Extracellular Histones Inhibit Complement Activation through Interacting with Complement Component 4

The Journal of Immunology : Official Journal of the American Association of Immunologists
Yasir QaddooriCheng-Hock Toh

Abstract

Complement activation leads to membrane attack complex formation, which can lyse not only pathogens but also host cells. Histones can be released from the lysed or damaged cells and serve as a major type of damage-associated molecular pattern, but their effects on the complement system are not clear. In this study, we pulled down two major proteins from human serum using histone-conjugated beads: one was C-reactive protein and the other was C4, as identified by mass spectrometry. In surface plasmon resonance analysis, histone H3 and H4 showed stronger binding to C4 than other histones, with KD around 1 nM. The interaction did not affect C4 cleavage to C4a and C4b. Because histones bind to C4b, a component of C3 and C5 convertases, their activities were significantly inhibited in the presence of histones. Although it is not clear whether the inhibition was achieved through blocking C3 and C5 convertase assembly or just through reducing their activity, the outcome was that both classical and mannose-binding lectin pathways were dramatically inhibited. Using a high concentration of C4 protein, histone-suppressed complement activity could not be fully restored, indicating C4 is not the only target of histones in those pathways. In ...Continue Reading

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Citations

Sep 18, 2020·Xenotransplantation·Tao LiYi Wang
Apr 16, 2019·The Journal of Clinical Investigation·Taylor S CohenBret R Sellman
Dec 28, 2018·Parasites & Vectors·Zixia WangXinping Zhu
Dec 29, 2020·Thrombosis and Haemostasis·Alicia A C WaiteIngeborg D Welters
Aug 3, 2021·Frontiers in Immunology·Hongbin Wang, Mengyao Liu

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