Role of plasmacytoid dendritic cells in autoimmunity

浆细胞样树突状细胞在自身免疫中的作用

• 批准号: 10348769
• 负责人: Franck Barrat
• 金额: $ 44万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-09 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348769
• 关键词: Adaptive Immune System; Adrenal Cortex Hormones; Antigen-Antibody Complex; Autoimmune; Autoimmune Diseases; Autoimmunity; Bleomycin; Cells; Chronic; Clinical; Cutaneous; DNA; Data; Defect; Dendritic Cells; Dendritic cell activation; Dermatomyositis; Development; Disease; Disease Progression; Disease model; Engineering; Epigenetic Process; Face; Fibrosis; Functional disorder; Gene Expression; Human; Immunologics; Inflammation; Inflammatory; Inflammatory Arthritis; Innate Immune System; Interferon-alpha; Interferons; Lead; Life; Lupus; Maintenance; Mediating; Modeling; Modification; Morbidity - disease rate; Mus; Nature; Nucleic Acids; Organ; Outcome Measure; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Process; Production; RNA; Reporting; Rheumatism; Role; Scleroderma; Serology; Signal Transduction; Signaling Molecule; Skin; Skin injury; Standardization; Stimulus; Symptoms; Systemic Lupus Erythematosus; Systemic Scleroderma; TLR7 gene; TLR8 gene; Testing; Therapeutic; Toll-Like Receptor Pathway; Toll-like receptors; Ursidae Family; Vascular Diseases; cell type; chemokine; disease heterogeneity; endothelial dysfunction; in vivo; indium-bleomycin; mortality; mouse model; novel therapeutics; peripheral blood; prevent; receptor; receptor expression; response; skin disorder; skin fibrosis; symptom treatment

Systemic Sclerosis (SSc) is a multisystem, fibrosing disorder in which vasculopathy, autoimmunity, and inflammation lead to diverse life-altering and life-threatening clinical manifestations. Treatment is typically focused on specific organ involvement and there is no standardized drug to treat the symptoms with significant differences in the therapeutic approaches between experts. Furthermore, the development of new drug is complicated by the heterogeneity of the disease but also by the absence of validated outcome measures. Recent reports have demonstrated that the chronic activation of plasmacytoid dendritic cell (pDCs) and subsequent secretion of both IFN-α and the chemokine CXCL4 is associated with the pathogenesis of SSc. Our preliminary data show that pDCs have a key role in promoting skin fibrosis in a mouse model of scleroderma. We also show that the pattern of TLR expression is altered in the pDCs of SSc patients with high expression of TLR8, a receptor that is absent in pDCs from healthy donors or SLE patients. Signaling though TLR8 induced both IFN and CXCL4. Using mice that we have engineered so they bear human TLR8, we show that TLR8 promotes fibrosis as these mice have exacerbated disease. We will test the hypothesis that pDCs is the critical cell type promoting SSc due to the aberrant expression of TLR8 on pDCs that impacts the response to self-nucleic acids in patients. The project will use two separate mouse models of scleroderma to define the role of pDCs, TLRs and key signaling molecules of the TLR pathway such as PI3Kδ in the development of disease. We will also dissect the underlying defect that leads to the production of CXCL4 in pDCs from SSc patients and will aim to better understand the interplay between CXCL4 and the IFN response following TLR triggering in patients. To tackle these questions, we are proposing to (1) determine what controls pDCs activation in SSc patients and how these cells promote disease and (2) to characterize the nature of TLR8 stimulation of SSc pDCs and evaluate how CXCL4 and IFN impact TLR8 response. We will also determine whether key signaling molecules induced following TLR triggering are involved in disease progression. The data generated here will provide key understanding of the role of pDCs in skin pathology and the factors that control pDCs activation in SSc patients, thus identifying new ways to manipulate these cells in pathological conditions.

系统性硬化症（SSc）是一种多系统的纤维化疾病，其中血管病变，自身免疫， 炎症导致多种改变生命和威胁生命临床表现。处理通常 集中在特定的器官受累，没有标准化的药物来治疗症状， 专家之间的治疗方法存在显著差异。此外，发展 由于疾病的异质性以及缺乏有效的结果， 措施最近的研究表明，浆细胞样树突状细胞的慢性激活， pDCs的表达以及随后IFN-α和趋化因子CXCL 4的分泌与肿瘤的发生有关。 SSc的发病机制。我们的初步数据表明，pDC在促进皮肤纤维化中具有关键作用， 硬皮病小鼠模型。我们还表明，TLR表达的模式在pDC中发生了改变， 具有TLR 8高表达的SSc患者，TLR 8是一种在来自健康供体或SLE的pDC中不存在的受体 患者通过TLR 8的信号传导诱导IFN和CXCL 4两者。使用我们设计的老鼠， 他们携带人类TLR 8，我们表明TLR 8促进了纤维化，因为这些小鼠已经恶化了疾病。 我们将检验pDC是由于异常表达而促进SSc的关键细胞类型的假设。 pDC上的TLR 8影响患者对自身核酸的应答。该项目将使用两个 单独的硬皮病小鼠模型，以确定pDC、TLR和硬皮病的关键信号分子的作用。 TLR通路如PI 3 K δ在疾病发展中的作用。我们还将剖析潜在的缺陷 导致SSc患者pDC中产生CXCL 4，并将旨在更好地了解 CXCL 4和患者TLR触发后IFN应答之间的相互作用。解决这些 问题，我们建议（1）确定什么控制SSc患者中的pDC激活，以及这些pDC如何激活。 细胞促进疾病和（2）表征SSc pDC的TLR 8刺激的性质并评估 CXCL 4和IFN如何影响TLR 8应答。我们还将确定关键的信号分子 TLR触发后诱导的免疫反应参与疾病进展。这里生成的数据将提供 对pDC在皮肤病理学中的作用以及控制SSc中pDC活化的因素的关键理解 患者，从而确定在病理条件下操纵这些细胞的新方法。

项目成果

TLR8: No gain, no pain.

• DOI: 10.1084/jem.20181899
• 发表时间: 2018-12-03
• 期刊: The Journal of experimental medicine
• 作者: Barrat FJ