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Immunity. 2015 May 19;42(5):890-902. doi: 10.1016/j.immuni.2015.04.010. Epub 2015 May 12.

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

Author information

1
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.
2
Immunology Division, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
3
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.
4
Molecular Development Section, Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
5
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.

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.

PMID:
25979420
DOI:
10.1016/j.immuni.2015.04.010
[Indexed for MEDLINE]
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