title: Mononuclear phagocyte system dysfunction in murine SLE: abnormal clearance kinetics precede clinical disease.
abstract: Although several studies have reported abnormal immune clearance in murine models of systemic lupus erythematosus (SLE), a consistent defect in mononuclear phagocyte function in SLE-prone mice has not been described. To evaluate the mechanism(s) of immune clearance in murine SLE, we applied the technique of kinetic analysis to clearance studies of radiolabeled, immunoglobulin-sensitized red blood cells in normal BALB/c and autoimmune BXSB, MRL-lpr/lpr, New Zealand black (NZB) and New Zealand black/white (NZB/W) mice. Clearance studies were performed in 4-week-old to 18-month-old mice with a complement-fixing rabbit IgG antimouse red blood cell antibody. Four clearance rate constants governing complement- and Fc-mediated clearance function were evaluated: complement-mediated sequestration (k1), C3b deactivation and release (k2), complement-dependent phagocytosis (k4), and Fc-mediated sequestration and phagocytosis (k3). BXSB male, MRL-lpr/lpr female and male, NZB female, and NZB/W female and male mice all had significantly decreased Fc-mediated clearance function (k3) when compared with control BALB/c mice (p less than 0.0001). This defect in Fc-mediated clearance was present in all four strains of autoimmune mice by 6 months of age and preceded the onset of serologic and clinical disease activity in NZB mice. Abnormal complement-mediated clearance was detected in MRL-lpr/lpr female and male mice, NZB female, and NZB/W female and male mice, but not in BXSB mice. In MRL-lpr/lpr mice decreased complement-mediated sequestration (k1, p less than 0.0001) and complement-dependent phagocytosis (k4, p less than 0.0001) were present as early as 4 weeks of age. In contrast, the change in complement-mediated clearance in NZB and NZB/W mice was characterized by decreased C3b deactivation and release (k2, p less than 0.001) and resulted in an enhanced early phase of clearance. Decreased k2 values in New Zealand mice occurred as early as 2 months of age, preceding serologic and clinical disease activity as well as decreased Fc receptor function. These studies demonstrated an early, progressive, and uniform defect in Fc-mediated clearance in the four murine strains of SLE studied. Complement-mediated clearance, however, varied considerably in lupus-prone mice, ranging from severe impairment in MRL-lpr/lpr to normal function in BXSB and accelerated clearance in NZB and NZB/W mice. Accelerated clearance in New Zealand mice was characterized by decreased C3b deactivation and release of antibody sensitized cells, which in turn led to increased phagocytosis of sensitized cells sequestered by complement-dependent processes.
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
authors.forename: N L
authors.initials: NL
authors.lastname: Meryhew
authors.forename: C
authors.initials: C
authors.lastname: Shaver
authors.forename: R P
authors.initials: RP
authors.lastname: Messner
authors.forename: O A
authors.initials: OA
authors.lastname: Runquist
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D003167:Complement Activation; D003165:Complement System Proteins / Q000276:immunology / Q000502:physiology; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D010585:Phagocyte Bactericidal Dysfunction / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D003165:Complement System Proteins