Department of Immunology, and Key Laboratory of Medical Immunology of Ministry of Health, Peking University Health Science Center, Beijing, China.
PLoS One. 2012;7(8):e44131. doi: 10.1371/journal.pone.0044131. Epub 2012 Aug 29.
Altered Toll-like receptor (TLR) signaling has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The present study was undertaken to characterize responses of B cells from SLE patients to TLR7 and TLR9 stimulation and to explore the potential role of single immunoglobulin interleukin-1 receptor related molecule (SIGIRR) in the regulation of TLR-mediated responses of SLE B cells.
METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood mononuclear cells (PBMC) were isolated from 64 patients with SLE and 37 healthy donors. CD19+ B cells purified using microbeads were cultured with TLR7 or TLR9 agonists. Cell proliferation was measured by thymine incorporation and the frequency of antibody-secreting cells was determined by ELISPOT assay. SIGIRR expression in PBMCs and B cells was analyzed using flow cytometry analysis. In contrast to the enhanced proliferation following B cell receptor (BCR) engagement, B cells from SLE patients exhibited a virtually normal proliferative response to TLR7 or TLR9 stimulation. Moreover, B cells from SLE patients and healthy donors were almost equally competent to differentiate into antibody-secreting cells upon TLR engagement except for a reduction in the generation of IgG-secreting cells by TLR9-stimulated lupus B cells. In line with these somehow unexpected observations, SLE B cells were found to express a significantly higher level of SIGIRR than normal B cells.
CONCLUSIONS/SIGNIFICANCE: Despite the reported upregulation of TLR7 and TLR9 expression in B cell from SLE patients, their responses to TLR stimulation were largely normal. The increased expression of the negative regulator SIGIRR may be partly responsible for the "balance of terror".
改变 Toll 样受体 (TLR) 信号已被认为与系统性红斑狼疮 (SLE) 的发病机制有关。本研究旨在描述 SLE 患者 B 细胞对 TLR7 和 TLR9 刺激的反应，并探讨单一免疫球蛋白白细胞介素-1 受体相关分子 (SIGIRR) 在调节 SLE B 细胞 TLR 介导的反应中的潜在作用。
方法/主要发现：从 64 例 SLE 患者和 37 名健康供体中分离外周血单核细胞 (PBMC)。使用微珠纯化 CD19+B 细胞，并用 TLR7 或 TLR9 激动剂培养。通过胸苷掺入测量细胞增殖，通过 ELISPOT 测定确定抗体分泌细胞的频率。使用流式细胞术分析 PBMC 和 B 细胞中的 SIGIRR 表达。与 B 细胞受体 (BCR) 结合后增强的增殖相反，SLE 患者的 B 细胞对 TLR7 或 TLR9 刺激表现出几乎正常的增殖反应。此外，SLE 患者和健康供体的 B 细胞在 TLR 结合后几乎同样能够分化为抗体分泌细胞，除了 TLR9 刺激的狼疮 B 细胞产生 IgG 分泌细胞减少。与这些有些出乎意料的观察结果一致，SLE B 细胞被发现表达明显高于正常 B 细胞的 SIGIRR。
结论/意义：尽管报道 SLE 患者 B 细胞中 TLR7 和 TLR9 的表达上调，但它们对 TLR 刺激的反应在很大程度上是正常的。负调节剂 SIGIRR 的表达增加可能部分是“恐怖平衡”的原因。
