FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production

The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE+ plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated “rogue GC B cells,” are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease. [Display omitted] •FAS is not required to eliminate conventional self-reactive GC B cells•FAS is required to prevent development of rogue GC (GCr) B cells•GCr B cells escape normal selection and show extensive plasma cell differentiation•GCr B cells might explain the production of IgE and autoantibodies in ALPS and SLE FAS deficiency is associated with autoimmunity. Brink and colleagues show that FAS prevents development of “rogue” germinal center (GCr) B cells that escape normal regulatory controls and produce high amounts of IgE and autoantibodies, which might explain the presence of such antibodies in autoimmune disease.