Monocytes in Lupus Pathogenesis

健康的单核细胞是免疫静止的细胞。我们发现分离的单核细胞 SLE患者外周血中有树突状细胞(DC)功能，部分可归因于I干扰素。 比较正常人和系统性红斑狼疮患者单核细胞的转录模式发现 982个转录本，其中1)608个是由于接触I型干扰素，2)116个不能归因于I型干扰素 但在健康的血液髓系树突状细胞(MDCS)中也有表达，3)258既不是I型干扰素，也不是 MDCS基因，我们称之为独特的SLE单核细胞转录模式。因此，系统性红斑狼疮单核细胞携带I型 可能反映其他血细胞变化的干扰素相关和无关转录特征 并解释了B细胞室改变的原因。因此，我们提出了一个假设 认为单核细胞在SLE的发病机制中处于中心地位。我们设计了三个目标来测试我们的 假设：目标1将确定可用于患者随访的SLE单核细胞标记物。目标 2将确定触发SLE单核细胞转录模式的因素。我们将确定细胞是否 (中性粒细胞或浆细胞样树突状细胞)和/或细胞产物(免疫复合体)有助于SLE单核细胞 表型和功能。我们还将评估免疫调节性ODN的治疗效果。目标3将 证明SLE单核细胞激活B细胞。因此，我们在这里提出的研究计划将 产生：1)疾病随访和治疗反应的标记物；2)与 疾病发病机制和新的治疗靶点。

Healthy blood monocytes are immunologically quiescent cells. We found that monocytes isolated from the blood of SLE patients have dendritic cell (DC) function that could partially be ascribed to Type IIFN. Comparison of transcriptional patterns of healthy and SLE monocytes revealed the differential expression of 982 transcripts of which 1) 608 were due to Type I IFN exposure, 2) 116 could not be ascribed to Type I IFN but were also expressed in healthy blood myeloid DCs (mDCs), and 3) 258 were neither type I IFN nor mDCs genes which we call unique SLE monocytes transcription patterns. Thus, SLE monocytes carry type I IFN-related and unrelated transcriptional signatures which might reflect alterations in other blood cell compartments and provide explanation for altered B cell compartment. Therefore, we propose a hypothesis that SLE monocytes are central to etiopathogenesis of SLE. We have designed three aims to test our hypothesis: Aim 1 will identify markers of SLE monocytes that can be used in patients follow-up. Aim 2 will determine factors that trigger SLE monocytes transcription patterns. We will establish if cells (neutrophils or plasmacytoid DCs) and/or cell products (immune complexes) contribute to SLE monocytes phenotype and function. We will also assess therapeutic effect of ImmunoRegulatory ODN. Aim 3 will demonstrate that SLE monocytes activate B cells. Thus, the research plan that we propose here will generate: 1) markers for disease follow up and response to therapy; and 2) novel molecules relevant for disease pathogenesis and novel therapeutic targets.