ArticleThe Journal of experimental medicine2020
Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production.
Article in The Journal of experimental medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 43 citations in OpenAlex.
- BAFF and APRIL Receptors in B Cell Immunity and Autoimmunity.Immunological reviews · 2026Review
- Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10 expression.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function.Nature immunology · 2026Article
- Genetic burden across core genes of the PI3K-AKT-mTOR pathway is associated with susceptibility to microscopic polyangiitis: a Chinese cohort study.Frontiers in immunology · 2026Article
- B cell receptor signaling in autoimmune rheumatic diseases: regulatory mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- The toxicological impact of PET-MPs exposure on atherosclerosis: insights from network toxicology, molecular docking, and machine learning.Scientific reports · 2025Article
- PI3K GOF leads to dysregulation of T and B cells that both contribute to extrinsically driving activation and differentiation of other CD4Immunology and cell biology · 2025Article
- Review
- Inborn errors of immunity presenting with lymphoproliferation: lessons from a case series.Annals of hematology · 2025Review
- The influence of the gut microbiota on B cells in autoimmune diseases.Molecular medicine (Cambridge, Mass.) · 2025Review
- Phenotypic and Immunological Characterization of Patients with Activated PI3Kδ Syndrome 1 Presenting with Autoimmunity.Journal of clinical immunology · 2024Article
- Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.The Journal of experimental medicine · 2024Article
- Failed Downregulation of PI3K Signaling Makes Autoreactive B Cells Receptive to Bystander T Cell Help.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond.The journal of allergy and clinical immunology. In practice · 2024Article
- Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2.The Journal of experimental medicine · 2023Article
- ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome.Frontiers in pediatrics · 2023Review
- Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment.Frontiers in immunology · 2023Review
- Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease.Frontiers in immunology · 2023Article
- Role of inhibitory signaling in peripheral B cell tolerance.Immunological reviews · 2022Review
- B-cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells.Immunological reviews · 2022Review
Corrections and comments
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Authors and funding
25 authors at 10 institutions in 5 countries.
Funding
Abstract
Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.
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Registered trials
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.