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2016 ; 213
(5
): 733-50
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B cell IFN-? receptor signaling promotes autoimmune germinal centers via
cell-intrinsic induction of BCL-6
#MMPMID27069113
Jackson SW
; Jacobs HM
; Arkatkar T
; Dam EM
; Scharping NE
; Kolhatkar NS
; Hou B
; Buckner JH
; Rawlings DJ
J Exp Med
2016[May]; 213
(5
): 733-50
PMID27069113
show ga
Dysregulated germinal center (GC) responses are implicated in the pathogenesis of
human autoimmune diseases, including systemic lupus erythematosus (SLE). Although
both type 1 and type 2 interferons (IFNs) are involved in lupus pathogenesis,
their respective impacts on the establishment of autoimmune GCs has not been
addressed. In this study, using a chimeric model of B cell-driven autoimmunity,
we demonstrate that B cell type 1 IFN receptor signals accelerate, but are not
required for, lupus development. In contrast, B cells functioning as
antigen-presenting cells initiate CD4(+) T cell activation and IFN-? production,
and strikingly, B cell-intrinsic deletion of the IFN-? receptor (IFN-?R)
abrogates autoimmune GCs, class-switched autoantibodies (auto-Abs), and systemic
autoimmunity. Mechanistically, although IFN-?R signals increase B cell T-bet
expression, B cell-intrinsic deletion of T-bet exerts an isolated impact on
class-switch recombination to pathogenic auto-Ab subclasses without impacting GC
development. Rather, in both mouse and human B cells, IFN-? synergized with B
cell receptor, toll-like receptor, and/or CD40 activation signals to promote
cell-intrinsic expression of the GC master transcription factor, B cell lymphoma
6 protein. Our combined findings identify a novel B cell-intrinsic mechanism
whereby IFN signals promote lupus pathogenesis, implicating this pathway as a
potential therapeutic target in SLE.
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