Murine complement-mediated immune clearance dysfunction is associated with the lymphoproliferative (lpr) gene

Abstract

Using a branched series model of immune clearance and an iterative curve fitting process, we have previously demonstrated abnormal in vivo clearance of opsonized erythrocytes in autoimmune MRL-lpr/lpr mice. This technique allows simultaneous evaluation of four rate constants governing both complement- and Fc-mediated clearance; i.e., complement-mediated sequestration (k1), C3b deactivation and release (k2), complement-dependent phagocytosis (k4), and Fc gamma-mediated sequestration and phagocytosis (k3). To evaluate genetic factors which may contribute to abnormal clearance in MRL-lpr/lpr mice, serial clearance studies were performed in congenic MRL-(+/+) mice, as well as in several mouse strains homozygous for the lymphoproliferative gene; i.e., BALB/c-lpr/lpr and C57BL/6-lpr/lpr mice. Rate data were obtained from mice 3 months through 12-18 months of age, and mean rate constant values compared to control BALB/c and/or C57BL/6 mice. Clearance of opsonized cells in MRL-lpr/lpr mice was characterized by both abnormal complement and Fc gamma receptor function with decreased complement-mediated sequestration, complement-dependent phagocytosis, and Fc gamma-mediated sequestration and phagocytosis. In contrast, abnormal clearance in congenic MRL-(+/+) mice was characterized by decreased Fc gamma-mediated sequestration and phagocytosis (P < 0.0001) only. Both complement-mediated sequestration and complement-dependent phagocytosis were significantly decreased in BALB/c-lpr/lpr and C57BL/6-lpr/lpr mice (P < 0.0001), with the pattern and magnitude of abnormal complement clearance kinetics similar to that occurring in MRL-lpr/lpr mice and contrasting with normal complement-mediated clearance in control BALB/c and C57BL/6 mice. Since decreased complement-mediated clearance was observed in three differing strains of mice homozygous for the lymphoproliferative gene, these data suggest that clearance of opsonized cells in mice is in part genetically determined, and that there may be a specific association between complement-mediated clearance dysfunction and the murine lymphoproliferative gene.