Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice.
Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice.
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BXSB 小鼠中，B 细胞受体与抗原的结合不同程度地影响 B 细胞对 Toll 样受体 7 激动剂和拮抗剂的反应。
DOI：
10.1111/j.1365-2249.2010.04307.x
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发表时间：
2011
影响因子：
4.6
通讯作者：
Lenert,P
中科院分区：
文献类型：
--
作者：
Layer,T;Steele,A;Goeken,JA;Fleenor,S;Lenert,P
Toll样受体（TLR）家族的核酸传感器在狼疮的发病机制中发挥着公认的作用。这对于单链RNA敏感TLR-7受体尤其如此，因为缺乏TLR-7的狼疮小鼠显示出改善的疾病。相反，胞嘧啶-鸟苷二核苷酸（CpG）-DNA敏感TLR-9在系统性红斑狼疮（SLE）中具有复杂的调节作用。关于通过B细胞抗原受体（BCR）的信号是否会影响B细胞对次优TLR-7激动剂和拮抗剂的反应能力，人们知之甚少。我们在患病前的BXSB雄性和雌性B细胞中研究了这个问题。我们发现雄性B细胞对多种TLR-7配体的反应更强烈，并且这种反应性在BCR的共同参与下进一步增强。这种协同作用主要与白细胞介素（IL）-6分泌有关。一些具有核酸酶抗性硫代磷酸骨架的32-mer抑制性寡核苷酸（INH-ODNs）能够阻断TLR-7，但不能阻断BCR诱导的B细胞活化，抑制浓度（IC）50约为100 nm。 令人惊讶的是，虽然在ODN的5′端存在单个TGC基序并不增加其抑制能力，但含有多个TGC基序的INH-ODN具有更大的抑制效力。当BCR和TLR-7共同参与时，INH-ODNs对B细胞活化表现出不同的作用。而细胞凋亡保护和G1-M期进入完全逃脱抑制，IL-6分泌仍然敏感的抑制，虽然具有10倍的效力。我们的研究结果表明，虽然TLR-7拮抗剂可以被认为是狼疮治疗，同时共同参与的TLR-7和BCR可能有利于自身反应性B细胞的生存。这一假设需要进一步的实验验证。
Nucleic acid sensors of the Toll-like receptor (TLR) family play a well-established role in the pathogenesis of lupus. This is particularly true for a single-stranded RNA-sensing TLR-7 receptor, as lupus mice lacking TLR-7 show ameliorated disease. Cytosine–guanosine dinucleotide (CpG)-DNA-sensing TLR-9, conversely, has a complex regulatory role in systemic lupus erythematosus (SLE). Much less is known about whether signals through the B cell receptor for antigen (BCR) may affect the ability of B cells to respond to suboptimal TLR-7 agonists and antagonists. We studied this question in prediseased BXSB male and female B cells. We found that male B cells responded more vigorously to numerous TLR-7 ligands and this responsiveness was enhanced further upon co-engagement of the BCR. This synergy was seen primarily with the interleukin (IL)-6 secretion. A number of 32-mer inhibitory oligonucleotides (INH-ODNs) with a nuclease-resistant phosphorothioate backbone were capable of blocking TLR-7, but not BCR-induced B cell activation, with an inhibitory concentration (IC)50of approximately 100 nm. Surprisingly, while the presence of a single TGC motif at the 5′ end of an ODN did not increase its inhibitory capacity, INH-ODNs containing multiple TGC motifs had greater inhibitory potency. When BCR and TLR-7 were co-engaged, INH-ODNs showed a differential effect on B cell activation. Whereas apoptosis protection and G1-M entry completely escaped suppression, IL-6 secretion remained sensitive to inhibition, although with a 10-fold lower potency. Our results suggest that while TLR-7 antagonists may be considered as lupus therapeutics, simultaneous co-engagement of the TLR-7 and BCR might favour autoreactive B cell survival. This hypothesis needs further experimental validation.