Journal article

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

Danyal Butt, Tyani D Chan, Katherine Bourne, Jana R Hermes, Akira Nguyen, Aaron Statham, Lorraine A O'Reilly, Andreas Strasser, Susan Price, Peter Schofield, Daniel Christ, Antony Basten, Cindy S Ma, Stuart G Tangye, Giang Phan Tri, V Koneti Rao, Robert Brink

IMMUNITY | CELL PRESS | Published : 2015


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 num..

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Awarded by National Health and Medical Research Council (NHMRC)

Awarded by NHMRC

Awarded by Leukemia and Lymphoma Society (SCOR)

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.