Abstract
Clustering of Complement Receptor 1 (CR1) in the erythrocyte membrane is important for immune-complex transfer and clearance. CR1 contains the Knops blood group antigens, including the antithetical pairs Swain-Langley 1 and 2 (Sl1 and Sl2) and McCoy a and b (McCa and McCb), whose functional effects are unknown. We tested the hypothesis that the Sl and McC polymorphisms might influence CR1 clustering on erythrocyte membranes. Blood samples from 125 healthy Kenyan children were analysed by immunofluorescence and confocal microscopy to determine CR1 cluster number and volume. In agreement with previous reports, CR1 cluster number and volume were positively associated with CR1 copy number (mean number of CR1 molecules per erythrocyte). Individuals with the McCb/McCb genotype had more clusters per cell than McCa/McCa individuals. However, this association was lost when the strong effect of CR1 copy number was included in the model. No association was observed between Sl genotype, sickle cell genotype, α+thalassaemia genotype, gender or age and CR1 cluster number or volume. Therefore, after correction for CR1 copy number, the Sl and McCoy polymorphisms did not influence erythrocyte CR1 clustering, and the effects of the Knops polymorphisms on CR1 function remains unknown.
Highlights
Complement Receptor 1 (CR1) is a key regulator of complement cascade activation, namely through accelerating the decay of C3 and C5 convertases reducing production of anaphylotoxins C3a and C5a9, and acting as a cofactor with Factor I to inactivate C3b and C4b to iC3b and iC4b10
The strength of association between CR1 copy number and cluster number was such that the inclusion of CR1 copy number in the statistical model obscured any other associations
On review of individual explanatory variables, the McCb/McCb genotype was associated with significantly higher cluster number than the McCa/McCa genotype
Summary
CR1 is a key regulator of complement cascade activation, namely through accelerating the decay of C3 and C5 convertases reducing production of anaphylotoxins C3a and C5a9, and acting as a cofactor with Factor I to inactivate C3b and C4b to iC3b and iC4b10 These functions map to specific sites within the CR1 molecule, with site 1 (SCRs 1–3 in LHR-A) displaying high decay accelerating activity[11] and binding C4b12,13, and site 2 (SCRs. 8–10 in LHR B and SCRs 15–17 in LHR C) being responsible for cofactor activity with Factor I and the binding of C3b and C4b (Fig. 1)[12,13]. A marked geographical difference is seen in the frequency of Sl2 and McCb alleles, with the alleles being common in African populations and rare in Caucasians[18] This has led to the suggestion that these polymorphisms arose due to selection pressure from malaria[19], studies to date have been conflicting. Studies from The Gambia and Ghana did not find significant associations between the polymorphisms and severe malaria[21,22]
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