The complement component C1q is a member of the defense collagen family of proteins that have been shown to enhance phagocytosis of pathogens, cellular debris and apoptotic cells. Phagocytosis, while resulting in the killing and clearance of infectious agents, is also a first step in antigen processing and presentation necessary for the induction of an adaptive response. It is now being recognized that pattern recognition molecules of the innate immune system have significant influence in determining the nature of the subsequent adaptive response. Just as TLRs influence both effector function and gene expression profiles in response to pathogens, it is becoming increasingly evident that other recognition molecules, including specific complement components, not only play a role in the effector phase of the immune response, but also act as """"""""biosensors"""""""" contributing to the programming of a subsequent immune response. As such, this first response assesses the level of """"""""danger"""""""" of an intrusion or injury and initiates an appropriate program of protection (when the challenge is a pathogen) and/or suppression of detrimental responses (to avoid autoimmune responses and/or a tissue-damaging level of inflammation). Our preliminary results demonstrate that under specific conditions, C1q, while facilitating phagocytosis, can suppress specific proinflammatory cytokine production. We propose here to test the hypothesis that specific gene expression patterns are activated by ligation of the cell by C1q and other defense collagens, and that those patterns are modified by both the differentiation state of the phagocyte and the other simultaneous signals received by the cell. We propose to characterize the signaling pathways and parameters that lead to the specific cytokine gene expression. Therapeutic targeting of these """"""""biosensors"""""""", exemplified by C1q/MBL and the cell surface molecules/complexes that transfer the signals to the cell, should facilitate more effective protective responses to pathogens (including biodefense strategies), the development of more efficient and protective vaccine strategies, and suppression of autoimmunity. ? ? ? ?
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