The complement system is a group of plasma proteins and cell surface receptors that collaborate to defend the host by tagging and destroying microbes, forming part of the innate immune response.
Explanation
The complement system consists of more than 30 soluble and membrane-bound proteins that interact in a cascade to detect and eliminate pathogens. Discovered in the late nineteenth century, these proteins “complement” the action of antibodies and phagocytes by enhancing opsonization, inflammation and direct lysis. Complement activation can be initiated by three main pathways: the classical pathway, triggered by antibody–antigen complexes; the lectin pathway, activated by pattern-recognition molecules such as mannose-binding lectin binding to microbial carbohydrates; and the alternative pathway, which is continuously active at a low level and amplifies on pathogen surfaces.
All pathways converge on the cleavage of complement component C3 into C3a and C3b by C3 convertases. C3b covalently binds to microbial surfaces, marking them for recognition by phagocytes through complement receptors and promoting removal. Fragments C3a and C5a act as anaphylatoxins, inducing chemotaxis and inflammation by recruiting neutrophils and other immune cells. Subsequent steps lead to formation of the membrane attack complex (C5b-9), a ring-like structure that inserts into the lipid bilayers of bacteria and enveloped viruses, creating pores that disrupt membrane integrity and cause lysis. The complement system is tightly regulated by inhibitory proteins such as Factor H, decay-accelerating factor and CD59 to prevent host cell damage. Deficiencies or dysregulation of complement components can lead to increased susceptibility to infections, autoimmune diseases or inflammatory disorders. Thus, the complement system plays a central role in bridging innate and adaptive immunity and maintaining tissue homeostasis.
Activation Pathways and Roles
In the classical pathway, complement component C1q binds to antibodies bound to bacterial capsules or viral envelopes. This activates the proteases C1r and C1s, leading to cleavage of C4 and C2 and formation of C4b2a, a C3 convertase. In the lectin pathway, mannose-binding lectin or ficolins recognize microbial polysaccharides and activate MASP proteases to generate the same C3 convertase. The alternative pathway relies on spontaneous hydrolysis of C3 to C3(H2O), which associates with Factor B and Factor D to form C3bBb, an alternative C3 convertase that is stabilized on pathogen surfaces by properdin.
C3b deposition promotes phagocytosis by macrophages and neutrophils and facilitates clearance of immune complexes. The small fragments C3a and C5a induce degranulation of mast cells, increased vascular permeability, and leukocyte recruitment. The membrane attack complex targets Gram-negative bacteria and some parasites by forming transmembrane pores. Clinically, complement activation contributes to inflammation in autoimmune conditions and ischemia–reperfusion injury. Therapeutic modulation of the complement system, such as C5 inhibitors for paroxysmal nocturnal hemoglobinuria, demonstrates its relevance in medicine.
The complement system represents a coordinated network of proteins that detect and eliminate pathogens through opsonization, inflammation and direct lysis. Its multiple activation pathways ensure rapid response to diverse threats, while regulatory mechanisms maintain self‑tolerance. Understanding complement function and regulation is vital for appreciating innate immunity and for developing treatments for complement‑mediated diseases.
Related Terms: Innate immunity, C3 convertase, Membrane attack complex, Opsonization, Anaphylatoxin