Department of Medicine, Division of Experimental Medicine, San Francisco General Hospital, University of California San Francisco, 1001 Potrero Avenue, San Francisco, CA 94110, USA.
Arthritis Res Ther. 2012 Jun 27;14(3):R155. doi: 10.1186/ar3895.
Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-α, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.
Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-α and tumor necrosis factor alpha (TNF-α) was then analyzed by multiparameter flow cytometry.
After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-α and TNF-α was only observed in pDCs. TLR-7 and TLR-9 induced IFN-α and TNF-α production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-α, P < 0.0001; TLR-9/TNF-α P < 0.0001; TLR-7/TNF-α P = 0.01). TLR-9 and TLR-7 induced IFN-α and TNF-α production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-α, P = 0.0003; impaired TLR-7/IFN-α, P = 0.07; impaired TLR-9/TNF-α, P < 0.009; impaired TLR-7/TNF-α, P < 0.01).
Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-α and TNF-α upon stimulation with TLR-9 and TLR-7 agonists.
浆细胞样树突状细胞（pDCs）通过其表达的两个 Toll 样受体（TLR）家族成员 TLR-9 和 TLR-7 持续被激活，从而产生高水平的干扰素（IFN）-α，这是系统性红斑狼疮（SLE）发病机制的关键介质。鉴于羟氯喹（HCQ）在治疗 SLE 中的已知疗效，我们研究了其在体内抑制这种 pDC 功能的能力。
来自接受或未接受 HCQ 治疗的 SLE 患者和健康对照者的外周血单核细胞（PBMCs）用 TLR-9 激动剂 CpG 寡脱氧核苷酸（CpG-A ODN）-2216 和 TLR-7 激动剂咪喹莫特进行刺激。然后通过多参数流式细胞术分析产生 IFN-α 和肿瘤坏死因子-α（TNF-α）的单核细胞、B 细胞、髓样树突状细胞、pDC 和自然杀伤（NK）细胞的比例。
在 SLE 和健康受试者的 TLR-9/7 刺激后，仅在 pDC 中观察到 IFN-α 和 TNF-α 的显著产生。与对照组相比，SLE 患者的 TLR-7 和 TLR-9 诱导 pDC 产生 IFN-α 和 TNF-α 的能力降低（TLR-9/IFN-α，P <0.0001；TLR-9/TNF-α，P <0.0001；TLR-7/TNF-α，P = 0.01）。在 36%（TLR-9）和 33%（TLR-7）的 SLE 患者中，TLR-9 和 TLR-7 诱导 pDC 产生 IFN-α 和 TNF-α 的能力严重受损。在几乎所有情况下，这些患者都接受了 HCQ 治疗（HCQ 与无 HCQ：TLR-9/IFN-α 受损，P = 0.0003；TLR-7/IFN-α 受损，P = 0.07；TLR-9/TNF-α 受损，P <0.009；TLR-7/TNF-α 受损，P <0.01）。
接受 HCQ 治疗与 SLE 患者 pDC 在 TLR-9 和 TLR-7 激动剂刺激下产生 IFN-α 和 TNF-α 的能力受损有关。
