Complement is one of the first lines of defence in innate immunity and is important for cellular integrity, tissue homeostasis and modifying the adaptive immune response. The activated complement system recognizes and eliminates invading microorganisms and thus is beneficial for the host. In addition, complement facilitates the elimination of dead or modified self cells, such as apoptotic particles and cellular debris. The alternative pathway of complement forms a spontaneously and constantly activated immune surveillance system. The individual complement reactions develop in a sequential manner, allowing regulation that modulates the intensity of the response and adjusts the effector functions for the specific immune response.
Complement was identified more than 100 years ago as a result of its 'complementary' bactericidal activity and its role in phagocytosis of cellular debris. The activated complement system directs immune effector functions and modulates the intensity of the response in a self-controlling manner. This allows for the appropriate innate immune response, which is needed for recognition and removal of infectious agents or modified self cells. Now, 110 years after these initial reports, the central role of this system in immune defence is much better known: many of the biological effects of complement action are understood in molecular terms and a role for complement in tissue homeostasis is emerging. Complement activation in turn activates pro-inflammatory mediators, generates anaphylactic peptides, cytolytic compounds and antimicrobial compounds, recruits effector cells and induces effector responses. These result in a moderate and controlled outcome of complement activation, which is beneficial for the host but detrimental for the invading microorganism.
The beneficial aspects of a moderately activated complement system include immune surveillance, removal of cellular debris, organ regeneration and neuroprotection. The two anaphylatoxins complement component 3a (C3a) and C5a have a role during organ regeneration, in neuroprotection - including in migration of neurons and synapse elimination - and in the release of progenitor haematopoietic stem cells. In addition, crosstalk and cooperative effects between C3a receptor (C3aR), C5aR, C5a receptor-like 2 (C5L2) and Toll-like receptors have been reported. These additional physiological functions highlight the role of complement in physiology and homeostasis and demonstrate that appropriate regulation and balanced or targeted activation are crucial to keep the complement system in its proper physiological state.
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