THE COMPLEMENT SYSTEM

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The complement system consists of plasma and cell surface proteins that can interact directly with a foreign antigen or antibodies to a foreign antigen. These proteins are produced by a variety of cell types and tissue including the liver and macrophages.

There are two pathways for complement activation: the classical pathway and the alternative pathway; the former activated via complement protein interaction with antibody, and the latter through direct complement protein interaction with cell membrane components of the foreign pathogen. Both pathways lead to the formation of a complex of proteins, the membrane attack complex (MAC), on the cell membrane of the foreign pathogen that results in the osmotic lysis of the cell. The MAC can also lyse enveloped viruses.

The effector functions of the complement system are involved in a humoral immune response and inflammation. They include:

1. direct lysis of a foreign pathogen via the MAC,
2. opsonization of the foreign pathogen and its' removal via phagocytosis. The complement component C1 can bind to the C2 region of the heavy chain on IgG and IgM generating other complement components that can bind receptors (CR1) on the phagocytocytic cells, neutrophils and macrophages,
3. enhancement of the inflammatory response. Other complement components, C3a, C4a, and C5a are called anaphylatoxins. They can bind receptors on polymorphonuclear granulocytes, macrophages, and endothelial cells stimulating the release of proteolytic enzymes, vasoreactive molecules, or the contraction of smooth muscle,
4. solubilization of immune complexes and there removal by erythrocytes. By binding to the Fc portion of antibody, complement interferes with the formation of polymeric immune complexes. The CR1 receptor on erythrocytes can bind the complement component, C3b, thus removing immune complexes from circulation.

The spontaneous activation of the complement cascade is regulated by molecules that either interfere with complement component interaction or deactivates them. These include: Factor 1, membrane cofactor protein (MCP: CD46), Factor H, decay-accelerating factor (DAF: CD55), and CD59.

The receptors for complement components (CR) are found on a variety of cell types. These include CR1 on erythrocytes (immune complex removal), macrophages/neutrophils (Fc receptor mediated phagocytosis), and dendritic cells (binding of immune complexes for antigen presentation; CR2 on B-cells (B-cell activation and receptor for Epstein-Barr virus), and dendritic cells; CR3 (Mac-1) on macrophages/neutrophils//NK cells (cell adhesion and chemotaxis); CR4 on neutrophils/macrophages/platelets; and, CR's for complement anaphylatoxins.