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An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H
发布于：2013年7月2日 文字：【大】【中】【小】
J Immunol. 2013 Jun 14. [Epub ahead of print]
An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H.
Hebecker M, Alba-Domínguez M, Roumenina LT, Reuter S, Hyv?rinen S, Dragon-Durey MA, Jokiranta TS, Sánchez-Corral P, Józsi M.
Source
Junior Research Group for Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Kn?ll Institute, 07745 Jena, Germany;
Abstract
Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunction.
补体是存在于体液中的一种重要的固有免疫分子，其异常激活可以致病。H因子是补体旁路途径的调节因子，其基因的多态性、突变以及自身抗体的产生，均可导致各种疾病，如年龄相关性黄斑变性、不典型溶血尿毒综合症和C3肾小球肾炎。重建H因子的功能可能是治疗这些疾病的选择之一。这篇文献报道了一种工程学H因子的构建，这种工程学H因子包含了H因子的两个主要得功能区：N端补体调节区域和C端细胞结合区域。这种迷你H因子结合C3b的能力以及补体调节功能与全长H因子蛋白相似。我们进一步也证明了迷你H因子可以与H因子的配体-C反应蛋白、PTX3以及丙二醛结合。迷你H因子与细胞外基质以及内皮细胞结合后，可以发挥其生物学功能，抑制C3在细胞上的沉积。迷你H因子还可以抑制补体的激活，从而抑制由H因子基因突变或H因子自身抗体引起的宿主细胞的裂解。因此，迷你H因子可能可以作为宿主细胞表面补体抑制因子，在疾病治疗中替代免疫易引起不耐受的全长H因子。