Complement System The complement system is a complex group of serum proteins important for both intrinsic and adaptive immunity. Complement is present in the serum and is normally inactive. Protein hydrolysis activates complement, which mediates a range of immune-related responses, including: 1) disruption of cell membranes at the site of complement protein attachment; 2) production of inflammatory mediators to attract inflammatory cells (neutrophils and macrophages) to the site of infection or tissue breakdown; and 3) enhancement of phagocytic efficiency by conditioners to aid in the clearance of foreign pathogens. The complement system can be activated by three different mechanisms of activation pathways, all of which include the process of cell surface recognition of foreign agents. The two activation pathways most relevant to intrinsic immunity are the specific binding processes of mannose binders (MBL) or serum protein factor B to the bacterial cell surface through the recognition of abnormal carbohydrates present only on the bacterial surface. Once MBL is bound, other serum complement proteins (C2 and C4) are attracted and activated by protein hydrolysis and then interact with complement C3 to form an enzyme complex, which causes deposition of the terminal elements of this system (C5-C9) in the cell membrane and the formation of a membrane attack complex (MAC). This MAC causes lysis of the target cell by inserting into the lipid bilayer of the cytosol and lysing the cytosol to form small pores that allow water to flow through the cytosol. Protein factor B deposition on the cell surface similarly leads to MAC formation via a different pathway that does not include the involvement of complement proteins C4 and C2. Binding of protein factor B to other serum factors (D, H, P) causes activation of C3, deposition of C5-C9, and MAC formation. This pathway of activation of the complement system via protein factor B is called the bypass pathway of complement activation. Specific binding of antibodies to the cell surface also activates complement, and because this pathway was first identified, it is referred to as the classical pathway. The classical pathway is activated when antibodies IgG and IgM bind to antigenic immune complexes. This process often occurs on the surface of foreign cells and leads to the binding of complement C1 in the unique classical pathway. Complement C1 is structurally similar to MBL and both cause the activation of C2 and C4, thus leading finally to the formation of MAC as described above. The classical pathway is a major effector mechanism of antibody-mediated immune responses due to its ability to cause disintegration of antibody-encapsulated microorganisms and attract inflammatory cells to accumulate at the site of inflammation. The process leading to MAC formation involves a series of protein hydrolysis steps that can generate protein fragments with potent immune effects. Protein fragments C5a and C3a are allergenic toxins that induce the release of histamine and other vasoactive inflammatory mediators secreted by mast cells. Moreover, C5a attracts and activates neutrophils. C3b binds to the surface of microorganisms and then binds to receptors on macrophages and neutrophils to produce phagocytosis. The complement system, by enhancing the function of phagocytes, also promotes the clearance of immune complexes. Activation of the complement system plays an important role in the body’s resistance to infection. The complement system also plays a role in the development of many rheumatic diseases. For example, more than 50% of patients lacking complement proteins C2 and C4 suffer from systemic lupus erythematosus (SLE). Moreover, complement levels are decreased in the sera of patients with persistent immune activation or suffering from inflammation. C3 and C4 serum levels are often correlated with disease activity in SLE patients, and decreased serum levels indicate that immune complexes are activated and depleted of complement proteins.