Monoclonal antibodies against LDL further enhance macrophage uptake of LDL aggregates.
Self-aggregates of low density lipoprotein (LDL) are taken up and degraded more rapidly by macrophages than is native LDL. That enhanced uptake is attributable in part to phagocytosis via the LDL receptor pathway. However, arterial macrophages appear to express little LDL receptor activity. The present studies demonstrate an alternative mechanism by which LDL aggregates could contribute to foam cell formation. This could occur by the formation of large immune complexes that are taken up by macrophages via the Fc receptor. When immune complexes were formed with native, soluble LDL and MB47, a monoclonal antibody specific to the apoprotein B domain recognized by the LDL receptor, the subsequent uptake and degradation of the LDL by macrophages were inhibited 50-80% compared with native LDL alone. In contrast, when aggregated LDL was bound to MB47 at a similar molar ratio, the subsequent degradation of the insoluble immune complexes was two- to fivefold greater than that of aggregated LDL alone. The enhanced uptake was abolished when Fab or F(ab')2 fragments of MB47 were substituted for the intact antibody, indicating that the increased uptake was via the Fc receptor pathway. Furthermore, the uptake of the immune complexes of aggregated LDL was reduced by competition for the Fc receptor with heat-aggregated immunoglobulin. There was also an increase in the rate of cellular cholesterol esterification and an increase in macrophage cholesteryl ester mass. Since aggregates of LDL as well as autoantibodies against modified LDL have been demonstrated in atherosclerotic lesions, it is possible that immune complexes of aggregates of modified LDL may be generated in the intima.(ABSTRACT TRUNCATED AT 250 WORDS)
Khoo
J C
JC
Department of Medicine, University of California, San Diego, La Jolla 92093-0682.
Miller
E
E
Pio
F
F
Steinberg
D
D
Witztum
J L
JL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D008077:Lipoproteins, LDL