Self, non-self, and danger: a complementary view

Complement is a sophisticated system of molecules that is critical to the functional integrity of the body. Initially considered as a defense system to ward off infections, it becomes increasingly clear that the complement system is one of the most important humoral systems to sense danger, i.e., to recognize conserved patterns on pathogens and on altered/damaged self. In addition to this important role in danger recognition, the complement system has the ability to translate the danger information into an adequate cellular innate or adaptive immune response. This is accomplished by two distinct mechanisms: (a) danger sensors that have recognized altered cells or pathogens can directly activate cell-bound receptors (e.g., C1q/C1q receptor interaction), and/or (b) danger sensors initiate cleavage of complement factors C3 and C5, the fragments of which acquire the ability to bind to complement receptors and/or regulators. It is the specific interaction of the danger sensors and of the cleavage fragments with distinct cell-bound receptors/regulators that directs the immune response toward an innate or an adaptive phenotype. Further, the expression pattern of the complement receptors critically impacts the shape of the immune response. Complement has the ability to discriminate between physiological and pathological danger, i.e., physiological cell death and death in response to injury. In the former case, cells are merely flagged for enhanced phagocytosis (by C3 fragments) without accompanying inflammation (through CR3), whereas in the latter case inflammatory signals are accessorily triggered (e.g., by the release of ATs, which recruit and activate neutrophils, eosinophils, etc.). This function is of major importance for apoptotic cell clearance and tissue repair but plays also important roles in fibrotic tissue remodeling in response to chronic tissue injury. Further, complement cleavage fragments may prevent the development of maldaptive immune responses at the mucosal surface. Here, complement fragment C5a does not act as a danger transmitter but as a "homeostasis transmitter," as its interaction with the C5a receptor on DCs provides a signal that prevents DCs from activating CD4+ T cells. The generation of regulatory T cells in response to CD46 ligation may have a similar function, as injured cells lose CD46 expresssion, which may lead to decreased proliferation of Tregs and, consecutively, increased production of T effector cells. Although we are still at the beginning of understanding the complex interaction patterns within the complement system, recent data suggest substantial crosstalk between the signaling pathways downstream of complement receptors and other receptors of the innate immune system that function as immune sensors and/or transmitters (i.e., TLRs, FcgammaRs130,131). Given the importance of complement as a sensor and effector system of innate and adaptive immune responses, a complement-related view of the immune system might help to unravel some enigmas of autoimmunity, allergy, and transplantation.