Complement factor H and the hemolytic uremic syndrome

Abstract

Immune recognition is coupled to powerful proinflammatory effector pathways that must be tightly regulated. The ancient alternative pathway of complement activation is one such proinflammatory pathway. Genetic susceptibility factors have been identified in both regulators and activating components of the alternative pathway that are associated with thrombotic microangiopathies, glomerulonephritides, and chronic conditions featuring debris deposition. These observations indicate that excessive alternative pathway activation promotes thrombosis in the microvasculature and tissue damage during debris accumulation. Intriguingly, distinct genetic changes in factor H (FH), a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (dense deposit disease), or age-related macular degeneration (AMD). A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders.

Figure 1.

Activation and inactivation of the alternative complement pathway. (A) C3b binds FB, which is then converted to Bb, by the serine protease factor D (not depicted). The resulting C3bBb is the alternative pathway C3 convertase that cleaves additional C3 to C3b, thus amplifying the process. Properdin stabilizes this convertase (not depicted). (B) This process is controlled by regulatory proteins such as FH. It decays Bb from C3b and is a cofactor for degradation of C3b to iC3b by the serine protease FI. FH attaches to surfaces through its heparin/anionic-binding sites in its carboxyl-terminus (CCPs 16–20) while the decay-accelerating activity and cofactor activity sites are at the amino terminus (CCPs 1–4).