Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.
Front Immunol. 2022 Apr 12;13:860689. doi: 10.3389/fimmu.2022.860689. eCollection 2022.
As part of the innate immune system, the complement system plays a key role in defense against pathogens and in host cell homeostasis. This enzymatic cascade is rapidly triggered in the presence of activating surfaces. Physiologically, it is tightly regulated on host cells to avoid uncontrolled activation and self-damage. In cases of abnormal complement dysregulation/overactivation, the endothelium is one of the primary targets. Complement has gained momentum as a research interest in the last decade because its dysregulation has been implicated in the pathophysiology of many human diseases. Thus, it appears to be a promising candidate for therapeutic intervention. However, detecting abnormal complement activation is challenging. In many pathological conditions, complement activation occurs locally in tissues. Standard routine exploration of the plasma concentration of the complement components shows values in the normal range. The available tests to demonstrate such dysregulation with diagnostic, prognostic, and therapeutic implications are limited. There is a real need to develop tools to demonstrate the implications of complement in diseases and to explore the complex interplay between complement activation and regulation on human cells. The analysis of complement deposits on cultured endothelial cells incubated with pathologic human serum holds promise as a reference assay. This assay most closely resembles the physiological context. It has been used to explore complement activation from sera of patients with atypical hemolytic uremic syndrome, malignant hypertension, elevated liver enzymes low platelet syndrome, sickle cell disease, pre-eclampsia, and others. In some cases, it is used to adjust the therapeutic regimen with a complement-blocking drug. Nevertheless, an international standard is lacking, and the mechanism by which complement is activated in this assay is not fully understood. Moreover, primary cell culture remains difficult to perform, which probably explains why no standardized or commercialized assay has been proposed. Here, we review the diseases for which endothelial assays have been applied. We also compare this test with others currently available to explore complement overactivation. Finally, we discuss the unanswered questions and challenges to overcome for validating the assays as a tool in routine clinical practice.
作为先天免疫系统的一部分，补体系统在防御病原体和宿主细胞稳态方面发挥着关键作用。该酶级联反应在存在激活表面时会迅速触发。在生理条件下，它在宿主细胞上受到严格的调控，以避免不受控制的激活和自我损伤。在补体异常调节/过度激活的情况下，内皮细胞是主要靶点之一。在过去十年中，补体作为一个研究热点引起了人们的关注，因为其失调与许多人类疾病的病理生理学有关。因此，它似乎是一种有前途的治疗干预候选物。然而，检测异常的补体激活具有挑战性。在许多病理情况下，补体在组织中局部激活。标准的血浆补体成分浓度常规检测显示值在正常范围内。目前用于证明具有诊断、预后和治疗意义的这种失调的可用检测方法有限。因此，确实需要开发工具来证明补体在疾病中的作用，并探索补体激活与人类细胞调节之间的复杂相互作用。分析培养的内皮细胞在病理人血清孵育后补体沉积物具有作为参考测定的潜力。这种测定最接近生理情况。它已被用于探索来自非典型溶血性尿毒症综合征、恶性高血压、肝酶升高血小板减少综合征、镰状细胞病、子痫前期等患者血清中的补体激活。在某些情况下，它被用于用补体阻断药物调整治疗方案。然而，目前缺乏国际标准，并且不完全了解该测定中补体激活的机制。此外，原代细胞培养仍然难以进行，这可能解释了为什么没有提出标准化或商业化的测定方法。在这里，我们综述了已应用于内皮测定的疾病。我们还将该测试与目前可用的其他测试进行了比较，以探索补体过度激活。最后，我们讨论了验证该测定作为常规临床实践中的工具的未解决问题和挑战。
