasizing the significant function of Akirin2 not only in the innate, but also in adaptive immune cells.

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A hypomorphic IgH-chain allele affects development of B-cell subsets and favours receptor editing

Cited by 9 publications

References 46 publications

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

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