Category: General autoimmunity
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.Inborn errors of immunity resulting from single gene mutations that disrupt immune function can cause immune dysregulation resulting in both immune deficiency and autoimmunity. These “experiments of nature” provide key insights into the critical pathways that control appropriate immune function. Gain of function (GOF) mutations in PIK3CD, encoding the p110δ subunit of PI3-kinase, cause a primary immunodeficiency characterized by recurrent respiratory infections, lymphoproliferation, increased susceptibility to herpes viruses, poor Ab responses to polysaccharide Ags, and altered serum immunoglobulin levels. Interestingly, many of these patients also suffer from a range of autoimmune conditions such as autoimmune cytopenias, glomerulonephritis and autoimmune thyroiditis. Here we demonstrate that patients withPIK3CDGOF mutations have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding Pik3cdactivating 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, Pik3cdgain-of-function B cells are activated by self-Ag to form plasmablasts that secrete high titers of germline encoded IgM autoantibody and hypermutating germinal center B cells. These data show that PI3K is a pre-germinal center gatekeeper of B cell self-tolerance and thus represents an attractive druggable pathway to treat antibody-mediated autoimmunity.