ENHANCED METABOLISM OF LDL AGGREGATES MEDIATED BY SPECIFIC HUMAN MONOCYTE IGG FC-RECEPTORS

Macrophage-derived foam cells are important constituents of atheromatous lesions. In addition to the scavenger receptor pathway, uptake of immune complexed lipoproteins through IgG Fc receptors (Fc gamma receptors) represents an additional pathway of macrophage foam cell development that may be important during atherogenesis. The importance of this mechanism is suggested by studies showing that the titer of autoantibodies to modified lipoproteins correlated with the extent of occlusive disease in patients, and that those antibodies exist in human lesions. Human mononuclear phagocytes possess three structurally and functionally distinct classes of Fc gamma receptors, each of which could be associated with a unique pathway of lipoprotein metabolism. In order to determine whether uptake of an acute lipid load through each type of Fc gamma receptor was associated with foam cell development, we used bispecific antibodies consisting of anti-LDL monoclonal antibodies conjugated to anti-Fc gamma receptor monoclonal antibodies to study the effects of targeting LDL aggregates to each specific type of Fc gamma receptor on freshly isolated adherent human monocytes. Relative to appropriate controls, LDL degradation, cellular sterol mass, and foam cell development of monocytes were enhanced by targeting LDL aggregates to Fc gamma RI or Fc gamma RII, and this was accompanied by an apparent impairment of LDL degradation. Uptake was specific to the Fc gamma receptors and was not influenced by the presence of scavenger receptor ligands. Thus, with the bispecific approach, the functions of each class of Fc gamma receptor can be studied on an individual basis with respect to several aspects of cellular cholesterol metabolism. This will be critical for determining which of these receptors are potentially most important in the clearance of lipoprotein immune complexes during atherogenesis.