IMMUNE MECHANISMS IN PRISTANE INDUCED LUPUS NEPHRITIS

腹腔注射降植烷（2，6，10，14- 四甲基十五烷）诱导狼疮样综合征，几乎所有 “正常”近交系小鼠。 这种综合征的特点是 疾病特异性自身抗体产生（抗Sm、RNP、Su、核糖体 P，双链DNA），高丙种球蛋白血症，和严重的免疫 与狼疮性肾炎非常相似的复合物介导的肾小球肾炎。 在初步研究中，研究表明，这种疾病的发展在两个 阶段，每个阶段都有自身抗体的特征类型。细胞因子和 肾脏受累。 微生物刺激被发现是一个重要的 第二种是渐进的辅助因子。更严重的阶段。 这 该项目将检验免疫复合物沉积是 必要的，但不是足够的，为肾炎的发展， 降植烷引起的狼疮此外，假设系统性 降植烷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性细胞因子的产生 细胞因子和疾病进展。 该项目的目标是 确定降植烷处理小鼠中导致肾小球肾炎的途径 并最终将其与人类狼疮性肾炎联系起来。 三个具体 提出了目标。 将定义肾脏病变的病理学 目标1。 系膜和系膜血管毛细血管病变将通过 免疫组织化学技术，以确定是否过度细胞 反映内源性（系膜或内皮）细胞的增殖 vs.外源性巨噬细胞、淋巴细胞或嗜中性粒细胞的流入。 在 此外，将评价系膜基质沉积， 将研究肾脏变化的过程。 支持者与反对者的角色 将在目的2中评价炎性细胞因子。细胞因子产生 将肾小球中的吞噬细胞与肾小球中的吞噬细胞进行比较。 腹腔渗出液，脾脏和肝脏，以查看是否有系统异常 都在场 将研究精氨酸诱导标志物的表达 作为评价促炎或抗炎作用的手段， 细胞因子占优势。微生物刺激对 在降植烷诱导的狼疮中肾炎的发展将在 目标3。据推测，增强的肠道通透性 注射降植烷增加了 微生物产物，如脂多糖，进入血液。 这可能导致单核细胞和巨噬细胞的系统性激活， 然后在免疫复合物的作用下被募集到肾小球 沉积，导致肾脏疾病进展而非消退 损伤。 鉴于在“正常”小鼠中普遍存在易感性， 降植烷引起的狼疮，降植烷很可能会引起狼疮 通过其对狼疮的共同远端部分的影响， 途径，在很大程度上绕过了易患 疾病的自发形式。 这种新的机制 因此，SLE的可诱导模型可能与其他形式的 狼疮，包括人类SLE。 未来的研究将解决这个问题 与降植烷引起的肾脏异常相似的肾脏异常是否 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.