Stimulation and inhibition of FVIII-specific memory B-cell responses by CpG-B (ODN 1826), a ligand for Toll-like receptor 9
Stimulation and inhibition of FVIII-specific memory B-cell responses by CpG-B (ODN 1826), a ligand for Toll-like receptor 9
复制标题
DOI：
10.1182/blood-2010-06-289009
复制
发表时间：
2011-01-06
期刊：
影响因子：
20.3
通讯作者：
Reipert, Birgit M.
中科院分区：
文献类型：
--
作者：
Allacher, Peter;Baumgartner, Christina K.;Reipert, Birgit M.
因子VIII（FVIII）-特异性记忆B细胞是调节使用FVIII抑制剂的血友病A患者针对FVIII的记忆抗体应答的重要组分。我们询问了低浓度和高浓度FVIII分别对FVIII特异性记忆B细胞的刺激和抑制如何受到先天免疫系统同时激活的影响。使用FVIII处理的血友病小鼠的CD 138（-）脾细胞研究记忆B细胞的体外再刺激和分化，我们测试了Toll样受体（TLR）2、3、4、5、7和9激动剂的调节活性。TLR 7和9的配体是最有效的。它们不仅在存在刺激浓度的FVIII的情况下放大FVIII特异性记忆反应，而且在存在抑制浓度的FVIII的情况下对抗抑制。值得注意的是，CpG寡脱氧核苷酸（CpG-ODN），TLR 9的配体，表达双相效应。在体外和体内，它在低浓度下放大记忆反应，在高浓度下抑制记忆反应。CpG-ODN的刺激和抑制活性均来自与TLR 9的特异性相互作用。尽管TLR配体在存在FVIII的情况下具有强免疫调节作用，但在体外不存在FVIII的情况下TLR配体诱导的再刺激可忽略不计，在体内不存在FVIII的情况下TLR配体不诱导再刺激。（血。2011;117（1）：259-267）
Factor VIII (FVIII)-specific memory B cells are essential components for regulating anamnestic antibody responses against FVIII in hemophilia A with FVIII inhibitors. We asked how stimulation and inhibition of FVIII-specific memory B cells by low and high concentrations of FVIII, respectively, are affected by concurrent activation of the innate immune system. Using CD138(-) spleen cells from hemophilic mice treated with FVIII to study restimulation and differentiation of memory B cells in vitro, we tested modulating activities of agonists for Toll-like receptors (TLRs) 2, 3, 4, 5, 7, and 9. Ligands for TLR7 and 9 were most effective. They not only amplified FVIII-specific memory responses in the presence of stimulating concentrations of FVIII, but also countered inhibition in the presence of inhibitory concentrations of FVIII. Notably, CpG oligodeoxynucleotide (CpG-ODN), a ligand for TLR9, expressed biphasic effects. It amplified memory responses at low concentrations and inhibited memory responses at high concentrations, both in vitro and in vivo. Both stimulatory and inhibitory activities of CpG-ODN resulted from specific interactions with TLR9. Despite their strong immunomodulatory effects in the presence of FVIII, ligands for TLR induced negligible restimulation in the absence of FVIII in vitro and no restimulation in the absence of FVIII in vivo. (Blood. 2011;117(1):259-267)