A c-Myc/miR17-92/Pten Axis Controls PI3K-Mediated Positive and Negative Selection in B Cell Development and Reconstitutes CD19 Deficiency

Benhamou, David; Labi, Verena; Novak, Rostislav; Dai, Isabelle; Shafir-Alon, Shani; Hui, Vincent; Gaujoux, Renaud; Arnold, Rüdiger; Shen-Orr, Shai S.; Rajewsky, Klaus; Melamed, Doron

doi:10.1016/j.celrep.2016.05.084

Cited by 46 publications

(61 citation statements)

References 68 publications

(117 reference statements)

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“…These are B-cell-intrinsic mechanisms and are known to be controlled by B-cell antigen receptor signalling thresholds and regulators of the phosphoinositide 3-kinase pathway [19–21]. Recently, the miR-17–92 family of miRNA has been shown to regulate central B-cell tolerance by targeting phosphatase and tensin homolog [20, 22]. Additional removal of autoreactive B cells occurs by selection mechanisms in the periphery, which are less clear but can involve impaired survival and anergy [23].…”

Section: Breaking Immune Tolerance and The Development Of Autoimmunitymentioning

confidence: 99%

Pathways leading to an immunological disease: systemic lupus erythematosus

Zharkova

Celhar

Cravens³

et al. 2017

Rheumatology

140

102

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SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE.

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Section: Breaking Immune Tolerance and The Development Of Autoimmunitymentioning

confidence: 99%

Pathways leading to an immunological disease: systemic lupus erythematosus

Zharkova

Celhar

Cravens³

et al. 2017

Rheumatology

140

102

View full text Add to dashboard Cite

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“…Inducible ablation of Dicer (and thus all miRNAs) in transitional B cells has been documented to lead to a reduction of PI3K signaling and apoptosis in these cells [40]; these defects could be rescued by reducing levels of Pten in vivo, in mice [40]. Specifically, by using CD19-deficient mice where PI3K signaling is diminished [41], the authors showed that decreased levels of c-Myc (known to be regulated by PI3K), led to reduced miR-19 expression and increased Pten mRNA and protein levels [40]. This result suggests a regulatory loop where BCR signaling via PI3K induces c-Myc expression, in turn activating miR-17~92 expression, which presumably contributes to Pten-mediated inhibition of PI3K, and thus contributing to the regulation of central tolerance [40].…”

Section: Mirnas In Central Tolerancementioning

confidence: 99%

“…Specifically, by using CD19-deficient mice where PI3K signaling is diminished [41], the authors showed that decreased levels of c-Myc (known to be regulated by PI3K), led to reduced miR-19 expression and increased Pten mRNA and protein levels [40]. This result suggests a regulatory loop where BCR signaling via PI3K induces c-Myc expression, in turn activating miR-17~92 expression, which presumably contributes to Pten-mediated inhibition of PI3K, and thus contributing to the regulation of central tolerance [40]. Taken together, these results underscore the role of the miR-17~92 cluster in the regulation of B cell central tolerance and the fundamental role this cluster plays in maintaining immune homeostasis.…”

Section: Mirnas In Central Tolerancementioning

confidence: 99%

“…A study examining the functional role of the miR-17~92 cluster in late B cells revealed its potential importance in plasma cells [62] (thus, important not only in early B cell development and tolerance [30, 31, 40]). Indeed, conditional deletion of this cluster in mature B cells using CD19-Cre mice resulted in increased plasma cell homing to the BM upon immunization with a T-independent antigen, suggesting that this miRNA cluster regulated homing of plasma cells to their natural niche [62].…”

Section: Mirnas In Terminal Differentiation Of B Cellsmentioning

confidence: 99%

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miRNAs in B Cell Development and Lymphomagenesis

Coffre

Koralov

2017

Trends in Molecular Medicine

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B lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies is of B cell origin suggesting that development and activation of B cells need to be tightly regulated. In recent years, increasing evidence has emerged demonstrating that microRNAs (miRNAs) -- a class of non-coding RNAs that control gene expression -- are involved in the regulation of B cell development and function. Here, we provide an overview of the current knowledge on the role of miRNAs and their relevant targets in B cell development, B cell activation and B cell malignant transformation.

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“…Gadd45α was reported to induce translocation of Bim to mitochondria where Bim inhibits apoptosis 59 , and its defect causes lupus-like disease 60 . miR17-92 also regulates PTEN 57, 61 . Thus, Bim and the PI-3K pathway regulated by PTEN play a crucial role in microRNA-mediated regulation of B-cell tolerance.…”

Section: Regulation Of Central Tolerance and Clonal Anergy By Apoptosmentioning

confidence: 99%

B-cell tolerance and autoimmunity

Tsubata

2017

F1000Res

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Self-reactive B cells are tolerized at various stages of B-cell development and differentiation, including the immature B-cell stage (central tolerance) and the germinal center (GC) B-cell stage, and B-cell tolerance involves various mechanisms such as deletion, anergy, and receptor editing. Self-reactive B cells generated by random immunoglobulin variable gene rearrangements are tolerized by central tolerance and anergy in the periphery, and these processes involve apoptosis regulated by Bim, a pro-apoptotic member of the Bcl-2 family, and regulation of B-cell signaling by various phosphatases, including SHIP-1 and SHP-1. Self-reactive B cells generated by somatic mutations during GC reaction are also eliminated. Fas is not directly involved in this process but prevents persistence of GC reaction that allows generation of less stringently regulated B cells, including self-reactive B cells. Defects in self-tolerance preferentially cause lupus-like disease with production of anti-nuclear antibodies, probably due to the presence of a large potential B-cell repertoire reactive to nucleic acids and the presence of nucleic acid-induced activation mechanisms in various immune cells, including B cells and dendritic cells. A feed-forward loop composed of anti-nuclear antibodies produced by B cells and type 1 interferons secreted from nucleic acid-activated dendritic cells plays a crucial role in the development of systemic lupus erythematosus.

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A c-Myc/miR17-92/Pten Axis Controls PI3K-Mediated Positive and Negative Selection in B Cell Development and Reconstitutes CD19 Deficiency

Cited by 46 publications

References 68 publications

Pathways leading to an immunological disease: systemic lupus erythematosus

Pathways leading to an immunological disease: systemic lupus erythematosus

miRNAs in B Cell Development and Lymphomagenesis

B-cell tolerance and autoimmunity

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