Diversity supplement: Lymphatic regulation of lymph node function in lupus

多样性补充：狼疮淋巴结功能的淋巴调节

• 批准号: 10794867
• 负责人: Theresa T. Lu
• 金额: $ 7.04万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794867
• 关键词: Agonist; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CCL2 gene; Cell Count; Cell Proliferation; Cell Survival; Cell physiology; Chimera organism; Collagen; Communication; Data; Dendritic Cells; Dependence; Disease; Flare; Flow Cytometry; Functional disorder; Generations; Goals; Human; Immune; Immune response; Immune system; Immunize; In Vitro; Inflammation; Interferon Type I; Investigation; Link; Liquid substance; Lupus; Lymph; Lymphatic; Lymphatic function; Lymphocyte; Manual Lymphatic Drainage; Mediating; Mediator; Modeling; Mus; Organ; Parents; Patients; Phenotype; Photosensitivity; Plasmablast; Play; Positioning Attribute; Proliferating; RNA-Binding Proteins; Reactive Oxygen Species; Regulation; Reticular Cell; Role; Signal Transduction; Skin; Structure of germinal center of lymph node; Sunlight; System; Systemic Lupus Erythematosus; Systemic disease; T cell response; T-Lymphocyte; Testing; Time; Tissues; Transgenic Model; UV Radiation Exposure; UV induced; Up-Regulation; antagonist; disease phenotype; draining lymph node; imaging approach; immune function; immunoregulation; improved; lupus-like; lymph flow; lymph nodes; lymphatic vessel; lymphotoxin beta; monocyte; mouse model; podoplanin; response; sensor; systemic autoimmunity

Summary: Systemic lupus erythematosus (SLE) patients are photosensitive, where ultraviolet radiation exposure can induce skin inflammation and also trigger systemic disease flares characterized by increased autoimmunity and organ damage. The link between photosensitive skin and systemic autoimmunity is not well understood. The long-term goal of the parent R01 is to determine the mechanisms that connect photosensitivity with systemic disease flares. Skin communicates with the immune system via lymphatic vessels which carry antigens and mediators to regulate draining lymph node immune function. Within the lymph node, lymph fluid is channeled into a conduit system ensheathed by fibroblastic reticular cells (FRCs). The FRCs are thus potentially regulated by lymphatic flow alterations, and in turn can regulate B and T cells responses. How lymphatic flow alterations may regulate FRC functions is unknown. While lymph may directly regulate FRCs, dendritic cells (DCs) are in contact with both lymph and FRCs and we have previously shown roles for DCs in regulating FRC expansion via lymphotoxin beta (LTb) that regulates podoplanin (PDPN)-mediated FRC numbers. The extent to which DCs mediate a lymphatic modulation of FRCs is unknown. We recently showed that lymphatic flow is reduced in human SLE and murine lupus models and that improving lymphatic flow reduces lymph node B cell responses. The parent R01 investigates the hypothesis that lymphatic flow regulates FRC CCL2 expression to regulate lymph node immune responses and asks about the roles of type I interferon, reactive oxygen species, and the RNA binding protein IMP2 in lymphatic-regulated FRC function. Our goal with this Supplement is to extend the investigation proposed in the parent R01. We show in preliminary data that improving lymphatic flow also results in increased FRC numbers. This was associated with increased FRC proliferation and PDPN expression, and reduced T cell responses. This expansion was dependent on DCs. The FRC expansion, PDPN upregulation, and DC dependence recalled the DC- LTbR-FRC axis that we have previously established, suggesting that improved lymphatic flow-induced FRC expansion could be related to a DC- LTbR-FRC axis.Thus, we will test the hypothesis that improving lymphatic flow induces expansion of FRC via DCs and their signals, and the expanded FRCs reduce lymphocyte responses and autoimmunity. Our aims are to 1) delineate the FRC subsets that expand upon MLD and understand their functional phenotype in vitro, 2) understand the extent to which migratory vs resident DCs along with LT R are key mediators of MLD-induced FRC expansion, and 3) understand the effect of MLD and FRC manipulation over the long term on lupus disease phenotype. This proposal will help us understand how lymphatic function contributes to lupus-like disease and delineate mechanisms by which lymphatic flow regulates FRCs and by which FRCs regulate T cells. This will lead to a better understanding of the relationship between photosensitivity and autoimmunity.

摘要：系统性红斑狼疮（SLE）患者是光敏性的， 暴露可诱发皮肤炎症，也可引发全身性疾病发作，其特征在于增加 自身免疫和器官损伤。光敏性皮肤与全身性自身免疫之间的联系尚不清楚 明白亲本R 01的长期目标是确定连接光敏性的机制。 全身性疾病发作皮肤通过淋巴管与免疫系统沟通， 调节引流淋巴结免疫功能的抗原和介质。在淋巴结内，淋巴液是 通过成纤维细胞网状细胞（FRC）包裹的管道系统。因此，FRC可能 通过淋巴流动的改变调节，并且反过来可以调节B和T细胞应答。淋巴如何流动 改变可以调节FRC功能是未知的。虽然淋巴液可以直接调节FRC，但树突状细胞 (DCs)与淋巴和FRC都有接触，我们之前已经显示了DC在调节FRC中的作用 通过调节podoplanin（PDPN）介导的FRC数量的光毒素β（LTb）进行扩增。在多大程度 哪些DC介导FRC的淋巴调节是未知的。我们最近发现淋巴流 在人SLE和鼠狼疮模型中减少，并且改善淋巴流动减少淋巴结B细胞 应答亲本R 01研究了淋巴流调节FRC CCL 2表达的假设， 调节淋巴结免疫反应，并询问I型干扰素，活性氧， 以及RNA结合蛋白IMP 2在神经调节FRC功能中的作用。我们的目标与此补充是 扩展父R 01中提议的调查。我们的初步数据显示，改善淋巴流动 也导致FRC数量增加。这与FRC增殖和PDPN增加有关。 表达和降低的T细胞应答。这种扩张依赖于发展中国家。FRC扩展，PDPN 上调和DC依赖性回忆了我们先前建立的DC-LTbR-FRC轴， 这表明改善的淋巴流诱导的FRC扩增可能与DC-LTbR-FRC相关， 因此，我们将检验这样的假设，即改善淋巴流动通过DC及其受体诱导FRC的扩增。 信号，并且扩增的FRC减少淋巴细胞应答和自身免疫。我们的目标是1）描绘 在MLD基础上扩增并了解其体外功能表型的FRC亚群，2）了解 迁移性DC与居住性DC沿着与LT R是MLD诱导的FRC扩增的关键介导物的程度， 3）了解MLD和FRC操作对狼疮疾病表型的长期影响。 这一建议将帮助我们了解淋巴功能如何有助于狼疮样疾病，并描绘 淋巴流动调节FRC和FRC调节T细胞的机制。这将导致 更好地理解光敏性和自身免疫性之间的关系。