A Novel Inflammatory Dendritic Cell in Lupus Nephritis

狼疮性肾炎中一种新的炎性树突状细胞 摘要/项目摘要： 树突状细胞(DC)是一种重要的免疫调节细胞，在自身免疫中起着关键作用。 促进耐受性或促进自身反应性免疫反应。因此，DC的异常激活是 与大多数自身免疫性疾病的发病机制有关。我们已经确定了一个新的子集 狼疮性肾炎患者肾脏中丰富的炎性树突状细胞 (LN)是系统性红斑狼疮(SLE)最常见的严重器官并发症。这些inDC是 在活动性疾病期间，主要定位于人LN肾小球周围区域， 肾脏在LN中没有得到很好的研究。特别相关的是，在人类LN肾脏中，DC似乎 在空间上与转录上与Th17细胞相似的T细胞相关。这一点意义重大，因为 已知Th17通路在LN中的相关性。综上所述，我们认为肾小球周围共同定位 InfDC和Th17细胞在LN的启动和加重中起重要作用。这一点的中心假设是 认为InfDC是局部炎症性肾损伤的主要始发者和驱动者。 Th17细胞在LN过程中的作用，以及这些关系的特征将有助于我们对LN的理解 发病机制，并带来新的治疗机会。这一假设将在三个目标上得到检验。在目标1中， 肾小球周围树突状细胞和T细胞的表达模式将在人类LN中确定表达 异质性及其与疾病活动性的相关性。第二个目的是测试inDC是 在LN期间对肾脏的损害，表现为消耗或增加inDC可减弱或 在LN期间加重肾内炎症。第三个目标将检验以下假设：inDC启动一个 支持细胞因子环境使肾内幼稚T细胞分化为Th17的炎症途径 表型。这项提议意义重大，因为它将建立机制，使这一新的人口群体 InfDC在LN耀斑期间启动并维持组织损伤，进而识别相关的炎症 可靶向减弱耀斑和改善狼疮肾炎预后的途径。 综上所述，这项工作应该为在LN发作期间如何启动肾炎提供新的见解。 描述肾小球周围的InfDC如何驱动肾脏的局部免疫反应。因此我们的调查 有望在理解肾脏特异性自身免疫背后的基本生物学方面取得重大进展 在人类LN期间。

Title: A Novel Inflammatory Dendritic Cell in Lupus Nephritis Abstract/Project Summary: Dendritic cells (DC) are important immune regulators that play a pivotal role in autoimmunity by either promoting tolerance or promoting self-reactive immune responses. Accordingly, aberrant activation of DC is implicated in the pathogenesis of most autoimmune diseases. We have identified a new subset of inflammatory dendritic cells (infDC) that are found in abundance in the kidneys of patients with lupus nephritis (LN), the most common serious organ complication of systemic lupus erythematosus (SLE). These infDC are localized mainly to the periglomerular region of human LN kidney during active disease, a compartment of the kidney not well studied in LN. Of particular relevance is that is that in human LN kidneys infDC appear to spatially associate with T cells that transcriptionally resemble Th17 cells. This is significant because of the known relevance of Th17 pathways in LN. Taken together we suggest that the periglomerular co-localization of infDC and Th17 cells are consequential in initiating and exacerbating LN. The central hypothesis of this proposal is that infDC are the master initiators and drivers of local inflammatory kidney injury by activation of Th17 cells during LN, and that characterizing these relationships will improve our understanding of LN pathogenesis and lead to new therapeutic opportunities. This hypothesis will be tested in three aims. In Aim 1, periglomerular infDC and T cell expression patterns will be characterized in human LN to determine expression heterogeneity and correlation with disease activity. The second aim tests the hypothesis that infDC are damaging to the kidney during LN by demonstrating that depleting or increasing infDC attenuates or exacerbates intra-renal inflammation during LN. The third aim will test the hypothesis that infDC initiate an inflammatory pathway by supporting a cytokine milieu that differentiates intra-renal naïve T cells to a Th17 phenotype. This proposal is significant as it will establish the mechanisms by which this novel population of InfDC initiates and maintains tissue injury during LN flare, and in turn will identify the relevant inflammatory pathways that can be targeted to attenuate flare and improve outcomes in LN. In summary, this work should provide new insights into how renal inflammation is initiated during LN flare by describing how periglomerular InfDC drive the local immune response in the kidney. Thus our investigations are expected to yield a major advance in understanding the basic biology behind kidney-specific autoimmunity during human LN.