title: Further studies of the down-regulation by Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells as a source of CR1 on sera of different complotype.
abstract: In this paper we have extended our earlier studies of the action of increasing Factor I concentration on complement activation by using a soluble activator, lipopolysaccharide (LPS) endotoxin, and using human erythrocytes as a source of CR1 - the co-factor needed for the final clip of iC3b to C3dg by Factor I. Using this more physiological system, the results show that we can predict that a quite modest increase in Factor I concentration - 22 µg/ml of extra Factor I - will convert the activity of the highest risk sera to those of the lowest risk. Preliminary experiments have been performed with erythrocytes allotyped for CR1 number. While we have not been able to perform an adequate study of their co-factor activities in our assays, preliminary experiments suggest that when Factor I levels are increased the difference produced by different allotypes of red cells is largely overcome. This suggests that in patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with eculizumab, additional treatment with Factor I may be very useful in reducing the need for blood transfusion. We have also explored the age-related allele frequency for the two polymorphisms of Factor H and the polymorphism of C3. In our population, unlike the 1975 study, we found no age variation in the allele frequency in these polymorphisms. This may, however, reflect that the Cambridge BioResource volunteers do not include many very young or very elderly patients, and in general comprise a population not greatly at risk of death from infectious disease.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lachmann
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Lay
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Seilly
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Buchberger
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Schwaeble
authors.affiliation: Cambridge BioResource, Cambridge University and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Khadake
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D003179:Complement C3b / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics*; D017244:Complement Factor I / Q000032:analysis / Q000276:immunology*; D015536:Down-Regulation; D004912:Erythrocytes / Q000276:immunology*; D005787:Gene Frequency; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood* / Q000628:therapy; D006801:Humans; D007106:Immune Sera / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017463:Receptors, Complement 3b / Q000276:immunology*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C509991:CR1 protein, human; D007106:Immune Sera; D008070:Lipopolysaccharides; D017463:Receptors, Complement 3b; D003179:Complement C3b; D017242:Complement Factor H; C481642:eculizumab; D017244:Complement Factor I
keywords: C3b feedback cycle; CR1; Factor I; serum complotypes