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.

项目摘要 系统性红斑狼疮（SLE）患者是光敏性的，表现为皮肤增厚， 对紫外线辐射（UVR）敏感，即使暴露在阳光下也会导致 炎症性皮肤病变的发展。然而，在皮肤之外，UVR暴露也会引发全身性疾病。 疾病爆发，循环自身抗体增加，终末器官进一步损伤。的机制 在皮肤上的UVR暴露可导致全身性自身免疫的爆发尚不清楚。我们 长期目标是阐明光敏性与系统性疾病发作之间的联系机制。在 这个建议，我们专注于皮肤和免疫系统之间的沟通。皮肤间质液 作为淋巴通过淋巴管转运到引流淋巴结，在那里发生免疫应答， 是可以调节的。在淋巴结内，淋巴液从淋巴管流入导管 成纤维细胞网状细胞（FRC）内衬的系统。由于它们在管道中的位置，FRC 从皮肤流出的信号的第一细胞传感器之间。反过来，FRC直接接触 树突状细胞和淋巴细胞位于管道外，在调节免疫细胞中起关键作用。 功能我们最近表明，FRC衍生的CCL2限制了健康（即非糖尿病）患者的浆母细胞反应。 狼疮）小鼠，表明调节淋巴结基质CCL2的因子可能潜在地影响抗体或 自身抗体生成。我们现在提供的初步数据表明，在SLE模型小鼠中，表达CCL2的FRC 具有活化的表型，并且皮肤的UVR暴露触发这些FRC的损失和增加 皮肤引流淋巴结中的浆母细胞。我们还表明，非病变皮肤从狼疮患者和 鼠模型表达干扰素（IFN）特征，并且用I型IFN阻断剂预处理降低了 这些结果共同表明，IFN和其他信号， 激活并敏化引流淋巴结CCL2表达的FRC，使其更可能在UVR时死亡 暴露，随之增加浆母细胞积累。虽然我们的初步结果集中在 在表达CCL2的FRC上，我们的结果更广泛地表明FRC引发模型， 甚至SLE中的非病变皮肤也组成性地调节引流结中的FRC，其形成FRC（因此 淋巴结）对其他应激源（如UVR诱导的皮肤炎症）的反应。在这里，我们建议 假设存在非病变性SLE而非健康对照皮肤特异性信号影响FRC 表型我们将通过以下方式检验这一假设：1）评估IFN和淋巴信号在 在体内调节FRC和淋巴结功能，以及2）描绘所传递的信号的范围 从非病变皮肤到影响人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 系统性疾病发作和新的潜在治疗方法。