aHUS is a thrombotic microangiopathy caused by mutations of factor H, factor I, factor B, membrane cofactor protein, C3 convertase
component, and thrombomodulin gene.
In the alternative complement pathway, C3b reacts with the proteins factor B, adipsin, and properdin to compose C3 convertase
. C3 convertase
cleaves C3 into C3a and C3b.
All three pathways converge in the assembly of a C3 convertase
, which are enzyme complexes that consist of C4b2a and C3bBb (C4b2a for the classical and lectin pathways and C3bBb for the alternative pathway).
Hyperactivation of the alternative pathway of complement as seen in C3GN and DDD can be associated with the presence of C3 nephritic factors (C3Nefs), which stabilize C3 convertase
or its components against complement factor H- (CFH-) mediated decay, thus leading to prolonged and dysregulated activation of the complement system.
Under normal physiological conditions, C3 interacts with factor B and factor D to produce a very small amount of C3b and C3bBb (i.e., the C3 convertase
in the alternative pathway).
With respect to pathophysiology of paraproteinemia-associated C3GP and DDD, it has been suspected but not proved that the paraprotein is functioning as an autoantibody that stabilizes C3 convertase
(C3 nephritic factor) or possibly inhibits one of the CRPs, such as Factor H or I [9,10].
Complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP or CD46) and thrombomodulin (THBD) which are regulatory proteins of the alternative complement pathway and C3 and complement factor B (CFB) which are C3 convertase
proteins are involved in the pathogenesis of the disease (6).
Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase
proteins, C3 and factor B, in 2-10% and 1-4%.
It exerts inhibitory function by enhancing the decay of classical/lectin pathway C3 convertase
, C4b2a , as well as the alternative pathway C3 convertase
, C3bBb .
When complement proteins are triggered into action by a microbe, the proteins ultimately form a complex enzyme called C3 convertase
, which triggers a cascade of immune and inflammatory reactions.
Opsonization with activated C3 fragments (C3b and iC3b) fulfils three major functions: (i) cell debris elimination by phagocytic cells (e.g., macrophages or microglia) and the stimulation of the adaptive immune system (B and T cells); (ii) amplification of complement activation via the formation of a surface-bound C3 convertase
; and (iii) assemblage of the C5 convertase.