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

Macrophage-derived foam cells are important constituents of atheromato us lesions. In addition to the scavenger receptor pathway, uptake of i mmune complexed lipoproteins through IgG Fc receptors (Fc gamma recept ors) represents an additional pathway of macrophage foam cell developm ent that may be important during atherogenesis. The importance of this mechanism is suggested by studies showing that the titer of autoantib odies 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 function ally distinct classes of Fc gamma receptors, each of which could be as sociated with a unique pathway of lipoprotein metabolism. In order to determine whether uptake of an acute lipid load through each type of F c gamma receptor was associated with foam cell development, we used bi specific antibodies consisting of anti-LDL monoclonal antibodies conju gated to anti-Fc gamma receptor monoclonal antibodies to study the eff ects of targeting LDL aggregates to each specific type of Fc gamma rec eptor on freshly isolated adherent human monocytes. Relative to approp riate controls, LDL degradation, cellular sterol mass, and foam cell d evelopment of monocytes were enhanced by targeting LDL aggregates to F c gamma RI or Fc gamma RII, and this was accompanied by an apparent im pairment of LDL degradation. Uptake was specific to the Fc gamma recep tors and was not influenced by the presence of scavenger receptor liga nds. Thus, with the bispecific approach, the functions of each class o f Fc gamma receptor can be studied on an individual basis with respect to several aspects of cellular cholesterol metabolism. This will be c ritical for determining which of these receptors are potentially most important in the clearance of lipoprotein immune complexes during athe rogenesis.