Role of plasmacytoid dendritic cells in autoimmunity

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、自身免疫性和 炎症导致多种改变生命和威胁生命的临床表现。治疗通常是 集中在特定的器官受累，没有标准化的药物来治疗这些症状 专家之间在治疗方法上的显著差异。此外，中国的发展 新药因疾病的异质性而变得复杂，但也因缺乏有效的结果而变得复杂 措施。最近的报道表明，浆细胞样树突状细胞的慢性激活 (PDC)和随后分泌的干扰素-α和趋化因子CXCL4与 SSc的发病机制。我们的初步数据显示，PDCs在促进皮肤纤维化方面起着关键作用。 硬皮病小鼠模型。我们还表明，TLR在pDC中的表达模式发生了变化。 TLR8高表达的系统性硬化症患者，TLR8是一种健康供者或SLE患者pDC上缺失的受体 病人。TLR8信号通路可同时诱导干扰素和CXCL4。使用我们设计的小鼠 他们携带人类TLR8，我们表明TLR8促进了纤维化，因为这些小鼠加剧了疾病。 我们将检验这一假设，即pDCs是由于异常表达而促进SSC的关键细胞类型 PDC上TLR8的表达影响患者对自身核酸的反应。该项目将使用两个 分离硬皮病小鼠模型以确定PDCs、TLR和关键信号分子的作用 TLRPI3K等δ通路在疾病发生发展中的作用。我们还将剖析潜在的缺陷 这导致了SSC患者pDC中CXCL4的产生，并将旨在更好地了解 TLR激活后CXCL4与干扰素反应的相互作用。要解决这些问题 问题，我们建议(1)确定是什么控制了SSC患者的PDCs激活，以及这些控制是如何 细胞促进疾病和(2)表征TLR8刺激SSC pDCs的性质并评估 CXCL4和干扰素对TLR8反应的影响我们还将确定关键信号分子 TLR触发后的诱导参与了疾病的进展。此处生成的数据将提供 PDC在皮肤病理中的作用及SSC中控制PDC激活的因素的关键认识 从而确定在病理条件下操纵这些细胞的新方法。

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.