FAS inactivation releases unconventional germinal center B cells that escape antigen control and drive IgE and autoantibody production.
Details
Publication Year 2015-05-19,Volume 42,Issue #5,Page 890-902
Journal Title
Immunity
Publication Type
Journal Article
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.
Publisher
Cell Press
Research Division(s)
Molecular Genetics Of Cancer
PubMed ID
25979420
NHMRC Grants
NHMRC/1020363NHMRC/1009145NHMRC/1016701
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2015-04-28 11:00:06
Last Modified: 2015-06-10 01:47:25
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