Skin-lymph node axis in SLE

SLE 中的皮肤淋巴结轴

• 批准号: 10510072
• 负责人: Theresa T. Lu
• 金额: $ 25.26万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510072
• 关键词: Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CCL2 gene; Cell physiology; Collagen; Communication; Data; Dendritic Cells; Development; Disease; Event; Exposure to; Flare; Generations; Goals; Human; IFNAR1 gene; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Injury; Intercellular Fluid; Interferon Type I; Interferons; Lead; Liquid substance; Location; Lupus; Lymph; Lymphocyte; Lymphocyte Function; Mass Spectrum Analysis; Modeling; Mus; Nature; Organ; Patients; Phenotype; Photosensitivity; Plasmablast; Play; Proteomics; Reticular Cell; Role; Shapes; Signal Transduction; Skin; Stromal Cells; Sunlight; System; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Tissues; UV Radiation Exposure; UV induced; Ultraviolet Rays; draining lymph node; immune function; in vivo; insight; interest; lymph flow; lymph nodes; lymphatic vessel; mouse model; response; sensor; skin lesion; stressor; systemic autoimmunity

Project Summary Patients with systemic lupus erythematosus (SLE) are photosensitive, demonstrating an increased skin sensitivity to ultraviolet radiation (UVR) whereby even ambient exposure to sunlight can result in the development of inflammatory skin lesions. Beyond the skin, however, UVR exposure can also trigger systemic disease flares, with increased circulating autoantibodies and further injury of end organs. The mechanisms by which UVR exposure at the skin can lead to flares of systemic autoimmunity are not well understood. Our long-term goal is to delineate the mechanisms that connect photosensitivity with systemic disease flares. In this proposal, we focus on the communication between skin and the immune system. Interstitial fluid from skin is transported as lymph via lymphatic vessels to draining lymph nodes where immune responses occur and can be regulated. Within the lymph node, lymph fluid is channeled from the lymphatic vessels into a conduit system that is lined by fibroblastic reticular cells (FRCs). Because of their location in the conduits, FRCs are among the first cellular sensors of signals flowing from the skin. FRCs, in turn, are in direct contact with dendritic cells and lymphocytes sitting outside the conduits and play critical roles in regulating immune cell function. We have recently shown that FRC-derived CCL2 limits plasmablast responses in healthy (ie non- lupus) mice, indicating that factors that modulate lymph node stromal CCL2 can potentially impact antibody or autoantibody generation. We now present preliminary data that, in SLE model mice, CCL2-expressing FRCs have an activated phenotype and UVR exposure of the skin triggers both a loss of these FRCs and increased plasmablasts in skin-draining lymph nodes. We also show that non-lesional skin from lupus patients and murine models express interferon (IFN) signatures and that pre-treatment with type I IFN blockade reduces photosensitivity in two murine lupus models These results together suggest that IFNs and other signals activate and sensitize draining lymph node CCL2-expressing FRCs, making them more likely to die upon UVR exposure, with consequent increases in plasmablast accumulation. While our preliminary results are focused on CCL2-expressing FRCs, our results more broadly suggest a model of FRC priming whereby signals from even non-lesional skin in SLE constitutively modulate FRCs in draining nodes, which shapes FRC (and thus lymph node) responses to additional stressors such as UVR-induced skin inflammation. Here, we propose the hypothesis that there are signals specific to non-lesional SLE but not healthy control skin that impact FRC phenotype. We will test the hypothesis by 1) assessing the roles of IFNs and lymph-borne signals in modulating FRC and lymph node function in vivo, and 2) delineating the scope of signals that are transmitted from non-lesional skin to impact FRCs in human SLE. These studies are anticipated to provide insight into the importance and nature of skin-lymph node communication, the connection between photosensitivity and systemic disease flares, and new potential therapeutic approaches.

项目概要 系统性红斑狼疮 (SLE) 患者对光敏感，表现出皮肤增加 对紫外线辐射 (UVR) 的敏感性，即使环境暴露在阳光下也会导致 炎症性皮肤病变的发展。然而，除了皮肤之外，紫外线照射也会引发全身性的症状。 疾病爆发，循环自身抗体增加，并进一步损伤终末器官。其机制由 皮肤上的哪种紫外线照射会导致全身性自身免疫的爆发尚不清楚。我们的 长期目标是描绘光敏性与全身性疾病发作之间的联系机制。在 在这个建议中，我们重点关注皮肤和免疫系统之间的沟通。来自皮肤的间质液 作为淋巴液通过淋巴管输送到发生免疫反应的引流淋巴结， 可以被监管。在淋巴结内，淋巴液从淋巴管流入导管 由成纤维细胞网状细胞（FRC）排列的系统。由于 FRC 位于导管中，因此 是最早的从皮肤发出信号的细胞传感器之一。反过来，FRC 又与 树突状细胞和淋巴细胞位于导管外，在调节免疫细胞中发挥关键作用 功能。我们最近表明，FRC 衍生的 CCL2 限制健康（即非 狼疮）小鼠，表明调节淋巴结基质 CCL2 的因素可能会影响抗体或 自身抗体的产生。我们现在提供初步数据，在 SLE 模型小鼠中，表达 CCL2 的 FRC 具有激活的表型并且皮肤的 UVR 暴露会引发这些 FRC 的损失并增加 皮肤引流淋巴结中的浆母细胞。我们还表明，狼疮患者的非病变皮肤和 小鼠模型表达干扰素 (IFN) 特征，并且用 I 型 IFN 阻断进行预处理可减少 两种小鼠狼疮模型中的光敏性这些结果共同表明 IFN 和其他信号 激活表达 CCL2 的引流淋巴结 FRC 并使它们变得敏感，使它们更有可能在 UVR 下死亡 暴露，从而导致浆母细胞积累增加。虽然我们的初步结果集中在 对于表达 CCL2 的 FRC，我们的结果更广泛地提出了一种 FRC 启动模型，其中来自 即使是 SLE 中的非病变皮肤也会组成性调节引流节点中的 FRC，从而塑造 FRC（从而 淋巴结）对额外压力源（例如紫外线引起的皮肤炎症）的反应。在此，我们建议 假设存在影响 FRC 的非病变 SLE 特有信号，但健康对照皮肤没有特有信号 表型。我们将通过 1）评估 IFN 和淋巴信号在 调节体内 FRC 和淋巴结功能，以及 2) 描绘传输信号的范围 从非病变皮肤到影响人类 SLE 中的 FRC。这些研究预计将提供深入了解 皮肤淋巴结通讯的重要性和性质、光敏性和 全身性疾病爆发，以及新的潜在治疗方法。