Thurman Joshua M, Harrison Richard A
Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
School of Medicine, Cardiff University, Cardiff, UK.
Immunol Rev. 2023 Jan;313(1):327-338. doi: 10.1111/imr.13168. Epub 2022 Nov 12.
The glomerulus is often the prime target of dysregulated alternative pathway (AP) activation. In particular, AP activation is the key driver of two severe kidney diseases: atypical hemolytic uremic syndrome and C3 glomerulopathy. Both conditions are associated with a variety of predisposing molecular defects in AP regulation, such as genetic variants in complement regulators, autoantibodies targeting AP proteins, or autoantibodies that stabilize the AP convertases (C3- and C5-activating enzymes). It is noteworthy that these are systemic AP defects, yet in both diseases pathologic complement activation primarily affects the kidneys. In particular, AP activation is often limited to the glomerular capillaries. This tropism of AP-mediated inflammation for the glomerulus points to a unique interaction between AP proteins in plasma and this particular anatomic structure. In this review, we discuss the pre-clinical and clinical data linking the molecular causes of aberrant control of the AP with activation in the glomerulus, and the possible causes of this tropism. Based on these data, we propose a model for why the kidney is so uniquely and frequently targeted in patients with AP defects. Finally, we discuss possible strategies for preventing pathologic AP activation in the kidney.
肾小球常常是替代途径（AP）激活失调的主要靶点。特别是，AP激活是两种严重肾脏疾病的关键驱动因素：非典型溶血尿毒综合征和C3肾小球病。这两种病症都与AP调节中的多种易感性分子缺陷相关，例如补体调节因子的基因变异、靶向AP蛋白的自身抗体，或稳定AP转化酶（C3和C5激活酶）的自身抗体。值得注意的是，这些是全身性AP缺陷，但在这两种疾病中，病理性补体激活主要影响肾脏。特别是，AP激活通常局限于肾小球毛细血管。AP介导的炎症对肾小球的这种趋向性表明血浆中的AP蛋白与这种特定解剖结构之间存在独特的相互作用。在本综述中，我们讨论了将AP异常控制的分子原因与肾小球激活联系起来的临床前和临床数据，以及这种趋向性的可能原因。基于这些数据，我们提出了一个模型，解释为什么在AP缺陷患者中肾脏会如此独特且频繁地成为靶点。最后，我们讨论了预防肾脏中病理性AP激活的可能策略。
