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

概括 淋巴组织内的淋巴细胞受到由血液组成的血管基质室的调节 血管、淋巴窦和非血管间充质网状细胞，并了解其功能 这个隔室的调节可能会对更好地理解和治疗产生影响 淋巴增殖性疾病和自身免疫性疾病。我们最近发现，成纤维细胞网状细胞（FRC） 在稳态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 了解发炎淋巴结中血管间质室的其他功能特征，这些特征如何 特征有助于调节免疫反应，以及如何诱导发炎节点中的这些特征。 在这里，我们发现 FRC 在免疫反应的相应阶段上调 CCL2 浆细胞积聚。 FRC 在富含血管的髓质和富含血管的髓质中高水平表达 CCL2 T区区域，也是浆细胞定位的部位。我们证明 CCL2 限制血浆 细胞存活和血管通透性可能在诱导 FRC 功能表型中发挥作用 血管丰富的区域。我们建议检验以下假设：在免疫反应的这一阶段， 富含血管的微环境的特征调节浆细胞功能，血管活性调节 FRC 这些区域的功能表型。我们的目标是 1) 了解 CCL2 如何调节浆细胞存活 2) 了解血管活动如何有助于调节 FRC 功能表型。结果 该提案将为淋巴组织血管基质功能和调节提供新的见解， 浆细胞调节，以及心血管健康和免疫系统之间的潜在联系。这个链接是 尤其与以血管功能障碍为特征的自身免疫性疾病有关，例如狼疮 免疫系统功能障碍部分表现为浆细胞积聚