Concerted clearance of immune complexes bound to the human erythrocyte complement receptor: development of a heterologous mouse model.
Experiments in primates have demonstrated that immune complexes (IC) bound to erythrocytes (E) via complement receptor 1 (CR1) are cleared to the liver in a process which removes CR1, but otherwise spares the E. Human E are stabilized for >1 h in the circulation of the mouse if the terminal complement pathway is blocked, and we used this paradigm to examine clearance in a mouse model. Human E were opsonized with an anti-CR1 mAb cross-linked to dsDNA (antigen-based heteropolymer, AHP), and then incubated with systemic lupus erythematosus (SLE) plasmas containing IgG anti-dsDNA to form IC in situ. These IC stably bind to E CR1 in the complete absence of complement, thus allowing analysis in a model which does not require human C3b to facilitate E binding. Dual label experiments, based on RIA, flow cytometry and fluorescence microscopy, were employed to monitor separately E and IC. When opsonized E-IC were injected into A/J mice, >90% of the IC were rapidly removed from the E coincident with loss of CR1. The E remained in the circulation while IC were localized to the liver, mainly to Kupffer cells. Preliminary experiments in NZB/W mice, which spontaneously develop IgG anti-dsDNA, indicated that infusion of E-AHP led to rapid binding of murine IgG to the E-AHP, followed by removal of the nascent IC from E, and loss of CR1 in a concerted reaction. These studies provide additional evidence that E CR1 functions as a privileged site for IC clearance, and that the key step in clearance requires removal of CR1 from E to release bound IC for uptake by acceptor macrophages. This model can be extended to genetically altered mice to investigate the role of specific Fc gamma receptors as well as complement receptors in IC clearance.
Henderson
Andrea L
AL
Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, P.O. Box 800733, Charlottesville, VA 22908-0733, USA.
Lindorfer
Margaret A
MA
Kennedy
Adam D
AD
Foley
Patricia L
PL
Taylor
Ronald P
RP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology; D008099:Liver / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008856:Microscopy, Fluorescence / Q000379:methods; D023421:Models, Animal; D011863:Radioimmunoassay / Q000379:methods; D011951:Receptors, Complement / Q000276:immunology*
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D011951:Receptors, Complement