The alternative pathway is required, but not alone sufficient, for retinal pathology in XXXX laser-induced choroidal neovascularization.

@entity1 @entity29240 @entity13697 @entity19 @entity13785 @entity471 @entity39039 @entity1611 @entity2723 @entity130
@entity1 genetic studies have demonstrated that polymorphisms in different complement proteins can increase the risk for developing @entity13785 . There are three pathways of complement activation, classical ( @entity2723 ), alternative (AP), and lectin (LP), which all activate a final common pathway. Proteins encoded by the @entity13785 risk genes participate in the AP (CFB), @entity2723 /LP (C2), or in the AP and final common pathway (C3). Here we tested which pathway is essential in @entity19 laser-induced @entity471 . @entity471 was analyzed using single complement pathway knockouts (i.e., eliminating one complement pathway at a time), followed by a double knockout in which only the AP is present, and the @entity2723 and LP are disabled, using molecular, histological and electrophysiological outcomes. First, single-gene knockouts were analyzed and compared to wild type @entity19 ; @entity13697 (-/-) (no @entity2723 ), @entity39039 (-/-) (no LP), and CFB(-/-) (no AP). Six days after the laser-induced lesion, @entity19 without a functional AP had reduced @entity471 progression (P<0.001) and preserved ERG amplitudes, whereas those without a functional @entity2723 or LP were indistinguishable from the wild type controls (P>0.3). Second, AP-only @entity19 ( @entity13697 (-/-) @entity39039 (-/-)) were as protected from developing @entity471 as the CFB(-/-) @entity19 . The degree of pathology in each strain correlated with protein levels of the angiogenic and anti-angiogenic protein @entity1611 and @entity29240 , respectively, as well as levels of terminal pathway activation product C5a, and C9. The analysis of complement activation pathways in @entity19 laser-induced @entity471 allows for the following conclusions. Comparing the single pathway knockouts with those having only a functional AP showed: (1) that AP activation is necessary, but not alone sufficient for injury; and (2) that initial complement activation proceeds via both the LP and @entity2723 . Thus, these data indicate an important role for the AP in the generation of complement-dependent @entity130 of @entity2723 - and LP-initiated complement activation. Improving our understanding of the local regulation of this pathway in the eye is essential for developing improved treatment approaches for @entity13785 .
