Aiolos Regulates B Cell Activation and Maturation to Effector State

Wang, Jinhong; Avitahl, Nicole; Cariappa, Annaiah; Friedrich, Chr.; Ikeda, Tôru; Renold, Anja; Ανδρικόπουλος, Κωνσταντίνος; Liang, L.; Pillai, Shiv; Morgan, Bruce; Georgopoulos, Katia

doi:10.1016/s1074-7613(00)80637-8

Cited by 296 publications

(306 citation statements)

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“…Similar to lenalidomide and pomalidomide, which bind to CRBN, a critical component of a ubiquitin E3 CRL4 CRBN complex (120,121), CC-220 binds to CRBN to promote recruitment of Ikaros and Aiolos to CRL4 CRBN and the subsequent enhancement of the ubiquitination and degradation of these transcription factors (55-57). Ikaros and Aiolos are members of the Ikaros family of zinc-finger transcription factors crucial for the function of mature B cells in the periphery, and required for the generation and survival of high-affinity bone marrow plasma cells (60)(61)(62). We have shown in this study that CC-220 inhibits plasmablast differentiation, and Ab production is associated with reduction of Aiolos, Ikaros, and other transcription factors known to be required for plasmablast differentiation (Figs.…”

Section: Discussionmentioning

confidence: 74%

“…Aiolos and Ikaros are key ikaros family zinc-finger transcription factors that regulate lymphoid and myeloid cell development and immune homeostasis (59). Aiolos and Ikaros are crucial for the function of mature B cells in the periphery and are required for the generation of high-affinity Ab-secreting bone marrow plasma cells (60)(61)(62). Studies suggest an essential role of Aiolos at later stages of B cell differentiation (61,63).…”

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confidence: 99%

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Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…B1 cell development also appears to be dependent on Ag selection (11). Whereas alterations in some molecules that affect B cell signaling result in parallel changes in B1 and MZ B cells, e.g., Aiolos (12), other examples demonstrate that these two B cell subsets are not always regulated in tandem as observed in CD22 Ϫ mice in which B1 cells are increased but MZ B cells are reduced (13,14).…”

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confidence: 99%

Cutting Edge: Selection of B Lymphocyte Subsets Is Regulated by Natural IgM

Baker

Ehrenstein

2002

The Journal of Immunology

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Natural IgM has a wide range of actions in the immune system. Here we demonstrate that mice lacking serum IgM have an expansion in splenic marginal zone B cells with a proportionately smaller reduction in follicular B cells. The increase in the marginal zone-follicular B cell ratio (and an expansion in peritoneal B1a cells) is fully reversed by administration of polyclonal IgM, but not by two IgM monoclonals. Mice engineered to have a secreted oligoclonal IgM repertoire with an endogenous membrane IgM also exhibited a similar expansion of marginal zone B cells. We propose that natural IgM, by virtue of its polyreactivity, enhances Ag-driven signaling through the B cell receptor and promotes the formation of follicular B cells. These results demonstrate that natural IgM regulates the selection of B lymphocyte subsets.

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“…Indeed, there are some similarities between the phenotype of Aiolos-null mice and Vk2-Ik7tg mice, such as the decrease in recirculating B cells in the bone marrow, the hyperresponsiveness of B cells to mitogenic signals and the production of autoantibodies [38]. These phenotypes are not observed, however, in Aiolos +/-mice, suggesting that 50% of Aiolos activity is sufficient to prevent them if Ikaros is expressed at wild-type levels.…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Old mentioning

confidence: 99%

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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Aiolos Regulates B Cell Activation and Maturation to Effector State

Cited by 296 publications

References 40 publications

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Cutting Edge: Selection of B Lymphocyte Subsets Is Regulated by Natural IgM

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

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