Meryhew N L, Shaver C, Messner R P, Runquist O A
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
J Lab Clin Med. 1991 Mar;117(3):181-93.
Although several studies have reported abnormal immune clearance in murine models of systemic lupus erythematosus (SLE), a consistent defect in mononuclear phagocyte function in SLE-prone mice has not been described. To evaluate the mechanism(s) of immune clearance in murine SLE, we applied the technique of kinetic analysis to clearance studies of radiolabeled, immunoglobulin-sensitized red blood cells in normal BALB/c and autoimmune BXSB, MRL-lpr/lpr, New Zealand black (NZB) and New Zealand black/white (NZB/W) mice. Clearance studies were performed in 4-week-old to 18-month-old mice with a complement-fixing rabbit IgG antimouse red blood cell antibody. Four clearance rate constants governing complement- and Fc-mediated clearance function were evaluated: complement-mediated sequestration (k1), C3b deactivation and release (k2), complement-dependent phagocytosis (k4), and Fc-mediated sequestration and phagocytosis (k3). BXSB male, MRL-lpr/lpr female and male, NZB female, and NZB/W female and male mice all had significantly decreased Fc-mediated clearance function (k3) when compared with control BALB/c mice (p less than 0.0001). This defect in Fc-mediated clearance was present in all four strains of autoimmune mice by 6 months of age and preceded the onset of serologic and clinical disease activity in NZB mice. Abnormal complement-mediated clearance was detected in MRL-lpr/lpr female and male mice, NZB female, and NZB/W female and male mice, but not in BXSB mice. In MRL-lpr/lpr mice decreased complement-mediated sequestration (k1, p less than 0.0001) and complement-dependent phagocytosis (k4, p less than 0.0001) were present as early as 4 weeks of age. In contrast, the change in complement-mediated clearance in NZB and NZB/W mice was characterized by decreased C3b deactivation and release (k2, p less than 0.001) and resulted in an enhanced early phase of clearance. Decreased k2 values in New Zealand mice occurred as early as 2 months of age, preceding serologic and clinical disease activity as well as decreased Fc receptor function. These studies demonstrated an early, progressive, and uniform defect in Fc-mediated clearance in the four murine strains of SLE studied. Complement-mediated clearance, however, varied considerably in lupus-prone mice, ranging from severe impairment in MRL-lpr/lpr to normal function in BXSB and accelerated clearance in NZB and NZB/W mice. Accelerated clearance in New Zealand mice was characterized by decreased C3b deactivation and release of antibody sensitized cells, which in turn led to increased phagocytosis of sensitized cells sequestered by complement-dependent processes.
尽管多项研究报道了系统性红斑狼疮（SLE）小鼠模型中存在异常免疫清除现象，但尚未描述SLE易感小鼠单核吞噬细胞功能存在一致缺陷。为评估小鼠SLE中免疫清除的机制，我们将动力学分析技术应用于正常BALB/c小鼠以及自身免疫性BXSB、MRL-lpr/lpr、新西兰黑（NZB）和新西兰黑/白（NZB/W）小鼠对放射性标记的免疫球蛋白致敏红细胞的清除研究。使用补体固定兔IgG抗小鼠红细胞抗体，在4周龄至18月龄小鼠中进行清除研究。评估了四个控制补体和Fc介导清除功能的清除率常数：补体介导的隔离（k1）、C3b失活和释放（k2）、补体依赖性吞噬作用（k4）以及Fc介导的隔离和吞噬作用（k3）。与对照BALB/c小鼠相比，BXSB雄性、MRL-lpr/lpr雌性和雄性、NZB雌性以及NZB/W雌性和雄性小鼠的Fc介导清除功能（k3）均显著降低（p小于0.0001）。Fc介导清除的这种缺陷在6月龄时存在于所有四株自身免疫小鼠中，且早于NZB小鼠血清学和临床疾病活动的发作。在MRL-lpr/lpr雌性和雄性小鼠、NZB雌性以及NZB/W雌性和雄性小鼠中检测到补体介导的清除异常，但在BXSB小鼠中未检测到。在MRL-lpr/lpr小鼠中，早在4周龄时就出现补体介导的隔离降低（k1，p小于0.0001）和补体依赖性吞噬作用降低（k4，p小于0.0001）。相反，NZB和NZB/W小鼠中补体介导清除的变化特征是C3b失活和释放降低（k2，p小于0.001），并导致清除的早期阶段增强。新西兰小鼠中k2值降低早在2月龄时就出现，早于血清学和临床疾病活动以及Fc受体功能降低。这些研究表明，在所研究的四株SLE小鼠中，Fc介导的清除存在早期、进行性和一致的缺陷。然而，补体介导的清除在SLE易感小鼠中差异很大，从MRL-lpr/lpr中的严重受损到BXSB中的正常功能，以及NZB和NZB/W小鼠中的加速清除。新西兰小鼠中的加速清除特征是抗体致敏细胞的C3b失活和释放降低，这反过来又导致补体依赖性过程隔离的致敏细胞吞噬作用增加。
