title: FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production.
abstract: 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 numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease.
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Danyal
authors.initials: D
authors.lastname: Butt
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Tyani D
authors.initials: TD
authors.lastname: Chan
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bourne
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: Jana R
authors.initials: JR
authors.lastname: Hermes
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: Akira
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Statham
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Molecular Development Section, Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Schofield
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Christ
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Basten
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia.
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.affiliation: Molecular Development Section, Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, NSW 2010, Australia. Electronic address: r.brink@garvan.org.au.
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D019014:fas Receptor / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D019014:fas Receptor; D007073:Immunoglobulin E