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.

journal_name

Immunity

journal_title

Immunity

authors

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 R

doi

10.1016/j.immuni.2015.04.010

subject

Has Abstract

pub_date

2015-05-19 00:00:00

pages

890-902

issue

5

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(15)00170-3

journal_volume

42

pub_type

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