Journal article
FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production
D Butt, TD Chan, K Bourne, JR Hermes, A Nguyen, A Statham, LA O'Reilly, A Strasser, S Price, P Schofield, D Christ, A Basten, CS Ma, SG Tangye, TG Phan, VK Rao, R Brink
Immunity | CELL PRESS | Published : 2015
Abstract
The mechanistic links between genetic variation andautoantibody 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 number..
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Awarded by NIH Clinical Center
Funding Acknowledgements
We thank R. Salomon, C. Brownlee, and Garvan Institute Flow Facility staff for single-cell sorting and J. Kingham and the staff of Australian BioResources for animal husbandry. We also thank C. Goodnow, A. Collins, and J. Davies for their comments on the manuscript. D.B. is supported by an Australian Postgraduate Award and T.D.C., A. Strasser, D. C., C.S.M., S.G.T., T.G.P., and R.B. by National Health and Medical Research Council (NHMRC) fellowships 1054669, 1020363, 1050146, 1008820, 1042925, 1005097, and 1002280. This work was funded by Asthma Foundation NSW, R.G. Arnott Foundation, NHMRC Project Grant 1044477, and NHMRC Program Grant 1016953. Additional support came from NHMRC Project Grant 1009145, NHMRC Program Grant 1016701, Leukemia and Lymphoma Society (SCOR grants #7413 and #7001-13), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the NIH Clinical Center.