complement activation

Definition

Target type: biologicalprocess

Any process involved in the activation of any of the steps of the complement cascade, which allows for the direct killing of microbes, the disposal of immune complexes, and the regulation of other immune processes; the initial steps of complement activation involve one of three pathways, the classical pathway, the alternative pathway, and the lectin pathway, all of which lead to the terminal complement pathway. [GO_REF:0000022, GOC:add, ISBN:0781735149]

Complement activation is a cascade of biochemical reactions involving serum proteins that plays a critical role in innate immunity. It involves a complex interplay of complement proteins, which are synthesized mainly by hepatocytes and macrophages, and are found in inactive form in the blood. The complement system is initiated in response to the presence of pathogens, such as bacteria, viruses, fungi, or parasites, or by certain immune complexes. This activation can occur via three distinct pathways:

**1. Classical pathway:** Initiated by antigen-antibody complexes, particularly IgM or IgG antibodies bound to the surface of pathogens. C1q, the first protein in this pathway, binds to the Fc portion of these antibodies, triggering a conformational change that activates C1r and C1s. Activated C1s cleaves C4 and C2, generating the C4b2a complex, also known as C3 convertase.

**2. Lectin pathway:** Triggered by the binding of mannose-binding lectin (MBL) to mannose residues on the surface of pathogens. MBL associates with MBL-associated serine proteases (MASPs), such as MASP-2, which cleave C4 and C2, similar to the classical pathway, leading to the formation of the C3 convertase (C4b2a).

**3. Alternative pathway:** Activated spontaneously on pathogen surfaces, particularly those lacking sialic acid. It bypasses C1, C4, and C2. The initial step involves the spontaneous hydrolysis of C3 to C3(H2O), which can bind to factor B. This complex is stabilized by factor D, which cleaves factor B, generating Bb. The C3(H2O)Bb complex, also known as the C3 convertase, can then cleave more C3 molecules.

**The C3 convertase, regardless of the initiating pathway, plays a crucial role in complement activation by cleaving C3 into C3a and C3b. C3a is a potent anaphylatoxin, leading to the release of histamine and other inflammatory mediators. C3b, on the other hand, binds to the pathogen surface, serving as an opsonin to enhance phagocytosis by macrophages and neutrophils.**

**C3b can also bind to the C3 convertase to form the C5 convertase (C4b2a3b or C3bBb3b), which cleaves C5 into C5a and C5b.**

**C5a is another potent anaphylatoxin, while C5b initiates the formation of the membrane attack complex (MAC). C5b associates with C6, C7, C8, and multiple C9 molecules to create a pore in the pathogen's membrane, leading to cell lysis and death.**

**Overall, the complement system orchestrates a robust immune response through opsonization, chemotaxis, inflammation, and direct pathogen lysis. Its dysregulation can contribute to autoimmune diseases and inflammatory disorders.**
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Proteins (4)

Compounds (3)