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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

基本信息

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
项目类别：
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

项目摘要

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）患者具有光敏性，即紫外线辐射