ArticleJournal of immunology (Baltimore, Md. : 1950)2013
The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity.
Article in Journal of immunology (Baltimore, Md. : 1950), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- Inhibition of B cell receptor signaling induced by the human adenovirus species D E3/49K protein.Frontiers in immunology · 2024Article
- ArtinM Cytotoxicity in B Cells Derived from Non-Hodgkin's Lymphoma Depends on Syk and Src Family Kinases.International journal of molecular sciences · 2023Article
- Self-reactivity on a spectrum: A sliding scale of peripheral B cell tolerance.Immunological reviews · 2019Review
- Tonic Signals: Why Do Lymphocytes Bother?Trends in immunology · 2017Review
- A novel lectin from Artocarpus lingnanensis induces proliferation and Th1/Th2 cytokine secretion through CD45 signaling pathway in human T lymphocytes.Journal of natural medicines · 2017Article
- T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity.The Journal of allergy and clinical immunology · 2016Article
- An extracatalytic function of CD45 in B cells is mediated by CD22.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice.Journal of immunology (Baltimore, Md. : 1950) · 2014Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
CD45 is a receptor-like tyrosine phosphatase that positively regulates BCR signaling by dephosphorylating the inhibitory tyrosine of the Src family kinases. We showed previously that a single point mutation, E613R, introduced into the cytoplasmic membrane-proximal "wedge" domain of CD45 is sufficient to drive a lupus-like autoimmune disease on a susceptible genetic background. To clarify the molecular mechanism of this disease, we took advantage of a unique allelic series of mice in which the expression of CD45 is varied across a broad range. Although both E613R B cells and those with supraphysiologic CD45 expression exhibited hyperresponsive BCR signaling, they did so by opposite regulation of the Src family kinase Lyn. We demonstrated that the E613R allele of CD45 does not function as a hyper- or hypomorphic allele but rather alters the substrate specificity of CD45 for Lyn. Despite similarly enhancing BCR signaling, only B cells with supraphysiologic CD45 expression became anergic, whereas only mice harboring the E613R mutation developed frank autoimmunity on a susceptible genetic background. We showed that selective impairment of a Lyn-dependent negative-regulatory circuit in E613R B cells drove autoimmunity in E613R mice. This demonstrates that relaxing negative regulation of BCR signaling, rather than enhancing positive regulation, is critical for driving autoimmunity in this system.
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