BETA-2-GLYCOPROTEIN-I IS A MAJOR PROTEIN ASSOCIATED WITH VERY RAPIDLYCLEARED LIPOSOMES IN-VIVO, SUGGESTING A SIGNIFICANT ROLE IN THE IMMUNE CLEARANCE OF NON-SELF PARTICLES
A. Chonn et al., BETA-2-GLYCOPROTEIN-I IS A MAJOR PROTEIN ASSOCIATED WITH VERY RAPIDLYCLEARED LIPOSOMES IN-VIVO, SUGGESTING A SIGNIFICANT ROLE IN THE IMMUNE CLEARANCE OF NON-SELF PARTICLES, The Journal of biological chemistry, 270(43), 1995, pp. 25845-25849
Liposomes recovered from the blood of liposome-treated CD1 mice were p
reviously reported to have a complex protein profile associated with t
heir mem branes (Chonn, A., Semple, S. C., and Cullis, P. R. (1992) J.
Biol. Chem. 267, 18759-18765). In this study, we have further charact
erized and identified the major proteins associated with very rapidly
cleared large unilamellar vesicles. These liposomes contained phosphat
idylcholine, cholesterol, and anionic phospholipids (phosphatidylserin
e, phosphatidic acid, or cardiolipin) that dramatically enhance the cl
earance rate of Liposomes hom the circulation. These anionic phospholi
pids are normally found exclusively in the interior of cells but becom
e expressed when cells undergo apoptosis or programmed cell death, and
thus, they are believed to be markers of cell senescence, Analysis of
the proteins associated with these liposomes by SDS-polyacrylamide ge
l electrophoresis revealed that two of the major proteins associated w
ith the liposome membranes are proteins with electrophoretic mobilitie
s corresponding to M(r) of 66,000 and 50,000-55,000. The 66-kDa protei
n was identified to be serum albumin by immunoblot analysis. Using var
ious biochemical and immunological methods, we have identified the 50-
55-kDa protein as the murine equivalent of human beta(2)-glycoprotein
I. beta 2-glycoprotein I has a strong affinity for phosphatidylserine,
phosphatidic acid, and cardiolipin inasmuch as the levels of beta 2-g
lycoprotein I associated with these anionic liposomes approach or even
exceed those of serum albumin, which is present in serum at a concent
ration 200-fold greater than beta 2-glycoprotein I. Further, we demons
trate that the amount of beta 2-glycoprotein I associated with liposom
es, as quantitated by an enzyme-linked immunosorbent assay, is correla
ted with their clearance rates; moreover, the circulation residency ti
me of cardiolipin-containing liposomes is extended in mice pretreated
with anti-beta 2-glycoprotein I antibodies. These findings strongly su
ggest that beta 2-glycoprotein I plays a primary role in mediating the
clearance of liposomes and, by extension, senescent cells and foreign
particles.