Type
Text
Type
Dissertation
Advisor
Kenneth Marcu | Ghebrehiwet, Berhane | Patrick Hearing | Richard Kew | Gerald Thomsen | Wenchao Song
Date
2010-08-01
Keywords
autoimmunity, C1q, Dendritic cells, immunology, systemic lupus | Health Sciences, Immunology
Department
Department of Genetics
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/72539
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Growing evidence shows that the first component of complement, C1q, regulates the growth and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because C1q regulates both innate and acquired immune responses, we postulated that C1q modulates the monocyte-DC transition at the earliest stages, i.e. at the interface between innate and acquired immunity. Our results corroborate this hypothesis and show that C1q modulates GM-CSF+IL4 induced DC differentiation, as evidenced by retention of CD14 and reduced expression of DC maturation markers and co-stimulatory molecules. C1q induced the development of at least two immature DC (iDC) subsets (CD14hiCD11chiCD16+/-). Moreover, C1q treatment resulted in significantly increased secretion of IFN-γ and MIP-1α after 24 hours, while the number of cells producing these cytokines did not notably change. C1q treatment significantly enhanced the phagocytic uptake capacity of iDCs on day 3, while it did not change their allogeneic immunostimulatory capacity. Taken together, these data suggest that in the absence of danger signals C1q may help maintain steady state conditions by skewing DC differentiation toward cells with monocyte-macrophage-like characteristics. Further results revealed that freshly isolated peripheral blood monocytes carry C1q on their surface even at day 0, when they have not been exposed to DC growth factors. The binding pattern of a monoclonal antibody specific to the globular heads of C1q (gC1q) indicated that C1q is bound to monocytes and iDCs via its globular heads, presumably through gC1qR, the receptor for the globular heads of C1q. Culturing monocyte-DCs in the presence of a monoclonal antibody recognizing the C1q binding site on gC1qR resulted in the development of cells similar to those with C1q treatment, further indicating that C1q/gC1qR interaction is a requisite of early C1q signaling on these cells. Since C1q is synthesized and secreted predominantly by macrophages and DCs, we predict that a C1q-rich environment allows for specific C1q/C1q receptor interactions that may control the transition from the monocyte state (innate immunity) toward the professional antigen presenting cell state (adaptive immunity).
Recommended Citation
Hosszu, Kinga, "The Role of C1q in Regulation of Monocyte to Dendritic Cell Differentiation: Implications in Autoimmunity" (2010). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 1743.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/1743