Diversity supplement: Lymphatic regulation of lymph node function in lupus

摘要：系统性红斑狼疮(SLE)患者对光敏感，紫外线照射 暴露可引起皮肤炎症，也可引发全身性疾病发作，其特征是 自身免疫力和器官损伤。光敏性皮肤和全身自身免疫之间的联系不是很好。 明白了。亲本R01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，淋巴管携带 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 进入由成纤维细胞网状细胞(FRC)包裹的管道系统。因此，金融资源中心有可能 受淋巴流改变调节，进而调节B细胞和T细胞的反应。淋巴管如何流动 可能调节FRC功能的变化尚不清楚。虽然淋巴可以直接调节FRC，但树突状细胞 (DC)与淋巴和FRC都有联系，我们之前已经展示了DC在调节FRC中的作用 通过淋巴毒素β(LTB)扩张，调节足普宁(PDPN)介导的FRC数量。达到的程度 目前尚不清楚哪些树突状细胞参与FRC的淋巴调节。我们最近发现淋巴流动是 人类SLE和小鼠狼疮模型中淋巴流量的减少以及淋巴流量的改善减少了淋巴B细胞 回应。亲本R01研究了淋巴流动调节FRC CCL2表达的假设 调节淋巴结免疫反应，并询问I型干扰素、活性氧物种、 以及RNA结合蛋白IMP2在淋巴调节FRC中的作用。我们使用这份副刊的目的是 延长母公司R01中提出的调查范围。我们在初步数据中表明，改善淋巴流动 还会导致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依赖使我们想起了我们之前建立的DC-LTbR-FRC轴， 提示淋巴流诱导FRC扩张的改善可能与DC-LTbR-FRC有关 因此，我们将检验这一假说，即改善淋巴流量导致FRC通过DC和他们的 信号，扩大的FRC减少淋巴细胞反应和自身免疫。我们的目标是勾勒出 在MLD上扩展并在体外了解其功能表型的FRC亚群，2)了解 迁徙的DC与常驻的DC以及LT R在多大程度上是MLD诱导的FRC扩张的关键中介， 3)了解长期运用MLD和FRC手法对狼疮表型的影响。 这一建议将有助于我们理解淋巴功能是如何导致狼疮样疾病并描绘出 淋巴流调节FRC和FRC调节T细胞的机制。这将导致一个 更好地理解光敏和自身免疫之间的关系。

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.