ArticleProceedings of the National Academy of Sciences of the United States of America2014
Activation of Ras overcomes B-cell tolerance to promote differentiation of autoreactive B cells and production of autoantibodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 34 citations in OpenAlex.
- Case Report: Haemopoietic stem cell transplantation in refractory paediatric RAS-associated lymphoproliferative disorder.Frontiers in immunology · 2026Review
- RNA NExperimental & molecular medicine · 2025Article
- Arid2 promotes Follicular B-cell differentiation and antibody responsesbioRxiv : the preprint server for biology · 2025Article
- Ras-MAPK pathway in patients with lupus nephritis.Lupus science & medicine · 2025Article
- Regulation of Foxo1 expression is critical for central B cell tolerance and allelic exclusion.Cell reports · 2024Article
- NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy.Cell reports. Medicine · 2023Article
- A Race to the Finish.The New England journal of medicine · 2023Article
- CD19 Is Internalized Together with IgM in Proportion to B Cell Receptor Stimulation and Is Modulated by Phosphatidylinositol 3-Kinase in Bone Marrow Immature B Cells.ImmunoHorizons · 2023Article
- Ras family signaling pathway in immunopathogenesis of inflammatory rheumatic diseases.Frontiers in immunology · 2023Review
- LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- B-cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells.Immunological reviews · 2022Review
- A case of refractory systemic lupus erythematosus with monocytosis exhibiting somatic KRAS mutation.Inflammation and regeneration · 2022Article
- FCRL1 Regulates B Cell Receptor-Induced ERK Activation through GRB2.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- MicroRNA regulation of B cell receptor signaling.Immunological reviews · 2021Review
- Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Active PI3K abrogates central tolerance in high-avidity autoreactive B cells.The Journal of experimental medicine · 2019Article
- Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice.Frontiers in immunology · 2019Article
- Administration of activated lymphocyte-derived DNA accelerates and aggravates lupus nephritis in B6/lpr mice: a new approach to modify a lupus murine model.Clinical and experimental immunology · 2018Article
- Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.European journal of immunology · 2018Article
- Autoimmunity checkpoints as therapeutic targets in B cell malignancies.Nature reviews. Cancer · 2018Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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 Toll-like 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.