Abstract
The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.
Highlights
The Complement SystemWe describe those pathways and molecules from the complement system that are needed to understand the experimental results described in the upcoming sections
For more comprehensive reviews of specific aspects, the reader is referred to recent review works including [1,2,3].The complement system is an efficient weapon of innate immunity, which opsonizes the surface of invading organisms and apoptotic host cells for elimination through phagocytosis and cell lysis
lectin pathway (LP), a fluid phase alternative pathway (AP) C3 convertase may assemble after spontaneous C3 hydrolysis whereby a C3b-like molecule called C3(H2 O) is formed that is capable of binding to Factor B (FB) [34]
Summary
We describe those pathways and molecules from the complement system that are needed to understand the experimental results described in the upcoming sections. Besides starting from C3b deposited through the CP and LP, a fluid phase AP C3 convertase may assemble after spontaneous C3 hydrolysis (tickover mechanism) whereby a C3b-like molecule called C3(H2 O) is formed that is capable of binding to FB [34] This fluid phase proconvertase is activated by FD cleavage, the physiological role of the fluid phase AP C3 convertase is still debated [35,36]. FP circulates as dimeric, trimeric, or tetrameric homooligomers and recognizes primarily C3b within the AP C3 convertase [39] Both C4b and C3b are tightly regulated to avoid complement activation on host cells, but due to the strong amplification through the alternative pathway, C3b regulation is likely to be the most important in vivo. T cells, activated B cells, macrophages and basophils [56]
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