Sialic Acid-Binding Immunoglobulin-Type Lectin H-Positive Plasmacytoid Dendritic Cells Drive Spontaneous Lupus-like Disease Development in B6.Nba2 Mice
Sialic Acid-Binding Immunoglobulin-Type Lectin H-Positive Plasmacytoid Dendritic Cells Drive Spontaneous Lupus-like Disease Development in B6.Nba2 Mice
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DOI：
10.1002/art.38989
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发表时间：
2015-04-01
影响因子：
13.3
通讯作者：
Jorgensen, Trine N.
中科院分区：
文献类型：
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作者：
Davison, Laura M.;Jorgensen, Trine N.
Objective.系统性红斑狼疮（SLE）患者血清中干扰素-α（IFN α）水平升高。浆细胞样树突状细胞（pDC）由于其产生高水平IFN α的能力而被认为是SLE中IFN α的主要来源。在病毒感染期间，表达唾液酸结合免疫球蛋白型凝集素H（Siglec H）的pDC的子集产生大部分pDC衍生的IFN α。本研究的目的是提供Siglec H阳性pDC在IFN α依赖性B6.Nba2狼疮小鼠模型中具有致病性的证据。从4周龄或12周龄开始，用DT每周3次腹膜内处理B6.Nba2血液树突状细胞抗原2（BDCA-2）-白喉毒素受体（DTR）-转基因（Tg）小鼠，并分别在12周龄和18周龄时进行分析。狼疮样疾病的发展是通过血清中自身抗体水平升高来衡量的（通过酶联免疫吸附测定），IFN诱导基因的表达增加（通过实时逆转录-聚合酶链反应测定），肾小球中IgG免疫复合物沉积增加（通过免疫荧光染色确定）、自发淋巴细胞活化以及B细胞分化为产生抗体的浆细胞（通过流式细胞术确定）。结果。其中Siglec H阳性pDC耗尽6-8周的B6.Nba 2小鼠显示出IFN α诱导的基因转录物水平降低和血清中抗染色质自身抗体水平降低，以及活化的脾T细胞和B细胞、生殖中心B细胞、滤泡辅助T细胞和脾浆细胞显著减少。在18周龄的小鼠中，肾小球中IgG免疫复合物沉积也同样减少。同种B6.Nba2小鼠中狼疮样疾病的发展取决于Siglec H阳性pDC。我们认为Siglec H阳性pDC的耗竭代表SLE中的新细胞靶点。
Objective. Patients with systemic lupus erythematosus (SLE) often present with elevated levels of interferon-alpha (IFN alpha) in serum. Plasmacytoid dendritic cells (pDCs) have been suggested to be the primary source of IFN alpha in SLE due to their capacity to produce high levels of IFN alpha. During viral infection, a subset of pDCs expressing sialic acid-binding immunoglobulin-type lectin H (Siglec H) produces the majority of pDC-derived IFN alpha. The aim of this study was to provide evidence that Siglec H-positive pDCs are pathogenic in the IFN alpha-dependent B6.Nba2 mouse model of lupus.Methods. B6.Nba2 blood dendritic cell antigen 2 (BDCA-2)-diphtheria toxin receptor (DTR)-transgenic (Tg) mice were treated intraperitoneally with DT 3 times weekly starting at 4 weeks or 12 weeks of age and analyzed at 12 weeks and 18 weeks of age, respectively. Lupus-like disease development was measured by the presence of elevated levels of autoantibodies in serum (as determined by enzyme-linked immunosorbent assay), increased expression of IFN-inducible genes (as determined by real-time reverse transcription-polymerase chain reaction), increased IgG immune complex deposition in kidney glomeruli (as determined by immunofluorescence staining), spontaneous lymphocyte activation, and differentiation of B cells into antibody-producing plasma cells (as determined by flow cytometry).Results. B6.Nba2 mice in which Siglec H-positive pDCs were depleted for 6-8 weeks displayed reduced levels of IFN alpha-induced gene transcripts and decreased anti-chromatin autoantibody levels in serum, and significantly fewer activated splenic T cells and B cells, germinal center B cells, follicular helper T cells, and splenic plasma cells. In 18-week-old mice, IgG immune complex deposition in kidney glomeruli was similarly reduced.Conclusion. The development of lupus-like disease in congenic B6.Nba2 mice depends on Siglec H-positive pDCs. We suggest that depletion of Siglec H-positive pDCs represents a novel cellular target in SLE.