Complement components CR2, factor H and I : genetic polymorphism and immunoregulatory function

Zhou, Ming (1993) Complement components CR2, factor H and I : genetic polymorphism and immunoregulatory function. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

The Regulators of Complement Activation gene cluster on chromosome 1 includes genes for regulatory proteins which interact with complement component C3. The general aim of this project was to explore genetic variation and/or immunological function of certain of these proteins. -- One specific aim was to assess factor H, factor I and complement receptor 2 (CR2) genetic polymorphisms. An immunodetection system was developed to identify factor H variants separated by isoelectric focusing. The method is economical and suitable for population surveys. Allele frequencies estimated from 129 serum samples are FH*1 0.597 and FH*2 0.403. No association was observed between factor H types and rheumatoid arthritis. A new variant, IF*B1, was found when 288 Caucasians were typed for Factor I, The results from this survey also indicated that IF*A is present at a much lower frequency in Caucasians than in Asiatics. SDS-PACE followed by immunoblotting was used to define a new, 75 kDa variant (CR2 L) of CR2 (CR2 H). Six CR2 L heterozygotes and one homozygote were observed in 63 unrelated samples and segregation of CR2 L was demonstrated by a family study. Flow cytometry analysis of the binding of EBV and various anti-CR2 monoclonal antibodies to a CR2 L homozygous cell line did not clarify the molecular basis for the reduced size of CR2 L. -- A second specific objective was to explore in vivo, using a mouse model, the regulatory role of CR2 in the immune response. Pretreatment with anti-CR2 significantly depressed the primary response (mainly IgM) to a T-dependent antigen and impaired the generation of immunological memory, but did not eradicate an already established immunological memory. The suppressive effect was different from that initiated by cobra venom factor pretreatment (C3 depletion) where only the primary igG response was affected. Antigen complexed with anti-CR2 is physiologically analogous to C3d-Ag-Ab. Ag-anti-CR2 complexes evoked an in vivo secondary response at a 100-fold lower Ag dose than Ag alone. Taken together, these results suggest, but do not prove, that (i) when stimulated by a single signal from CR2, B cells can become anergic and (ii) CR2 can enhance the secondary response either by signaling via CR2 complexed to IgM or CD19, or by localizing Ag-Ab complexes on follicular dendritic cells. -- KEY WORDS: Factor H Factor I CR2 Polymorphism Immune response

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