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.
journal_name
Immunityjournal_title
Immunityauthors
Butt D,Chan TD,Bourne K,Hermes JR,Nguyen A,Statham A,O'Reilly LA,Strasser A,Price S,Schofield P,Christ D,Basten A,Ma CS,Tangye SG,Phan TG,Rao VK,Brink Rdoi
10.1016/j.immuni.2015.04.010subject
Has Abstractpub_date
2015-05-19 00:00:00pages
890-902issue
5eissn
1074-7613issn
1097-4180pii
S1074-7613(15)00170-3journal_volume
42pub_type
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