The aim of this proposal is to use a kinetic analysis of the clearance of immunoglobulin sensitized radiolabeled erythrocytes (RBC) to study the basic mechanisms of normal and abnormal murine immune mediated clearance. A model for clearance of sensitized RBC has been developed, and a rate equation derived which contains four rate constants corresponding to the four major clearance steps, i.e., hepatic sequestration, C3b deactivation and return of deactivated cells to the circulation, splenic clearance and phagocytosis of sequestered cells. The equation has successfully correlated rate data for the clearance of IgG and IgM sensitized RBC in normal guinea pigs and humans and IgG and complement sensitized cells in mice. Analysis of rate data from patients with systemic lupus erythematosus (SLE) has revealed a bipartite clearance defect with the most abnormal rate constants associated with active renal disease. Preliminary data indicates that immune clearance in murine models of SLE is also associated with abnormal clearance rate constants. These data suggest that studies further defining the mechanisms of normal and abnormal immune clearance in BALB/c mice and in strains of mice with SLE (BXSB, MRL/1) should provide further insights into the pathogenesis of murine and human autoimmune disease. The basic mechanisms of immune clearance will be further defined in BALB/c mice. Unmanipulated and medically or surgically manipulated animals will be studied. In addition, the roles of Fc subclass specific receptor clearance and platelet CR1 immune complex mediated clearance will be determined. Rate constant values from these studies will be compared to values obtained from similar clearance studies in autoimmune mice. Clearance function will also be serially analyzed in several strains of mice with SLE to explore the relationship between abnormal clearance, circulating immune complexes and immune complex mediated disease. These studies should determine whether MPS dysfunction plays and integral role in disease pathogenesis and how changes in clearance relate to tissue damage. Such studies have direct applicability to autoimmune disease in man, including SLE, immune hemolytic anemia and autoimmune thrombocytopenic purpura.
| Meryhew, N L; Tam, P E; Seim, J K et al. (1996) Abnormal complement-mediated immune clearance in MRL-lpr/+ heterozygote mice: dose-dependent effect of the Fas antigen mutation. Clin Immunol Immunopathol 78:236-44 |
| Meryhew, N L; Messner, R P (1993) Murine complement-mediated immune clearance dysfunction is associated with the lymphoproliferative (lpr) gene. Clin Immunol Immunopathol 69:324-32 |
| Meryhew, N L; Shaver, C; Messner, R P et al. (1991) Mononuclear phagocyte system dysfunction in murine SLE: abnormal clearance kinetics precede clinical disease. J Lab Clin Med 117:181-93 |
