Colonna Lucrezia, Parry Graham C, Panicker Sandip, Elkon Keith B
University of Washington, Division of Rheumatology, 750 Republican Street, Box 358060, Seattle, WA 98109, USA.
True North Therapeutics, Inc, 951 Gateway Blvd, South San Francisco, CA 94080, USA.
Clin Immunol. 2016 Feb;163:84-90. doi: 10.1016/j.clim.2015.12.017. Epub 2016 Jan 6.
Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.
补体激活在许多疾病中会导致炎症，但它也有助于生理性凋亡细胞（AC）的清除及其下游的免疫抑制作用。使用人工耗尽血清很难剖析单个补体成分在AC吞噬作用中的作用。利用人类体外系统和新型抗体补体C1s抑制剂TNT003，我们将经典途径的酶促激活作用与C1q在介导a）早期和晚期AC的吞噬作用以及b）早期AC的免疫抑制能力方面的调理作用分离开来。我们发现，抑制C1s对早期AC的生理性清除影响较小，其免疫抑制特性完全不受影响，而主要抑制晚期凋亡/继发性坏死细胞的吞噬作用。我们的数据表明，在没有AC吞噬缺陷的疾病中，抑制C1s可能是一种有价值的治疗策略，可控制经典途径的激活而不会导致AC大量积累。
