Scleroderma Renal Crisis as a Genetic Complementopathy

摘要 系统性硬化症(SSC)，又称硬皮病，是一种以结缔组织纤维化症为特征的罕见疾病。 纸巾。一些患有硬皮病的患者会出现一种称为硬皮病肾脏危象(SRC)的并发症。 以突然发作新的高血压和肾脏损害为特征。虽然病人 可用血管紧张素转换酶抑制剂治疗，仍有较高的发病率。许多人需要肾移植或 透析。SRC的病理与一组不同的突发性肾脏疾病惊人地相似，称为 血栓微血管病，或TMA。TMA通常有确定的遗传原因，主要是由于过度 激活补体级联。补体活性是一种酶的级联反应，用于 感染和处置细胞/组织碎片。在患有TMA的个体中，补体系统被激活 不适当，损害肾脏。由于这两个条件的相似性，我们建议 在一些人中，由于罕见基因的存在，补体激活实际上可能导致SRC 变种。我们将在两个高加索人中识别与补体功能改变相关的罕见变异(目标1) 和非洲裔美国人(AIM 2)，这些人患有硬皮病，并且已经或没有患上SRC。通过比较 只有患有硬皮病的个体相互遗传，我们才能增加发现硬皮病遗传风险变异的机会 仅限SRC。在目标3中，我们将对src肾活检组织进行免疫组织化学以确定补体。 证词。最终，如果我们的假设被证明是正确的，它将为小说的发展打开大门 临床测试以确定有肾脏危机风险的硬皮病患者，我们也将能够尝试新的 阻断补体过度激活的治疗方法。

Abstract Systemic sclerosis (SSc), also called scleroderma, is a rare disease characterized by fibrosis of connective tissues. Some patients with SSc develop a complication called scleroderma renal crisis (SRC), which is characterized by sudden onset of new high blood pressure and evidence of kidney damage. Though patients can be treated with ACE inhibitors, there is still a high morbidity. Many individuals require kidney transplant or dialysis. The pathology of SRC is strikingly similar to a different set of sudden onset kidney diseases called thrombomicroangiopathies, or TMAs. TMAs often have an identified genetic cause, primarily by excessive activation of the complement cascade. Complement activity is an enzymatic cascade that is used to fight infections and dispose of cellular/tissue debris. In individuals with TMAs the complement system activates inappropriately and damages the kidney. Because of the similarity to these two conditions, we propose that SRC may actually be caused in some people by complement activation due to the presence of rare genetic variants. We will identify rare variants associated with altered complement function in both Caucasians (Aim 1) and African-Americans (Aim 2) that have scleroderma and either did or did not develop SRC. By comparing only individuals with scleroderma to each other, we will increase our chances of finding genetic risk variants for SRC only. In Aim 3, we will perform immunohistochemistory on SRC kidney biopsies to identify complement deposition. Ultimately, if our hypothesis proves correct, it will open the door for the development of novel clinical tests to identify individuals with scleroderma at risk of renal crisis, and we would also be able to try new therapeutics that block excessive activation of complement.