Immune Complex Elimination by Sinusoid Endothelial FcgRIIb: Mechanism and Disease

正弦曲线内皮 FcgRIIb 消除免疫复合物：机制和疾病

• 批准号: 9042940
• 负责人: CLARK L ANDERSON
• 金额: $ 33.89万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-16 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042940
• 关键词: Antibodies; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; B-Lymphocytes; Bacteriophages; Binding; Blood; Blood Circulation; Cells; Complex; Data; Dendritic Cells; Deposition; Discontinuous Capillary; Disease; Endocytosis; Endothelial Cells; Endothelium; Experimental Designs; Experimental Models; Fc Receptor; Functional disorder; Glomerulonephritis; Goals; Health; Hepatocyte; Human; Immune; Immune system; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; Kidney; Kinetics; Knock-out; Knockout Mice; Kupffer Cells; Liver; Lymphoid Cell; Measurement; Measures; Mediating; Modeling; Mole the mammal; Molecular; Mouse Strains; Mus; Myeloid Cells; Organ; Outcome; Pathway interactions; Pinocytosis; Public Health; Reaction; Refractory; Research Personnel; Residual state; Science; Serum Sickness; Site; Study of serum; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Thinking; Time; Tissues; Virus; Work; base; immune function; in vivo; insight; macrophage; novel; prevent; receptor

DESCRIPTION (provided by applicant): Recent work has yielded new insight into how the body eliminates small immune complexes (sic) from the blood. We have long known that pathogenic IC, depositing in organs like kidneys, cause inflammation and disease such as glomerulonephritis and SLE. However, by far the majority of these ic are eliminated harmlessly by the liver, most believe by its macrophages (Kupffer cells, kc). Further, a particular Fc receptor, FcgRII (RIIb), expressed on B cells, macro- phages, and dendritic cells, is known to temper ic-mediated disease. With this background, these investigators present two remarkably novel findings: first, that RIIb on liver sinusoidal endothelium (lsec), not liver kc, eliminate th major fraction of sic from blood, and, second, that three-quarter of the body's RIIb is expressed on the lsec. Based on this information they hypothesize that RIIb on the lsec eliminates sic from blood and protects against SLE and other ic- mediated disease in humans and mice. This hypothesis has four specific predictions, each a specific aim of the proposal. The first aim affirms the hypothesis by measuring rates of in vivo decay of infused ic in conditional and chimeric knockout mice; and by showing that a wide spectrum of ic are effective in the same in vivo rate-of-decay measurement. The second aim isolates and purifies scavenger cells from liver and makes use of these in vitro for dissecting the mechanism of RIIb-mediated pinocytosis on lsec. The third aim is that clearance is efficient, rapid, recoverable, and robust; a prediction approached by careful kinetic analysis of in vivo de- cay; and confirmed by in vitro studies. The fourth aim is that RIIb controls the manifestations of inflammatory ic-mediated disease, a prediction approached using an experimental model of mouse serum sickness in mouse strains in which RIIb has been ablated in select tissues. The outcomes expected are that the lsec and not the kc is the major liver scavenger for sic; that RIIb on the lsec and not on myeloid or B cell is the operant scavenging receptor; that the capacity of the clearance mechanism is robust; that serum sickness can easily be produced in the absence of RIIb; and that lsec RIIb clearance of ic likely contributes to SLE and other ic-mediated dis- ease. The project challenges existing orthodoxy that the kc is the major liver scavenger for immune complexes, suggesting instead that the lsec is the scavenger. As well the project presents a new paradigm whereby RIIb on lsec clears pathogenic ic, thus protecting the host from ic-mediated inflammatory diseases such as SLE.

描述（由申请人提供）：最近的工作已经产生了新的见解，身体如何消除小免疫复合物（原文如此）从血液中。我们早就知道致病IC沉积在肾脏等器官中，引起炎症和疾病，如肾小球肾炎和SLE。然而，到目前为止，大多数这些ic被肝脏无害地消除，大多数人认为是通过其巨噬细胞（枯否细胞，kc）。此外，已知在B细胞、巨噬细胞和树突状细胞上表达的特定Fc受体FcgRII（RIIb）可缓和Fc介导的疾病。在此背景下，这些研究人员提出了两个非常新颖的发现：第一，肝窦内皮（lsec）上的RIIb，而不是肝KC，从血液中消除了SiC的主要部分，第二，身体四分之三的RIIb在lsec上表达。基于这一信息，他们假设lsec上的RIIb从血液中消除sic，并保护人类和小鼠免受SLE和其他ic介导的疾病。这个假设有四个具体的预测，每个预测都有一个具体的目标。第一个目的是通过测量条件和嵌合基因敲除小鼠中输注的ic的体内衰减速率，并通过显示广谱ic在相同的体内衰减速率测量中是有效的，来证实这一假设。第二个目的是从肝脏分离纯化清道夫细胞，并利用这些细胞在体外研究RIIb介导的胞饮对lsec的作用机制。第三个目标是，清除是有效的，快速的，可恢复的，和强大的;预测 通过仔细的体内降解动力学分析来接近;并通过体外研究来证实。第四个目的是RIIb控制炎性IC介导的疾病的表现，这是使用小鼠血清病的实验模型在小鼠品系中进行的预测，其中RIIb已在选择的组织中被消融。预期的结果是lsec而不是kc是sic的主要肝脏清除剂; lsec上而不是髓样或B细胞上的RIIb是操作性清除受体;清除机制的能力是稳健的;在RIIb不存在的情况下可以容易地产生血清病;并且lsec RIIb对ic的清除可能有助于SLE和其他ic介导的疾病。该项目挑战了现有的正统观念，即kc是免疫复合物的主要肝脏清道夫，而不是lsec是清道夫。此外，该项目提出了一种新的范例，其中lsec上的RIIb清除致病性ic，从而保护宿主免受ic介导的炎性疾病如SLE。