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Title: Investigation of Complement Protein C1q - Implications for its protective roles against systemic lupus erythematosus
Keywords: C1q, dendritic cells, SLE, interferon-gamma, interferon-alpha, dectin-1
Issue Date: 31-Jul-2010
Citation: TEH BOON KING (2010-07-31). Investigation of Complement Protein C1q - Implications for its protective roles against systemic lupus erythematosus. ScholarBank@NUS Repository.
Abstract: C1q is an abundant plasma protein and is the first component of the complement classical pathway. It binds to antibody-opsonized microbial pathogens or certain pathogenic self antigens and initiates the activation of the complement classical pathway. It is also known to have diverse functions beyond providing immunity against pathogens, and is implicated in the pathogenesis of diseases such as transmissible spongiform encephalopathy, Alzheimer¿s disease and familial dementia. Conversely, hereditary C1q deficiency in human almost always leads to the autoimmune condition known as systemic lupus erythematosus (SLE), and lupus-like conditions also developed in C1q-/- mice. In addition, SLE itself causes consumption of C1q in patients who can produce C1q normally, and these patients also developed anti-C1q antibodies that can deplete bioavailable C1q. C1q is produced by dendritic cells (DCs) and macrophages, the two main types of antigen presentation cells, and DCs are particularly important in the maintenance of tolerance as well as induction of immunity. In view of the strong association of C1q and DCs with autoimmune SLE conditions, we investigated the regulation of C1q production in DCs. We have developed assays to quantitate cellular C1q mRNA, protein expression and also developed an ELISA assay for measuring secreted C1q in the DC culture. By ELISA, we screened a large number of stimuli for their ability to modulate C1q production in DCs. Marked downregulation of C1q production was observed by two stimuli, i.e. zymosan and interferon alpha (IFN-a). On the other hand, IFN-gamma was found to be a potent inducer of C1q production. In terms of the signaling mechanisms involved, we found that zymosan signals through the Dectin-1 receptor to mediate the downregulation of C1q production. It resulted in a thorough reduction in C1q mRNA, cellular protein and secreted protein. In contrast, IFN-a upregulated C1q mRNA and cellular protein levels, but it reduced the secretion of C1q by DCs after prolonged treatments. In this case, we found that C1q was mainly trapped in the endoplasmic reticulum with little being detected in the Golgi apparatus which explains the retarded secretion. C1q production by DCs raises the possibility of autocrine DC regulation by C1q. We then proceeded to study how C1q may influence DC development and found that C1q primed the development of DCs with tolerogenic properties. These C1q-conditioned DCs, which are expected in vivo, are better at clearing apoptotic cells, produce less inflammatory cytokines, and are less able to activate Th1 and Th17 cells. Higher ERK activity seems to contribute to these tolerance-related features of DCs differentiated with C1q. These properties suggest that the C1qDCs may raise the threshold of immune reactions or enhance tolerance, thus negating the development of SLE which inevitably involves the breakdown of self-tolerance.
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