Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

Anthony Lau, Danielle T Avery, Katherine Jackson, Helen Lenthall, Stefano Volpi, Henry Brigden, Amanda J Russell, Julia Bier, Joanne H Reed, Joanne M Smart, Theresa Cole, Sharon Choo, Paul E Gray, Lucinda J Berglund, Peter Hsu, Melanie Wong, Michael O'Sullivan, Kaan Boztug, Isabelle Meyts, Gulbu UzelLuigi D Notarangelo, Robert Brink, Christopher C Goodnow, Stuart G Tangye, Elissa K Deenick

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalThe Journal of experimental medicine
Volume217
Issue number2
DOIs
Publication statusPublished - Feb 3 2020

Keywords

  • Animals
  • Antibody Formation/genetics
  • Autoantibodies/blood
  • Autoantigens/immunology
  • Autoimmunity/genetics
  • Class I Phosphatidylinositol 3-Kinases/blood
  • Female
  • Gain of Function Mutation
  • Germinal Center/immunology
  • Humans
  • Immune Tolerance/immunology
  • Immunoglobulin M/blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plasma Cells/immunology
  • Signal Transduction/genetics

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