Sera from a large panel of normal subjects were typed for three common polymorphisms, one in C3 (R102G) and two in
Factor H (V62I and Y402H), 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
Factor I when the alternative complement pathway is activated by
zymosan. Both the reduction in the maximum amount of
iC3b formed and the rate at which the
iC3b is converted to
C3dg are affected. For both reactions the at-risk complotype requires higher doses of
Factor I to produce similar down-regulation. Because
iC3b reacting with the
complement receptor CR3 is a major mechanism by which complement activation gives rise to
inflammation, the breakdown of
iC3b to
C3dg 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
Factor I. These results support the hypothesis that exogenous
Factor I may be a valuable therapeutic aid for down-regulating hyperactivity of the C3b feedback cycle, thereby providing a treatment for
age-related macular degeneration and other inflammatory diseases of later life.