Immune Complex Elimination by Sinusoid Endothelial FcgRIIb: Mechanism and Disease

描述（由申请人提供）：最近的工作对身体如何从血液中消除小免疫复合物（sic）产生了新的见解。我们早就知道，致病性IC沉积在肾脏等器官，可引起炎症和疾病，如肾小球肾炎和SLE。然而，到目前为止，这些ic中的大多数被肝脏无害地清除，大多数被其巨噬细胞（Kupffer细胞，kc）清除。此外，已知在B细胞、巨噬细胞和树突状细胞上表达的一种特殊Fc受体FcgRII （RIIb）可以缓解ic介导的疾病。在此背景下，这些研究人员提出了两个显著的新发现：第一，RIIb在肝窦内皮（lsec）上，而不是肝kc上，消除了血液中sic的主要部分；第二，身体四分之三的RIIb在lsec上表达。基于这些信息，他们假设lsec上的RIIb可以消除血液中的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输注ic在条件和嵌合敲除小鼠体内的衰变率来证实这一假设；并且通过显示广泛的IC在相同的体内衰减率测量中是有效的。第二个目的是从肝脏中分离纯化清除细胞，并利用这些细胞在体外解剖riib介导的肝细胞吞噬作用机制。第三个目标是清仓高效、快速、可恢复和稳健；一个预测

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.