The complement system is an evolutionarily conserved component of innate immunity that serves as a first line of defense against infection by lysing infected cells and opsonizing pathogens for their removal by phagocytes. There are three major pathways of complement activation that are triggered independently, including the classical, the lectin, and the alternative pathways, all of which merge at the step of C3 activation. These pathways function as cascades of proteases that activate each other in an enzymatic fashion to lyse infected cells.
Although most complement is produced by the liver to act systemically, complement may act locally within cells or in tissues. Complement components also are produced in a broad range of immune and other cell types, such as endothelial cells. In addition to functioning in the above-mentioned enzymatic cascades, individual complement components have been shown to play other critical roles in immune responses. Examples of non-canonical roles of complement include: C3 can serve as a damage-associated molecular pattern (DAMP) that enhances intracellular innate immunity and also acts as a controller of T lymphocyte survival; autocrine activation of complement regulator CD46 plays a key role in nutrient uptake and enhances cellular metabolism essential for Th1 responses; intracellular C5 activation was reported to be essential for NLRP3 inflammasome assembly in CD4+T cells; signaling through C5aR1 located on mitochondria is involved in the development of reactive oxygen species (ROS); C1q has been reported to enhance phagocytosis and efferocytosis in human monocytes and suppress inflammatory responses; C1qR is reported to be located in mitochondria where it is involved in mitochondrial biogenesis, can influence mitochondrial metabolism of CD8 T cells, and plays a pivotal role in regulating effector CD8 T cell responses in autoimmunity and viral infection. There are additional reports of interaction between individual complement components and innate signaling pathways, including Toll-Like Receptors.
While serving to protect against infection either directly or indirectly by influencing innate and adaptive immunity, dysregulation of complement can have deleterious effects. Pathogens induce local and systemic complement activation and inflammatory responses early during infection, which typically resolve. However, over activation or dysregulation of the complement cascade can cause collateral damage of cells and tissues, as illustrated by severe COVID-19 disease where over activation of the complement system appears to induce endothelial cell injury and death, leading to initiation of clotting cascades. These complications can lead to life-threatening illness and multi-organ failure.
The mechanisms by which complement components, receptors and pathways contribute to protective immune responses or pathogenesis remain to be fully elucidated. A better understanding of complement mechanism of action is critical for harnessing its positive effects in the development of adjuvants and vaccines, and for targeting it with therapeutics to reign in dysregulated complement responses.
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