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) 患者对光敏感，其中紫外线辐射 暴露会引起皮肤炎症，还会引发全身性疾病，其特征是增加 自身免疫和器官损伤。光敏性皮肤与系统性自身免疫之间的联系尚不明确 明白了。母体R01的长期目标是确定连接光敏性的机制 伴有全身性疾病发作。皮肤通过淋巴管与免疫系统沟通，淋巴管携带 抗原和介质调节引流淋巴结免疫功能。淋巴结内的淋巴液是 引导至由成纤维网状细胞（FRC）包裹的导管系统中。因此，FRC 有可能 受淋巴流变化调节，进而调节 B 和 T 细胞反应。淋巴液如何流动 改变可能调节 FRC 功能尚不清楚。虽然淋巴可能直接调节 FRC，但树突状细胞 (DC) 与淋巴和 FRC 接触，我们之前已经展示了 DC 在调节 FRC 中的作用 通过调节足足蛋白 (PDPN) 介导的 FRC 数量的淋巴毒素 β (LTb) 进行扩增。程度到 哪些 DC 介导 FRC 的淋巴调节尚不清楚。我们最近发现淋巴流动 在人类 SLE 和小鼠狼疮模型中减少，并且改善淋巴流动减少淋巴结 B 细胞 回应。亲代 R01 研究了淋巴流调节 FRC CCL2 表达以 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 IMP2 在淋巴调节 FRC 功能中的作用。我们制定本补充文件的目标是 扩大母文件 R01 中提议的调查。我们在初步数据中表明，改善淋巴流动 也会导致 FRC 数量增加。这与 FRC 增殖和 PDPN 增加有关 表达，并降低 T 细胞反应。这种扩张依赖于 DC。 FRC扩展，PDPN 上调和 DC 依赖性让人想起我们之前建立的 DC-LTbR-FRC 轴， 表明改善淋巴流诱导的 FRC 扩张可能与 DC-LTbR-FRC 有关 因此，我们将检验这样的假设：改善淋巴流动可通过 DC 及其它们诱导 FRC 扩张。 信号，并且扩大的 FRC 减少淋巴细胞反应和自身免疫。我们的目标是 1) 描绘 FRC 子集扩展了 MLD 并了解其体外功能表型，2）了解 迁移与驻留 DC 以及 LT R 在多大程度上是 MLD 诱导的 FRC 扩张的关键介质， 3) 了解 MLD 和 FRC 操作对狼疮疾病表型的长期影响。 该提议将帮助我们了解淋巴功能如何导致狼疮样疾病并描述 淋巴流调节 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之间的关系。