Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
PLoS One. 2011;6(8):e23855. doi: 10.1371/journal.pone.0023855. Epub 2011 Aug 19.
Pattern recognition receptors (PRRs) such as Toll-like receptors are aberrantly expressed of peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients, for playing immunopathological roles.
METHODOLOGY/PRINCIPAL FINDINGS: We investigated the expression and function of the PRR nucleotide-binding oligomerization domain (NOD2) in SLE. NOD2 expression in T, B lymphocytes, monocytes, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) was assessed in SLE patients and healthy controls (HCs) using flow cytometric analysis. Ex vivo production of cytokines from PBMCs upon NOD2 agonist muramyl dipeptide (MDP) stimulation was assessed using Cytometric Bead Array. Over-expression of NOD2 in monocytes was observed in immunosuppressant naïve SLE patients, and was positively associated with longer disease duration. Immunosuppressive therapy was an independent explanatory variable for downregulating NOD2 expression in CD8+ T, monocytes, mDCs and pDCs. Ex vivo basal productions of cytokines (IL-6, IL-8 and IL-10) were significantly increased in immunosuppressant naïve patients and patients with active disease despite immunosuppressants compared with HCs. Upon MDP stimulaiton, relative induction (%) of cytokines (IL-1β) from PBMC was significantly increased in immunosuppressant naïve patients with inactive disease, and patients with active disease despite immunosuppressant treatment compared with HCs. Immunosuppressant usage was associated with a decreased basal production and MDP induced relative induction (%) of IL-10 in patients with inactive disease compared with immunosuppressant naïve patients and HCs.
CONCLUSIONS/SIGNIFICANCE: Bacterial exposure may increase the NOD2 expression in monocytes in immunosuppressant naïve SLE patients which can subsequently lead to aberrant activation of PBMCs to produce proinflammatory cytokines, implicating the innate immune response for extracellular pathogens in the immunopathological mechanisms in SLE. Immunosuppressant therapy may downregulate NOD2 expression in CD8+ T lymphocytes, monocytes, and DCs in SLE patients which subsequently IL-10 reduction, contributing towards the regulation of immunopathological mechanisms of SLE, at the expense of increasing risk of bacterial infection.
模式识别受体（PRRs）如 Toll 样受体在系统性红斑狼疮（SLE）患者外周血单个核细胞（PBMCs）中异常表达，发挥免疫病理作用。
方法/主要发现：我们研究了 PRR 核苷酸结合寡聚结构域（NOD2）在 SLE 中的表达和功能。采用流式细胞术分析 SLE 患者和健康对照（HCs）中 T、B 淋巴细胞、单核细胞、髓样树突状细胞（mDCs）和浆细胞样树突状细胞（pDCs）中 NOD2 的表达。采用细胞因子流式微球分析（Cytometric Bead Array）检测 PBMC 经 NOD2 激动剂 muramyl dipeptide（MDP）刺激后细胞因子的体外产生情况。在未接受免疫抑制剂治疗的 SLE 患者中观察到单核细胞中 NOD2 的过度表达，并与疾病持续时间较长呈正相关。免疫抑制剂治疗是下调 CD8+T 细胞、单核细胞、mDC 和 pDC 中 NOD2 表达的独立解释变量。与 HCs 相比，未接受免疫抑制剂治疗的患者和接受免疫抑制剂治疗但仍有疾病活动的患者，其细胞因子（IL-6、IL-8 和 IL-10）的体外基础分泌明显增加。与 HCs 相比，在未接受免疫抑制剂治疗且疾病无活动的患者以及接受免疫抑制剂治疗但仍有疾病活动的患者中，MDP 刺激后 PBMC 中细胞因子（IL-1β）的相对诱导（%）明显增加。与未接受免疫抑制剂治疗的患者和 HCs 相比，接受免疫抑制剂治疗且疾病无活动的患者的 IL-10 基础分泌和 MDP 诱导的相对诱导（%）降低。
结论/意义：细菌暴露可能会增加未接受免疫抑制剂治疗的 SLE 患者单核细胞中 NOD2 的表达，进而导致 PBMC 异常激活以产生促炎细胞因子，提示固有免疫反应可能参与 SLE 的免疫病理机制。免疫抑制剂治疗可能会下调 SLE 患者 CD8+T 淋巴细胞、单核细胞和 DC 中的 NOD2 表达，随后减少 IL-10，有助于调节 SLE 的免疫病理机制，但会增加细菌感染的风险。
