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Fas mutation liberates rogue germinal center B cells to initiate uncontrolled IgG and IgE antibody production

Abstract

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.

Type Journal
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
Garvan Authors Dr Danyal Butt
Publisher Name IMMUNITY
Published Date 2015-05-16 00:00:00
Published Volume 42
Published Issue 5
Published Pages 890-902
Status Published in-print