FAS inactivation releases "Rogue" Germinal Center B cells that escape antigen control and drive IgE and autoantibody production
The production of autoantibodies and IgE antibodies by B lymphocytes must be tightly controlled to avoid rampant autoimmune and allergic disease. Mutation of the pro-apoptotic receptor Fas causes Autoimmune Lymphoproliferative Syndrome (ALPS), a disease in which production of autoantibodies is thought to occur through failure of Fas-mediated deletion of self-reactive germinal center (GC) B cells. Here we show that Fas is in fact not required for the removal of self-reactive GC B cells. Instead, Fas-deficiency leads to the emergence of ""rogue"" GC B cells that escape normal antigen selection and differentiate into clonally restricted pools of antibodysecreting plasma cells. Significantly, this includes 100-fold increased numbers of IgE+ plasma cells, consistent with the identification of a major cohort of ALPS patients exhibiting hyper-IgE. These results redefine the role of Fas in autoimmunity and reveal its B cell intrinsic function in suppressing IgE antibody responses in both humans and mice.
|Authors||Butt D, Chan TD, Bourne K, Hermes JR, Nguyen A, O'Reilly L, Strasser A, Schofield P, Christ D,; Basten A, Ma C, Tangye S, Phan TG, Rao VK and Brink R|
|Responsible Garvan Author||(missing name)|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12507|