Excessive activation of the complement system in atypical hemolytic uremic syndrome: is it ready for prime time?

Abstract

Complement factor I (CFI) mutations are implicated in the pathogenesis of atypical hemolytic uremic syndrome (aHUS). Nevertheless, there is evidence that CFI deficiency is a weak effector of aHUS. Bienaime et al. report that homozygous deletion of CFHR-1 in the RCA gene cluster of chromosome 1q is a major risk factor for poor outcome for patients with CFI mutations. The basic and clinical implications of the findings are further elaborated here.

Figure 1. Deficiency of complement factor H-related protein 1 aggravates the atypical hemolytic uremic syndrome in patients with complement factor I (CFI) mutations

This scheme depicts the roles of complement factor H (CFH), CFI, and CFH-related protein 1 (CFHR-1) in regulating the activation of the alternative complement pathway and the formation of the terminal complement complex C5b-9. Because activation of the alternative pathway is spontaneous, regulators are particularly critical for preventing its excessive activation. CFH, by binding to C3b, promotes the cleavage of the latter by CFI to iC3b. In addition, CFH also prevents the association of C3b with factor B, thereby preventing the formation of C3 convertase (C3bBb) and C5 convertase (C3bBbC3b). CFHR-1 binds to C5, inhibiting its activation by C5 convertase and the formation of the terminal complement complex (C5b-9). This scheme explains why, compared with CFH deficiency, CFI deficiency is a weak cause of atypical hemolytic uremic syndrome (aHUS). It also explains why CFHR-1 deficiency does not cause aHUS but markedly worsens aHUS in association with CFI deficiency. Other complement pathways, regulators, and receptors are not shown in this simplified scheme.