Complementopathies: biology, biomarkers, and targets

这项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严重形式的COVID-19，并发现新的 生物标志物和治疗靶点。补体疾病是终末器官损伤由 不能调节宿主细胞上的补体和补体抑制减轻了细胞和终末器官损伤。 典型的例子包括阵发性夜间血红蛋白尿（PNH）、非典型溶血性尿毒综合征 （阿胡斯）和冷凝集素病（CAD）。补体疾病通常由炎症引发， 通常与严重的血栓形成表型相关，通常发生在微循环中。一个标志是 由于内皮损伤（血栓性微血管病）导致的微静脉和微动脉中的微血栓。我们先前 一份名为《补体病变：基因型和表型》的资助论文，引起了许多关于补体病变的研究。 发现。我们验证并完善了一种基于细胞的检测方法（改良Ham检测，mHam）， 调节人体细胞，并建立了HELLP（溶血升高肝功能试验和低血小板） 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COVID-19作为补体病。mHam得到验证，因为 发现mHam阳性的疾病在补体调节基因中有生殖系突变， 基因（阿胡斯，HELLP），激活补体的抗体或蛋白质（抗？2-GPI抗体，COVID-19）或 生殖系突变和抗体（CAPS）。此外，我们能够改变护理标准， 通过证明在大多数阿胡斯患者中可以中断终末抑制来证实阿胡斯。这项建议是一项 我们以前资助的工作的自然延伸，并寻求通过解决许多未解决的问题来扩展这项工作。 现场提问。具体来说，我们将：1）通过定义哪些生物标志物，开发更可靠的APS/CAPS生物标志物， APS自身抗体激活补体; 2）识别可能不需要终身抗凝的APS患者; 3)证明补体调节基因的种系突变在CAPS中很常见; 4）证明终末器官 SARS-CoV-2感染引起的损伤/微血管血栓形成/内皮损伤是由于不受调节的活性 和5）证明补体调节基因中的种系突变更常见， 在患有更严重形式的COVID 19的患者中。如果获得资助，我们希望将我们的发现转化为临床试验 导致批准用于治疗严重APS/CAPS和COVID 19的药物。

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.