Complement plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells

Elward, Kristina 2005. Complement plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells. PhD Thesis, Cardiff University.

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Abstract

Complement is the canonical innate immune system involved in host defence and, tissue repair with the clearance of apoptotic cells and other toxic cell debris. The aim of the study was to shed new light on the role of complement activators - Clq, C3b, and complement regulators - CD46, CD55 and CD59 in selective recognition and finely tuned removal of 'altered self (i.e. apoptotic versus necrotic cells) in the CNS and to ascertain the capacity of macrophage and brain cells to express complement and other phagocyte receptors involved in the clearance of apoptotic cells. Key differences were observed for complement regulators with a rapid release of soluble forms of CD46, CD55 and CD59 from necrotic cells along with detection of the lytic membrane attack complex (MAC), while only CD46 was dramatically reduced on apoptotic cells to promote complement C3 opsonisation without the MAC. Although CD46 is evenly distributed on normal cells, a remarkable clustering of CD46 to apoptotic blebs at associated site of phosphatidylserine exposure was observed. CD46 was removed from nuclear and cytoplasmic/membrane stores to apoptotic blebs without involving Src kinases, and released from the cell in microparticles together with phosphatidylserine, Clq, C3b and iC3b. Interestingly, nucleic acid exposure at the apoptotic cell surface was observed. DNAse/RNAse treated camptothecin-induced apoptotic Jurkat cells displayed markedly reduced levels of PI staining (NA exposure) at the cell membrane, and the removal of NA was also shown to affect the activation of the classical pathway on apoptotic cells with reduced Clq binding and C3 levels at the cell surface. Therefore a possible central role for Clq in the early detection of membrane bound NA on apoptotic cells could be proposed.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303170898
Funders:	Medical Research Council
Date of First Compliant Deposit:	30 March 2016
Last Modified:	31 Jan 2020 06:29
URI:	https://orca.cardiff.ac.uk/id/eprint/55609

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