Activated PI3Kdelta breaches multiple B cell tolerance checkpoints and causes autoantibody production
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 p110delta 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.
|ISBN||1540-9538 (Electronic) 0022-1007 (Linking)|
|Authors||Lau, A.; Avery, D. T.; Jackson, K.; Lenthall, H.; Volpi, S.; Brigden, H.; Russell, A. J.; Bier, J.; Reed, J. H.; Smart, J. M.; Cole, T.; Choo, S.; Gray, P. E.; Berglund, L. J.; Hsu, P.; Wong, M.; O'Sullivan, M.; Boztug, K.; Meyts, I.; Uzel, G.; Notarangelo, L. D.; Brink, R.; Goodnow, C. C.; Tangye, S. G.; Deenick, E. K.|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF EXPERIMENTAL MEDICINE|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/31841125|