A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus

被引:289
作者
Menon, Madhvi [1 ]
Blair, Paul A. [1 ]
Isenberg, David A. [1 ]
Mauri, Claudia [1 ]
机构
[1] UCL, Ctr Rheumatol, Div Med, 5 Univ St, London WC1E 6JF, England
基金
英国惠康基金;
关键词
I INTERFERON; IFN-ALPHA; T-CELLS; AUTOIMMUNE-DISEASES; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; GENE-EXPRESSION; DIFFERENTIATION; SIGNATURE; DEPLETION;
D O I
10.1016/j.immuni.2016.02.012
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-alpha and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN-alpha production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-alpha. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.
引用
收藏
页码:683 / 697
页数:15
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