Complement Regulators: Complement Factor H

Complement Regulator of Complement System: Complement Component Factor H Background

An analogue of C4bp in the alternative pathway is factor H (β1H-globulin). It is a fluid-phase inhibitor of the alternative pathway C3 convertase enzyme C3bBb. As such, factor H is a key regulator since in its absence the alternative pathway will deplete itself almost completely. Factor H is composed of 20 tandemly arranged SCR units. The factor H gene is close to the genes for other complement regulators containing SCR units. Collectively, the genes of complement regulators constitute the regulators of complement activation (RCA) gene cluster on the long arm of chromosome 1.

The principal functional domain and one binding site on complement factor H for C3b has been located to the N-terminal SCRs. In addition,two other sites for C3b have been detected in the central and the C-terminal (SCR) parts of H. Upon binding to C3b factor H competes with factor B for binding to C3b. Complement factor H also displaces Bb from the C3bBb convertase (decay-accelerating activity). The third mechanism whereby factor H inhibits the alternative pathway C3 convertase is to act as a cofactor for factor I in the cleavage of C3b to iC3b. Together, these activities efficiently keep the alternative pathway under control. Fluid-phase C3b molecules are rapidly inactivated. On surfaces, factor H appears to be capable of discriminating between activator- and nonactivator-bound C3b molecules. 'Activators' include microbes and other foreign substances that are in particulate form. ‘Nonactivators’ include host cells and other structures that carry polyanionic substances, like sialic acid or glycosaminoglycans, on their surfaces. The high affinity of factor H for nonactivator-bound C3b seems to be due to a joint recognition of both C3b and surface structures. At least two binding sites for polyanionic substances exist on factor H.

Various microbes have capsules (group B streptococcus, Escherichia coli capsule type K1 and group B meningococcus) or lipo-oligosaccharides (Neisseria gonorrhoeae) rich in sialic acid. Sialic acid appears to help bacteria in escaping alternative pathway activation, opsonization by C3b and phagocytosis. Group A streptococcus has M protein on its surface. Direct binding of factor H to the N-terminal hypervariable region of M protein also seems to block alternative pathway activation and prevent phagocytosis of group A streptococcus.

In addition to factor H, human plasma has proteins that have antigenic similarity to complement factor H. Factor H-like protein (FHL-1) is an alternatively spliced product of the CFH gene that contains the seven most N-terminal SCR fragments of factor H. As such, it is equipped with most of the regulatory activity of H. The other factor H related proteins (FHR-1) in human plasma are encoded by separate genes. The products of these genes have either four or five SCR units. The FHR proteins bind to C3b but have only a weak complement regulatory activity.

Complement Regulator of Complement System: Complement Component Factor H Reference

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