A specific ligand for β2-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages (original) (raw)
Related papers
Clinical & Developmental Immunology, 2003
that b 2 -glycoprotein I (b 2 GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of b 2 GPI/oxLDL complexes and IgG autoantibodies against b 2 GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The b 2 GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-b 2 GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with b 2 GPI in SLE and APS patients. In contrast, anti-b 2 GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against b 2 GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2001
Autoantibodies to oxidation-specific epitopes of low density lipoprotein (LDL), such as malondialdehydemodified LDL (MDA-LDL), occur in plasma and atherosclerotic lesions of humans and animals. Plasma titers of such antibodies are correlated with atherosclerosis in murine models, and several such autoantibodies have been cloned. However, human-derived monoclonal antibodies to epitopes of oxidized LDL (OxLDL) have not yet been reported. We constructed a phage display antibody library from a patient with high plasma anti-MDA-LDL titers and isolated 3 monoclonal IgG Fab antibodies, which specifically bound to MDA-LDL. One of these, IK17, also bound to intact OxLDL as well as to its lipid and protein moieties but not to those of native LDL. IK17 inhibited the uptake of OxLDL by macrophages and also bound to apoptotic cells and inhibited their phagocytosis by macrophages. IK17 strongly immunostained necrotic cores of human and rabbit atherosclerotic lesions. When 125 I-IK17 was injected intravenously into LDL receptor-deficient mice, its specific uptake was greatly enriched in atherosclerotic plaques versus normal aortic tissue. Human autoantibodies to OxLDL have important biological properties that could influence the natural course of atherogenesis. (Arterioscler Thromb Vasc Biol. 2001;21:1333-1339.)
The Journal of Lipid Research, 2004
This study tests the hypothesis that autoantibodies to oxidation epitopes on oxidized LDL (OxLDL) promote the clearance of OxLDL from the plasma. Human LDL (hLDL) was injected into immune-competent apolipoprotein E-deficient (apoE ؊ / ؊ ) mice and immune-deficient apoE ؊ / ؊ /recombination-activating gene-deficient mice that lack mature T and B cells and thus antibodies. There was a progressive decrease in human apoB-100 in the plasma in all mice, but the rate of clearance was not greater in the immune-competent mice than in the immune-deficient mice. Interestingly, oxidized phospholipid (OxPL) epitopes as detected by the EO6 antibody on the hLDL increased over time, suggesting de novo oxidation of the LDL or transfer of OxPL to the particles. Because the native LDL was not extensively modified, we also examined the clearance of copper OxLDL. Although the extensively OxLDL was cleared faster than the native LDL, there was no difference in the rate of clearance as a function of immune status. There appeared to be some transfer of OxPL to the endogenous murine LDL. Together, these results suggest that oxidation-specific antibodies do not participate to any great extent in the clearance of OxLDL from plasma. However, it is possible that such antibodies may bind to oxidation epitopes and modulate lesion formation within the vessel wall. -Reardon, C. A., E. R. Miller, L. Blachowicz, J. Lukens, C. J. Binder, J. L. Witztum, and G. S. Getz. Autoantibodies to OxLDL fail to alter the clearance of injected OxLDL in apolipoprotein E-deficient mice. J. Lipid Res. 2004. 45: 1347-1354.
Apolipoprotein B of oxidized LDL accumulates in the lysosomes of macrophages
Biochimica et biophysica acta, 1994
We have studied the intracellular fate of the apolipoprotein B of copper-oxidized LDL in cultured J774 macrophages, using subcellular fractionation and immunofluorescence techniques. The oxidized apolipoprotein B, using cell fractionation, was located primarily in secondary lysosomes (identified using the lysosomal marker-enzyme aryl sulfatase). Light microscopy using antibodies to the mannose-6-phosphate receptor, the lysosomal membrane protein lgp 120, and oxidized LDL (biotinylated) confirmed that apo B of oxidized LDL did accumulate in secondary lysosomes rather than in endosomes. We conclude from these results that the oxidized apolipoprotein B of LDL reaches the secondary lysosomes, but is not efficiently degraded, leading to intracellular accumulation within this compartment. If this occurs in vivo it may influence the physiology of the macrophage and their subsequent roles in forming foam cells and the development of the fatty streaks of early atherosclerosis.
Clinical and Experimental Immunology, 1999
Cardiovascular manifestations are common in systemic lupus erythematosus (SLE). Oxidized low-density lipoprotein (oxLDL) is implicated in cardiovascular disease, especially atherosclerosis, and cross-reacts with antibodies to cardiolipin (aCL). β2-GPI is a plasma protein participating in the coagulating cascade, and is also cofactor for aCL, and some aCL have been shown to be directed against β2-GPI and/or complexes between β2-GPI and phospholipids. Lysophosphatidylcholine (LPC) is a phospholipid present both in oxLDL and in damaged endothelium, and we recently showed that LPC is involved in the antigenicity of oxLDL. Antibodies to endothelial cells (aEC) correlate with disease activity in SLE and vasculitis, and we recently showed that aEC are enhanced in cardiovascular diseases such as borderline hypertension and early atherosclerosis. aEC were determined using EC from adult V. Saphena Magna. Antibody levels were determined by ELISA. aEC of IgG type were enhanced in 184 patients with SLE compared with 85 healthy controls. There was a close correlation between aoxLDL, aCL, aLPC, aβ2-GPI and aEC. Binding of sera to EC was competitively inhibited by β2-GPI, LPC and oxLDL. Taken together, the data indicate that EC share antigenic epitopes with β2-GPI and with oxLDL, especially LPC. Phospholipids in EC membranes may thus be antigenic epitopes. β2-GPI may bind to these phospholipids, and become an autoantigen. LPC is formed by oxidation of phospholipids and/or proinflammatory factors leading to activation of phospholipase A2, and the findings indicate the potential role of both lipid oxidation and phospholipase A2 in SLE.
Receptors involved in cell activation by antiphospholipid antibodies
Thrombosis Research, 2013
The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2 +-binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS.
Biochimica Et Biophysica Acta-biomembranes, 1999
The aim of this study was to investigate the interaction of antiphospholipid antibodies (aPL) from two different populations (patients with autoimmune or infectious disorders) with cardiolipin (CL) arranged in a defined bilayer. β2-Glycoprotein I (β2GPI), an apolipoprotein that plays a critical role in the aPL binding to phospholipids, was quantified by dot blot in purified IgG-aPL samples, further classified according to apparent avidity to CL. In solid-phase assays, β2GPI increased, preferentially, the binding of low-avidity autoimmune aPL to CL but inhibited the binding of low-avidity syphilitic aPL. In the absence of β2GPI, both autoimmune and infectious aPL induced the leakage of the entrapped fluorescent probe, carboxyfluorescein (CF), from small unilamellar vesicles containing CL. aPL-induced probe leakage was protein concentration-dependent and characterized by a lag-phase onset of 100–120 min. β2GPI increased the leakage rate induced by low-avidity autoimmune aPL only and inhibited the leakage induced by all syphilitic aPL. The following conclusions were provided: (1) in the absence of β2GPI, autoimmune and infectious aPL bind to CL in a bilayer, inducing liposome leakage; (2) the leakage mechanism induced by aPL is suggested to be intravesicular; (3) β2GPI requirement for phospholipid binding in both solid and fluid phase is associated to aPL avidity; (4) CL alone or the CL–β2GPI complex are the most likely epitopes for autoimmune aPL; (5) aPL from syphilis patients can only form the CL–aPL complex, supporting that β2GPI is not (part of) the target epitope.