Interaction of Clq on Phagocytic Cells

描述(由申请人提供)：补体成分C1q是防御性胶原蛋白家族的成员，已被证明能增强病原体、细胞碎片和凋亡细胞的吞噬作用。吞噬作用在杀死和清除感染性病原体的同时，也是抗原处理和呈递的第一步，这是诱导适应性反应所必需的。现在人们认识到，先天免疫系统的模式识别分子在决定随后的适应性反应的性质方面具有重大影响。正如TLRs影响病原体应答的效应器功能和基因表达谱一样，越来越明显的是，包括特定补体成分在内的其他识别分子不仅在免疫应答的效应器阶段发挥作用，而且还充当有助于随后免疫应答编程的“生物传感器”。因此，这种第一反应评估入侵或伤害的“危险”程度，并启动适当的保护计划(当挑战是病原体时)和/或抑制有害反应(以避免自身免疫反应和/或组织破坏性炎症水平)。我们的初步结果表明，在特定条件下，C1q在促进吞噬的同时，可以抑制特定的促炎细胞因子的产生。我们在这里提出的假设是，特定的基因表达模式是通过C1q和其他防御性胶原蛋白连接细胞而激活的，并且这些模式被吞噬细胞的分化状态和细胞接收的其他同时信号所改变。我们建议表征导致特定细胞因子基因表达的信号通路和参数。以C1q/MBL和将信号传递到细胞的细胞表面分子/复合体为例的这些“生物传感器”的治疗性靶向，应该有助于对病原体做出更有效的保护性反应(包括生物防御策略)，开发更有效和保护性的疫苗策略，并抑制自身免疫。

DESCRIPTION (provided by applicant): 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.