Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Fas mutation liberates rogue germinal centre B cells to produce aberrant IgG and IgE antibodies (#78)

Danyal Butt 1 2 , Tyani Chan 1 2 , Katherine Bourne 1 , Jana Hermes 1 , Akira Nguyen 1 , Tri Phan 1 2 , Lorraine O’Reilly 3 , Andreas Strasser 3 , Gulbu Uzel 4 , Antony Basten 1 2 , Stuart Tangye 1 2 , V. Koneti Rao 5 6 , Robert Brink 1 2
  1. Immunology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Molecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  4. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda , MD , USA
  5. Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  6. NIAID Clinical Genomics Program, National Institute of Allergy and Infectious Diseases , National Institutes of Health, Bethesda, MD, USA

Production of autoantibodies and Immunoglobulin E (IgE) by B lymphocytes triggers autoimmune and allergic diseases, and consequently is actively suppressed.  Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) due to mutation of the death receptor Fas develop autoantibodies, which has been presumed to result from the 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 purging of self-reactive GC B cells. Instead, Fas-deficiency leads to the emergence of "rogue" GC B cells that escape negative selection and differentiate into clonally restricted pools of antibody-secreting plasma cells that include 100-fold increased numbers of IgE+ plasma cells. Significantly, a major cohort of ALPS patients was also found to have high levels of serum IgE. These results redefine the role of Fas in counteracting autoimmunity and reveal Fas to have a B cell intrinsic function in suppressing IgE antibody responses in both humans and mice.