The complement system is an evolutionarily conserved component of innate immunity that serves as a first line of defense against infection. Complement-associated molecules, known as C1 through C9, operate in a cascade of enzymatic reactions that can ultimately lead to lysis of infected cells and opsonization of pathogens to aid in phagocytic clearance. Three major pathways of complement activation have been described that are triggered independently, namely the classical, the lectin, and the alternative pathways, all of which merge at the step of C3 activation.
Although most complement is produced by the liver to act systemically, complement may act locally within cells or in tissues. Complement components can also be 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 acts as a controller of T lymphocyte survival; intracellular C5 activation appears to be essential for NLRP3 inflammasome assembly in CD4+T cells; and C1q has been reported to enhance phagocytosis and efferocytosis in human monocytes and suppress inflammatory responses. There are additional reports of interaction between individual complement components and innate signaling pathways, including Toll-Like Receptors.
While the protective benefits of complement have been, and continue to be, described, dysregulation of complement can have deleterious effects. Immune sensing of pathogens or foreign objects can induce local and systemic complement activation and subsequent inflammation at early timepoints during infection. These inflammatory responses typically resolve; however, over-activation or dysregulation of the complement cascade can cause collateral damage of cells and tissues. For example, complement dysregulation has been observed in severe COVID-19 disease where over-activation of the complement system induces 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’s role in fundamental immunology is critical for harnessing its positive effects and avoiding deleterious effects caused by dysregulation.