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.
Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production
S.G. Tangye and E.K. Deenick contributed equally to this paper.
- Views Icon Views
- Share Icon Share
- Tools Icon Tools
- Search Site
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 Uzel, Luigi D. Notarangelo, Robert Brink, Christopher C. Goodnow, Stuart G. Tangye, Elissa K. Deenick; Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production. J Exp Med 3 February 2020; 217 (2): e20191336. doi: https://doi.org/10.1084/jem.20191336
Download citation file: