Vascular-stromal function and regulation in immunity

血管基质功能和免疫调节

• 批准号: 10062843
• 负责人: Theresa T. Lu
• 金额: $ 44万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062843
• 关键词: Affect; Antibodies; Area; Autoimmune Diseases; B-Lymphocytes; Blood; Blood Vessels; CCL2 gene; Cell Survival; Cell physiology; Cells; Chimera organism; Chronic; Data; Dendritic Cells; Dependence; Disease; Elements; Endothelial Cells; Fibroblasts; Goals; Health; Homeostasis; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Ligands; Link; Lupus; Lymphatic; Lymphocyte; Lymphoid Tissue; Lymphoproliferative Disorders; Mediating; Mesenchymal; Modeling; Myeloid Cells; Pathologic; Permeability; Phase; Phenotype; Plasma Cells; Plasmablast; Play; Process; Regulation; Reticular Cell; Role; Running; Series; Sinus; Site; Testing; Tissues; Up-Regulation; Vascular Diseases; Vascular Permeabilities; Vascular Permeability Alteration; arginase; cardiovascular health; insight; lymph nodes; podoplanin

Summary Lymphocytes within lymphoid tissues are regulated by a vascular-stromal compartment comprised of blood vessels, lymphatic sinuses, and non-vascular mesenchymal reticular cells, and understanding the functions and regulation of this compartment can have implications for better understanding and treating lymphoproliferative and autoimmune diseases. We have recently shown that fibroblastic reticular cells (FRCs) are in distinct functional states at homeostasis and in inflamed lymph nodes. Our long-term goal is to understand other functional features of the vascular-stromal compartment in inflamed nodes, how these features contribute to regulating immune responses, and how these features in inflamed nodes are induced. Here, we show that FRCs upregulate CCL2 during a phase of the immune response that corresponds to plasma cell accumulation. FRCs express CCL2 at high levels in the vascular-rich medulla and vascular-rich regions of the T zone, which are also the sites of plasma cell localization. We show that CCL2 limits plasma cell survival and that vascular permeability may play a role in inducing the FRC functional phenotype in these vascular-rich regions. We propose to test the hypothesis that, during this phase of the immune response, features of vascular-rich microenvironments regulate plasma cell function and vascular activity regulates FRC functional phenotype in these areas. Our aims are 1) to understand how CCL2 regulates plasma cell survival and 2) to understand how vascular activity contributes to modulating FRC functional phenotype. The results from this proposal will provide new insights into lymphoid tissue vascular-stromal function and regulation, plasma cell regulation, and a potential link between cardiovascular health and the immune system. This link is especially relevant for autoimmune diseases such as lupus that are characterized both by vascular dysfunction and immune system dysfunction marked in part by plasma cell accumulation

总结 淋巴组织内的淋巴细胞受血管间质区室的调节， 血管，淋巴窦和非血管间充质网状细胞，并了解其功能 调节这个区室可以更好地理解和治疗 淋巴增生性和自身免疫性疾病。我们最近发现成纤维网状细胞（FRC） 在体内平衡和发炎的淋巴结中处于不同的功能状态。我们的长期目标是 了解炎症结节中血管间质室的其他功能特征，这些功能如何影响淋巴结的功能。 特征有助于调节免疫反应，以及炎症节点中的这些特征是如何诱导的。 在这里，我们表明，FRC上调CCL2在一个阶段的免疫反应，对应于 浆细胞积聚。FRC在富含血管的髓质中高水平表达CCL 2， T区的区域，这也是浆细胞定位的位点。我们表明，四氯化碳限制血浆 细胞存活和血管通透性可能在诱导FRC功能表型中起作用， 血管丰富的区域。我们建议测试的假设，在这一阶段的免疫反应， 富含血管的微环境调节浆细胞功能，血管活性调节FRC 功能表型在这些领域。我们的目标是1）了解CCL2如何调节浆细胞存活 和2）了解血管活性如何有助于调节FRC功能表型。结果 从这个建议将提供新的见解淋巴组织血管基质的功能和调节， 浆细胞调节，以及心血管健康和免疫系统之间的潜在联系。这个环节 尤其与自身免疫性疾病相关，例如狼疮，其特征在于血管功能障碍 以及免疫系统功能障碍，部分表现为浆细胞积聚