Complementopathies: biology, biomarkers, and targets

这一竞争性更新的总体目标是定义抗磷脂抗体综合征的生物学， 灾难性抗磷脂抗体综合征和重症新冠肺炎，并发现新的 生物标志物和治疗靶点。复合性疾病是由以下因素引起的终末器官损害的疾病 未能调节宿主细胞上的补体和补体抑制可以减轻细胞和终末器官的损伤。 经典的例子包括阵发性睡眠性血红蛋白尿(PNH)、非典型溶血性尿毒症综合征 (AHUS)和冷凝集素病(CAD)。补体疾病通常由炎症和 通常与严重的血栓表型有关，通常在微循环中。一个标志就是存在 由于内皮损伤(血栓性微血管病)，小静脉和小动脉出现微血栓。我们以前的 由基金资助的题为《复杂性疾病：基因和表型》的提交，导致了一些精液 发现。我们验证和改进了一种基于细胞的测试(改进的Ham测试，mHam)，该测试测量补体 对人体细胞的调节，并建立了HELLP(溶血升高肝功能试验和低血小板试验) 综合征、抗磷脂抗体综合征(APS)、灾难性抗磷脂抗体综合征 (CAPS)，以及最近的严重新冠肺炎作为补充。验证mHam是因为 MHAM阳性的疾病在补体调节方面存在种系突变并增加 基因(aHUS，HELLP)，一种能激活补体的抗体或蛋白质(抗2-GPI抗体，新冠肺炎)或 既有生殖系突变，又有抗体(CAPS)。此外，我们还能够改变护理标准 通过证明在大多数aHUS患者中可以停止终末抑制。这项建议是一项 自然扩展我们以前资助的工作，并寻求通过解决许多未解决的问题来扩展这项工作 在现场的问题。具体地说，我们将：1)开发更可靠的APS/CAPS生物标记物，通过定义 APS自身抗体激活补体；2)识别可能不需要终生抗凝的APS患者； 3)证明补体调节基因的胚系突变在CAPS中是常见的；4)证明末端器官 SARS-CoV-2感染引起的损伤/微血管血栓形成/内皮损伤是由于无调控的活动所致 以及5)证明补体调节基因的胚系突变更为常见 在患有更严重形式的柯萨奇病毒19的患者中。如果获得资金，我们希望将我们的发现转化为临床试验 这导致了治疗严重APS/CAPS和COVID19的药物被批准。

The overall goal of this competitive renewal is to define the biology of antiphospholipid antibody syndrome, catastrophic antiphospholipid antibody syndrome and severe forms of COVID-19, and to discover novel biomarkers and therapeutic targets. Complementopathies are diseases where end-organ damage is driven by failure to regulate complement on host cells and complement inhibition mitigates cellular and end-organ damage. Classic examples include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (ahUS), and cold agglutinin disease (CAD). Complementopathies are frequently triggered by inflammation and are often associated with a severe thrombotic phenotype, often in the microcirculation. A hallmark is the presence of microthrombi in venules and arterioles due to endothelial injury (thrombotic microangiopathy). Our previously funded submission entitled, Complementopathies: genotype and phenotype, led to a number of seminal discoveries. We validated and refined a cell-based assay (modified Ham test, mHam) that measures complement regulation on human cells, and established the HELLP (hemolysis elevated liver function tests and low platelets) syndrome, antiphospholipid antibody syndrome (APS), catastrophic antiphospholipid antibody syndrome (CAPS), and most recently, severe COVID-19 as complementopathies. The mHam was validated because diseases with a positive mHam were found to have and increase in germline mutations in complement regulatory genes (aHUS, HELLP), an antibody or protein that activates complement (anti-?2-GPI antibodies, COVID-19) or both a germline mutation and an antibody (CAPS). Furthermore, we were able to change standard of care for aHUS by demonstrating that terminal inhibition can be discontinued in most aHUS patients. This proposal is a natural extension of our previously funded work and seeks to extend this work by addressing many unresolved questions in the field. Specifically, we will: 1) develop more reliable biomarkers for APS/CAPS by defining which APS autoantibodies activate complement; 2) identify APS patients who may not require lifelong anticoagulation; 3) prove that germline mutations in complement regulatory genes are common in CAPS; 4) prove that end-organ damage/microvascular thrombosis/endothelial damage from SARS-CoV-2 infection is due to unregulated activity of complement; and 5) demonstrate that germline mutations in complement regulatory genes are more common in patients with more severe forms of COVID19. If funded, we expect to translate our findings into clinical trials that lead to approved drugs for the treatment of severe APS/CAPS, and COVID19.