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2017 ; 199
(7
): 2388-2407
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gab.com Text
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Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and
BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of
Cereblon Activity
#MMPMID28848067
Nakayama Y
; Kosek J
; Capone L
; Hur EM
; Schafer PH
; Ringheim GE
J Immunol
2017[Oct]; 199
(7
): 2388-2407
PMID28848067
show ga
BAFF is a B cell survival and maturation factor implicated in the pathogenesis of
systemic lupus erythematosus (SLE). In this in vitro study, we describe that
soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent
inducer of human B cell proliferation, plasmablast differentiation, and IgG
secretion from circulating CD27(+) memory and memory-like CD27(-)IgD(-)
double-negative (DN) B cells, but not CD27(-)IgD(+) naive B cells. In contrast,
soluble CD40L in combination with IL-2 and IL-21 induces these activities in both
memory and naive B cells. Blood from healthy donors and SLE patients have similar
circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B
cells and reduced IL-21. B cell differentiation transcription factors in memory,
DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros
levels are unchanged. Treatment with CC-220, a modulator of the cullin ring
ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein
levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation,
and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21
induce memory and DN B cell activation and differentiation has implications for
extrafollicular plasmablast development within inflamed tissue. Inhibition of B
cell plasmablast differentiation by reduction of Aiolos and Ikaros may have
utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may
prime CD27(+) memory and DN memory-like B cells to become Ab-producing
plasmablasts in the presence of BAFF and proinflammatory cytokines.