Complotype affects the extent of down‐regulation by F actor I of the C 3b feedback cycle in vitro

Summary Sera from a large panel of normal subjects were typed for three common polymorphisms, one in C 3 ( R 102 G ) and two in F actor H ( V 62 I and Y 402 H ), that influence predisposition to age‐related macular degeneration and to some forms of kidney disease. Three groups of sera were tested; those that were homozygous for the three risk alleles; those that were heterozygous for all three; and those homozygous for the low‐risk alleles. These groups vary in their response to the addition of exogenous F actor I when the alternative complement pathway is activated by zymosan. Both the reduction in the maximum amount of i C 3b formed and the rate at which the i C 3b is converted to C 3dg are affected. For both reactions the at‐risk complotype requires higher doses of F actor I to produce similar down‐regulation. Because i C 3b reacting with the complement receptor CR 3 is a major mechanism by which complement activation gives rise to inflammation, the breakdown of i C 3b to C 3dg can be seen to have major significance for reducing complement‐induced inflammation. These findings demonstrate for the first time that sera from subjects with different complement alleles behave as predicted in an in‐vitro assay of the down‐regulation of the alternative complement pathway by increasing the concentration of F actor I . These results support the hypothesis that exogenous F actor I may be a valuable therapeutic aid for down‐regulating hyperactivity of the C 3b feedback cycle, thereby providing a treatment for age‐related macular degeneration and other inflammatory diseases of later life.