A Novel Inflammatory Dendritic Cell in Lupus Nephritis

狼疮性肾炎中的一种新型炎症树突状细胞

• 批准号: 10475392
• 负责人: Latha Prabha Ganesan
• 金额: $ 10万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475392
• 关键词: Adoptive Transfer; Affect; Attenuated; Autoimmune Diseases; Autoimmunity; Biological Response Modifiers; Biology; CD14 gene; CD3 Antigens; CD34 gene; Cells; Chronic; Complication; Consequentialism; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; FCGR3B gene; Feedback; Flare; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Hematopoietic stem cells; Heterogeneity; Histologic; Human; IL3RA gene; ITGAM gene; ITGAX gene; IgG Receptors; Immune; Immune response; Immunologics; In Situ; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Injury to Kidney; Investigation; Kidney; Knowledge; Lead; Lupus; Lupus Nephritis; Mediating; Methods; Modeling; Morbidity - disease rate; Mus; Organ; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Proteins; Role; Synapses; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transcript; Work; cell type; cost; cytokine; disorder control; improved; improved outcome; in vivo; insight; kidney biopsy; new therapeutic target; novel; novel therapeutics; overexpression; polarized cell; prevent; public health relevance; renal damage; side effect; tissue injury; transcriptomics

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.

标题：狼疮性肾炎中的一种新型炎症性树突状细胞 摘要/项目摘要： 树突状细胞（DC）是重要的免疫调节因子，其通过以下任一途径在自身免疫中发挥关键作用： 促进耐受性或促进自身反应性免疫应答。因此，DC的异常激活是 参与大多数自身免疫性疾病的发病机制。我们发现了一个新的 在狼疮肾炎患者的肾脏中大量发现的炎性树突状细胞（infDC） (LN)是系统性红斑狼疮（SLE）最常见的严重器官并发症。这些infDC是 在活动性疾病期间，主要局限于人LN肾的肾小球周围区域， 肾脏在LN中未得到充分研究。特别相关的是，在人LN肾中，infDC似乎 在空间上与转录上类似于Th 17细胞T细胞相关。这一点很重要，因为 Th 17通路与LN的相关性。综上所述，我们认为球周共定位 infDC和Th 17细胞在LN的发生和加重中起重要作用。这个问题的核心假设是 这一观点认为，infDC是通过激活炎症因子而引起的局部炎症性肾损伤的主要引发者和驱动者。 Th 17细胞在LN中的作用，表征这些关系将提高我们对LN的理解 发病机制，并导致新的治疗机会。这一假设将在三个目标进行检验。在目标1中， 将在人LN中表征肾小球周infDC和T细胞表达模式以确定表达 异质性和与疾病活动相关性。第二个目的是检验infDC是 通过证明消耗或增加infDC减弱或减少了LN期间对肾脏的损害， 加剧LN期间的肾内炎症。第三个目标是检验infDC启动一个 通过支持将肾内幼稚T细胞分化为Th 17细胞的细胞因子环境， 表型这一提议是重要的，因为它将建立这种新的群体的机制， 在LN发作期间，InfDC启动并维持组织损伤，并且反过来将识别相关的炎症反应。 可以靶向减弱发作并改善LN结局的途径。 总之，这项工作应该提供新的见解，如何在LN发作期间启动肾脏炎症， 描述肾小球周围InfDC如何驱动肾脏中的局部免疫应答。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础生物学方面取得重大进展 在人类LN中。