IMMUNE MECHANISMS IN PRISTANE INDUCED LUPUS NEPHRITIS

普里斯坦(2，6，10，14- 四甲基十五烷)在几乎所有人中都会导致狼疮样综合征 近亲交配小鼠的“正常”品系。这种综合征的特点是 疾病特异性自身抗体的产生(抗Sm、RNP、SU、核糖体 P，双链DNA)，高丙种球蛋白血症，严重免疫 复杂介导性肾小球肾炎与狼疮性肾炎相似。 初步研究表明，这种疾病在两种情况下发展。 阶段，每个阶段都有特有的自身抗体类型。细胞因子，以及 肾脏受累。微生物刺激被发现是一种重要的 在向第二个发展的过程中的辅助因素。更严重的阶段。这 该项目将检验免疫复合体沉积是 肾炎的发生是必要的，但不是充分的。 普里斯坦诱发的狼疮。此外，还假设一个系统性的 Pristane引起的巨噬细胞或单核细胞表型异常 和/或微生物刺激导致促炎因子的产生 细胞因子与疾病进展。这个项目的目标是 明确导致Pristane治疗的小鼠肾小球肾炎的途径 并最终将它们与人类狼疮性肾炎联系起来。三个具体的 提出了目标。肾脏损害的病理将被定义。 在目标1.系膜和系膜毛细血管病变将通过 免疫组织化学技术确定细胞增多症 反映内源性(系膜或内皮)细胞的增殖 与外源性巨噬细胞、淋巴细胞或中性粒细胞的流入相比。在……里面 此外，将评估系膜基质沉积，并将时间 肾脏变化的过程将被研究。支持与支持的角色反- 炎性细胞因子将在AIM 2中进行评估。 将与吞噬细胞在肾小球中的表达进行比较 腹膜渗出物，脾和肝，看看是否有全身异常 都在现场。将研究细胞因子诱导标记的表达 作为一种评估促炎或抗炎效果的手段 细胞因子占主导地位。微生物刺激对生物多样性的贡献 将在#年检查Pristane诱导的狼疮肾炎的发展。 目的3.假设增加肠道通透性 注射Pristane导致的移位增加 微生物产物，如脂多糖，进入血液。 这可能会导致单核细胞和巨噬细胞的系统性激活，从而 然后被招募到肾小球以响应免疫复合体 沉积，导致进展而不是肾脏的溶解 损伤。鉴于在“正常”小鼠中普遍存在易感性 对于Pristane诱导的狼疮，似乎Pristane导致了狼疮- 由于其对狼疮常见的、远端的部分的影响而类似于疾病 途径，很大程度上绕过了易患高血压的基因异常 自发性疾病的形式。这项新技术所涉及的机制 因此，可诱导的SLE模型可能与其他形式的SLE相同 狼疮，包括人类系统性红斑狼疮。未来的研究将解决这个问题 是否存在类似于Pristane所致的肾脏异常 参与人类狼疮性肾炎的发病机制。

Intraperitoneal injection of pristane (2,6, 10, 14- tetramethylpentadecane) induces a lupus-like syndrome in nearly all "normal" strains of inbred mice. This syndrome is characterized by disease-specific autoantibody production (anti-Sm, RNP, Su, ribosomal P, double stranded DNA), hypergammaglobulinemia, and severe immune complex-mediated glomerulonephritis closely resembling lupus nephritis. In preliminary studies, it was shown that the disease develops in two phases, each with characteristic types of autoantibodies. cytokines, and renal involvement. Microbial stimulation was found to be an important co-factor in progression to the second. more severe, phase. This project will examine the hypothesis that immune complex deposition is necessary, but not sufficient, for the development of nephritis in pristane-induced lupus. Further, it is hypothesized that a systemic abnormality in macrophage or monocyte phenotype resulting from pristane and/or microbial stimulation leads to the production of proinflammatory cytokines and disease progression. The goal of this project is to define pathways leading to glomerulonephritis in pristane-treated mice and ultimately to relate them to human lupus nephritis. Three specific aims are proposed. The pathology of the renal lesions will be defined in Aim 1. Mesangial and mesangiocapillary lesions will be studied by immunohistochemical techniques to determine whether hypercellularity reflects proliferation of endogenous (mesangial or endothelial) cells vs. influx of exogenous macrophages, lymphocytes or neutrophils. In addition, mesangial matrix deposition will be evaluated, and the time course of the renal changes will be studied. The roles of pro-vs. anti- inflammatory cytokines will be evaluated in Aim 2. Cytokine production in the glomerulus will be compared with that by phagocytes in the peritoneal exudate, spleen and liver to see if systemic abnormalities are present. Expression of cytokine-inducible markers will be studied as a means to evaluate whether the effects of pro-or anti-inflammatory cytokines predominate. The contribution of microbial stimulation to the development of nephritis in pristane-induced lupus will be examined in Aim 3. It is hypothesized that enhanced intestinal permeability resulting from pristane injection increases the translocation of microbial products, such as lipopolysaccharide, into the bloodstream. This may cause systemic activation of monocytes and macrophages, which then are recruited to the glomerulus in response to immune complex deposition, causing progression instead of resolution of the renal lesion. In view of the widespread susceptibility among "normal" mice to pristane-induced lupus, it seems likely that pristane causes lupus- like disease by its effects on a common, distal, part of a lupus pathway, largely bypassing the genetic abnormalities that predispose to spontaneous forms of the disease. The mechanisms involved in this new inducible model of SLE may, therefore, be common to other forms of lupus, including human SLE. Future studies will address the question of whether renal abnormalities similar to those induced by pristane are involved in the pathogenesis of human lupus nephritis.