Department of Biochemistry and Medical Biotechnologies, Federico II University, Naples, Italy.
Immunobiology. 2012 Nov;217(11):1080-7. doi: 10.1016/j.imbio.2012.07.014.
The recent availability of eculizumab as the first complement inhibitor renewed the interest for complement-mediated damage in several human diseases. Paroxysmal nocturnal hemoglobinuria (PNH) may be considered the paradigm a disease caused by complement dysregulation specifically on erythrocytes; in fact, PNH is a clonal, non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins, including the two complement regulators CD55 and CD59. As a result, PNH erythrocytes are incapable to modulate on their surface physiologic complement activation, which eventually enables the terminal lytic complement leading to complement-mediated intravascular anemia - the typical clinical hallmark of PNH. In the last decade the anti-C5 monoclonal antibody has been proven effective for the treatment of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis, with a remarkable clinical benefit. Since then, different diseases with a proved or suspected complement-mediated pathophysiology have been considered as candidate for a clinical complement inhibition. At the same time, the growing information on biological changes during eculizumab treatment in PNH have improved our understanding of different steps of the complement system in human diseases, as well as their modulation by current anti-complement treatment. As a result, investigators are currently working on novel strategy of complement inhibition, looking at the second generation of anti-complement agents which hopefully will be able to modulate distinct steps of the complement cascade. Here we review PNH as a disease model, focusing on the observation that led to the development of novel complement modulators; the discussion will be extended to other hemolytic disorders potentially candidate for clinical complement inhibition.
近年来，首个补体抑制剂依库珠单抗的问世，重新激起了人们对多种人类疾病中补体介导损伤的兴趣。阵发性睡眠性血红蛋白尿症（PNH）可被视为一种由补体失调引起的疾病的范例，其主要作用于红细胞；事实上，PNH 是一种克隆性、非恶性的血液学疾病，其特征是造血干细胞和成熟血细胞的增殖，这些细胞缺乏一些表面蛋白，包括两种补体调节剂 CD55 和 CD59。结果，PNH 红细胞无法在其表面调节生理性补体激活，这最终导致终末补体裂解，从而导致补体介导的血管内贫血——这是 PNH 的典型临床特征。在过去的十年中，抗 C5 单克隆抗体已被证明对 PNH 的治疗有效，可有效控制补体介导的血管内溶血，并带来显著的临床获益。从那时起，具有已证实或疑似补体介导病理生理学的不同疾病已被认为是临床补体抑制的候选疾病。同时，关于 PNH 患者在接受依库珠单抗治疗期间的生物学变化的信息不断增加，这提高了我们对补体系统在人类疾病中的不同步骤及其被当前抗补体治疗调节的理解。因此，研究人员目前正在研究新型补体抑制策略，着眼于第二代抗补体药物，这些药物有望能够调节补体级联反应的不同步骤。在这里，我们将 PNH 作为一种疾病模型进行综述，重点关注导致新型补体调节剂发展的观察结果；讨论将扩展到其他潜在的临床补体抑制候选溶血性疾病。
