TUNABLE COMPLEMENT ACTIVATION BY PARTICLES WITH VARIABLE SIZE AND Fc DENSITY.
TUNABLE COMPLEMENT ACTIVATION BY PARTICLES WITH VARIABLE SIZE AND Fc DENSITY.
复制标题
通过具有可变尺寸和 Fc 密度的颗粒来激活可调补体。
DOI：
10.1142/s1793984413410018
复制
发表时间：
2013
期刊：
影响因子：
0.8
通讯作者：
Sulchek,Todd
中科院分区：
文献类型：
--
作者：
Pacheco,PatriciaM;LE,Benjamin;White,David;Sulchek,Todd
补体系统是由酶蛋白级联组成的固有免疫组分，所述酶蛋白一旦被激活，就导致入侵病原体的裂解、调理作用或其他先天和/或获得性免疫应答者的募集，或三者的某种组合。由于级联反应中信号放大和控制点的重要性，补体对起始条件的细微变化高度敏感，包括分子间距的纳米级变化。使用Fc功能化的微粒和纳米颗粒，我们发现激活需要至少20%表面覆盖率的Fc的最小阈值表面浓度。该结果表明，高表面密度的Fc对于通过经典途径激活微/纳米颗粒补体是必要的。此外，响应的大小取决于颗粒的大小，较大的颗粒会导致活化降低。我们假设需要高密度的Fc才能有效结合并紧密附着补体级联反应的分子引发剂，从起始到末端补体复合物形成。这些微粒和纳米颗粒与免疫系统相互作用的基础研究表明，通过补体系统影响免疫刺激的颗粒大小和分子密度的设计规则。提供治疗剂以调节补体应答可有助于多种治疗策略。在分子活化剂之间具有受控间隙的工程纳米颗粒可能导致新型免疫调节剂。
The complement system is an integral innate immune component that is made up of a cascade of enzymatic proteins that, once activated, results in lysis of invading pathogens, opsonization or recruitment of other innate and/or acquired immune responders, or some combination of the three. Due to the importance of the signal amplification and control points present in the cascade, complement is highly sensitive to subtle variations in initiation conditions, including nanoscale changes to molecular spacing. Using Fc-functionalized microparticles and nanoparticles, we find that activation requires a minimum threshold surface concentration of Fc of at least 20% surface coverage. This result indicates that a high surface density Fc is necessary for micro/nanoparticle complement activation through the classical pathway. In addition, the magnitude of the response was dependent on the size of the particle, with larger particles causing decreased activation. We hypothesize that a high density of Fc is needed to efficiently bind and closely appose molecular initiators of the complement cascade, from initiation to terminal complement complex formation. These fundamental studies of the interaction of microparticles and nanoparticles with the immune system suggest design rules for particle size and molecular density that impact immunostimulation through the complement system. Providing a therapeutic agent to modulate the complement response could aid a variety of treatment strategies. Engineered nanoparticles with controlled gaps between molecular activators could lead to new types of immunomodulatory agents.