Factors influencing the endocytosis of immune complexes

The MPS plays an important role in the removal of both particulate and soluble immunogenic material from the circulation. E.IgG adhere to mononuclear phagocytes if the Fc portion of the IgG can interact with the phagocyte's Fc receptors (Fc gamma R). Simultaneous sensitization with IgG and C3b via complement activation enhances the effectiveness of binding and ingestion. E.IgM adhere mainly via C3b to C3b receptors (C3bR) of macrophages. Unstimulated macrophages do not ingest E.C3b. Stimulated macrophages, on the other hand, can ingest E.C3b. If soluble material cannot adhere to the surface of macrophages, it will be endocytosed in vitro via fluid-phase pinocytosis at the concentration that is present in the medium. If the material adheres to the cell's surface via its chemical properties or via specific receptors, it will be selectively concentrated at the cell's surface and endocytosed by adsorptive pinocytosis. Ingestion of IC via Fc gamma R and C3b depends on the ability of the antibodies to interact with Fc gamma R and their capacity to activate the complement system. IC-bound C3b enhances the adsorptive pinocytosis of IC. Soluble AIgG are also pinocytosed more effectively when C3b is bound to AIgG. The degree of endocytosis varies with the level of C3b sensitization. The highly effective C3b-mediated pinocytosis can be abolished by treating with trypsin to inactivate C3bR. This observation illustrates that C3b-mediated pinocytosis can replace Fc-mediated pinocytosis in unstimulated macrophages. When macrophages are stimulated in vivo, Fc-mediated pinocytosis increases significantly. Under these conditions, the binding of C3b no longer stimulates; instead, it sterically interferes with Fc-Fc gamma R interaction. In vivo, E.IgG are removed mainly by splenic macrophages. C4-deficient guinea pigs clear E.IgG less effectively than guinea pigs with an intact complement system. On the other hand, soluble IC and AIgG are removed from the circulation mainly by hepatic Kupffer cells. Complement depletion does not seem to influence the clearance rates of these soluble IC or AIgG. The different results obtained in vitro and in vivo and the finding that different effector organs are responsible for the removal of sensitized erythrocytes and soluble Ic in vivo, suggest that more reliable techniques have to be developed to measure IC clearance in patients with a supposedly deficient or saturated MPS.