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Title: The role of extracellular histones in complement activation and phagocytosis
Author: Qaddoori, Yasir
ISNI:       0000 0004 7659 1046
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Complement activation leads to membrane-attack complex (MAC) 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-associate molecular pattern (DAMP), 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 complement component C4 as identified by mass spectrometry. In Surface Plasmon Resonance (SPR) analysis, histone H3 and H4 showed stronger binding to C4 than other histones with KD around 1.0 nM. The interaction did not affect C4 cleavage to C4a and C4b. Since 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 mannan-binding lectin (MBL) 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 contrast, the alternative pathway was almost spared but the overall complement activity activated by zymosan was inhibited by histones. Therefore, we believe that histones inhibiting complement activation is a natural feedback mechanism to prevent the excessive injury of host cells. In addition, the effect of extracellular histones on phagocytosis has been investigated. Surprisingly, histone-induced inhibition of complement activation did not reduce phagocytosis because histones themselves are able to enhance phagocytosis. The underlying molecular mechanism is not clear. Blocking toll-like receptors 2 and 4 only partially reduced the phagocytic activity. Further study is required. In summary, histone release not only damages cells contacted but also initiates protective mechanisms, including limiting excess complement activation and facilitating bacterial clearance through phagocytosis.
Supervisor: Toh, Cheng-Hock ; Wang, Guozheng ; Christmas, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral