Complotype affects the extent of down-regulation by Factor I of the C3b feedback cycle in vitro.

Abstract

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.

• Authors: E Lay, S Nutland, J E Smith, I Hiles, R A G Smith, D J Seilly, A Buchberger, W Schwaeble, P J Lachmann
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 181 Issue 2 Pg. 314-22 (Aug 2015) ISSN: 1365-2249 [Electronic] England
• PMID: 25124117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 British Society for Immunology.

Chemical References

• Peptide Fragments
• complement C3d,g
• Complement C3b
• Complement Factor H
• Fibrinogen
• Zymosan

Topics

• Alleles
• Complement C3b (genetics, immunology)
• Complement Factor H (genetics, immunology)
• Complement Pathway, Alternative (drug effects)
• Feedback, Physiological
• Fibrinogen (immunology, pharmacology)
• Gene Expression Regulation (immunology)
• Genotype
• Heterozygote
• Homozygote
• Humans
• Peptide Fragments (genetics, immunology)
• Polymorphism, Single Nucleotide
• Zymosan (pharmacology)