Alternative complement pathway

    The alternative pathway of the complement system is a humoral component of the immune system's natural defence against infections which can operate without antibody participation.

The alternative pathway is one of three complement pathways that opsonizes and kills pathogens. The alternative pathway does not require a specific antibody to commence.

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Cascade

It is initiated by the spontaneous hydrolysis of C3, which is abundant in the plasma in the blood. "Tickover" occurs through the spontaneous cleavage of the thioester bond in C3 to form C3(H₂O).

This change in shape allows the binding of plasma protein Factor B which allows Factor D to cleave Factor B into Ba and Bb.

Bb remains part of the C3(H₂O) to form C3(H₂O)Bb, this complex is also known as a fluid-phase C3 convertase. This convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b.

The alternative pathway C3-convertase consists of the activated B and D factors, forming an unstable compound that can become stable after binding properdin, a serum protein.

After the creation of C3 convertase, the complement system follows the same path regardless of the means of activation (alternative, classical, or MBL). Binding of another C3b-fragment to the C3-convertase of the alternative pathway creates a C5-convertase analoguous to the MBL or classical pathway.

The C5-convertase of the alternative pathway consists of C3bBbC3b also referred to as C3b2Bb (instead of C4b2a3b in the other pathways)

Regulation

Since C3b is free and abundant in the plasma, it can bind to either a host cell or pathogen surface. To prevent complement activation from proceeding on the host cell, there are several different kinds of regulatory proteins that disrupt the complement activation process:

• Complement Receptor 1 (CR1 or CD35) and DAF (decay accelerating factor also known as CD55) compete with Factor B in binding with C3b on the cell surface and can even remove Bb from an already formed C3bBb complex
• The formation of a C3 convertase can also be prevented when a plasma protease called Factor I cleaves C3b into its inactive form, iC3b. Factor I works with C3b-biding proteins cofactors such as CR1 and Membrane Cofactor of Proteolysis (MCP or CD46)
• Another complement regulatory protein is Factor H which either competes with factor B, displaces Bb from the convertase, acts as a cofactor for Factor I, or preferentially binds to C3b bound to vertebrate cells (because of affinity to sialic acid residues)

See also

• Classical complement pathway
• Mannan-binding lectin pathway

Further reading

• Immunobiology. Janeway, et al. 5th 3ed. ISBN 0-8153-4101-6. (5th ed. text online at [1].)
• BioCarta's diagram of the alternative pathway, [2]