No abstract

Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds β2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that β2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Oxidized low-density lipoprotein (oxLDL)/beta(2)-glycoprotein I (beta2GPI) complexes have been implicated in atherogenesis. oxLDL/beta2GPI complexes were measured in 339 patients with suspected acute coronary syndromes. Approximately 68% had angiographically documented coronary artery disease (CAD) and significantly higher mean + or - SD levels of oxLDL/beta2GPI (3.75 + or - 6.31 U/mL) than patients with normal coronary arteries (2.21 + or - 3.03 U/mL; P = .0026). Patients with severe CAD had significantly higher mean + or - SD levels of oxLDL/beta2GPI (8.71 + or - 12.87 U/mL) compared with the overall mean of 3.25 U/mL (P < .05) and a significantly higher rate (28.9%) of adverse events than the overall rate of 11.2% (P < .05). Patients with adverse events had higher mean + or - SD levels of oxLDL/beta2GPI (4.05 + or - 5.38 U/mL) than patients without adverse events (3.15 + or - 5.53; P = .029). The relative risk for adverse events in higher oxLDL/beta2GPI quartiles was 3.1 (95% confidence interval, 1.0-9.1; P = .06) for quartile 3 and 3.5 (95% confidence interval, 1.2-10.4; P = .02) for quartile 4. Our results support the concept that oxLDL/beta2GPI complexes are associated with severity of CAD and a 3.5-fold increased risk for adverse outcomes.

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with b2-glycoprotein I (b2GPI), implicating oxLDL/b2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/b2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/b2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and b2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/b2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/b2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/b2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.-Tabuchi, M., K.

Oxidized low-density lipoprotein (oxLDL) interacts with beta2GPI, forming oxLDL/beta2GPI complexes. Autoimmune vascular inflammation (and oxidative stress) may promote the formation of these complexes. The coexistence of oxLDL/beta2GPI complexes with autoantibodies to these complexes suggests an active pro-atherogenic role in vascular thrombosis and atherosclerosis. Immunoglobulin G (IgG) anti-oxLDL/beta2GPI antibodies have been regarded as pro-atherogenic, whereas IgM antibodies are thought to be anti-atherogenic. For this study, oxLDL/beta2GPI complexes, IgG, and IgM anti-oxLDL/beta2GPI antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Measurements were taken in two patient groups: (1) those with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA); and (2) those with primary and secondary antiphospholipid syndrome (APS). For oxLDL/beta2GPI complexes, SLE and SSc patients had the highest mean optical densities (ODs) (P <.001), followed by RA (P = .139) and healthy controls. IgG anti-oxLDL/beta2GPI antibody distribution followed the same pattern observed with oxLDL/beta2GPI complexes, SLE and SSc (P <.001), RA (P = .08), and controls. IgM antibodies showed a reverse pattern, with the highest mean OD in RA (P <.001), followed by SSc (P = .007) and SLE (P = 143). Both IgG and IgM anti-oxLDL/beta2GPI antibodies were significantly higher in secondary APS patients compared with SLE controls without APS. In addition, the highest mean OD and prevalence of IgG anti-oxLDL/beta2GPI antibodies were observed in APS patients with a history of arterial thrombosis. These results may reflect the widespread vascular involvement seen in SLE and SSc, in contrast to the relatively low vascular involvement in RA. In SLE and SSc, high serum levels and prevalence of circulating oxLDL/beta2GPI complexes and IgG anti-oxLDL/beta2GPI antibodies indicate significant vascular oxidative stress as well as a possible pathogenic role in autoimmune-mediated atherosclerosis.

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that β2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of β2GPI/oxLDL complexes and IgG autoantibodies against β2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The β2GPI/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-β2GPI/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 β2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against β2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

beta2-glycoprotein I (beta2GPI) is a major antigenic target for antiphospholipid antibodies. Oxidized low-density lipoprotein (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with beta2GPI and immunoreactive lymphocytes. oxLDL/beta2GPI complexes appeared in the blood circulation of patients with diseases, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis, diabetes mellitus and chronic renal diseases. Thus, the complexes may be associated with systemic and chronic inflammation of the vasculature. IgG anti-oxLDL/beta2GPI complexes autoantibodies and their immune complexes were detected only in SLE/APS patients and in its animal model and were strongly associated with arterial thrombosis. The oxLDL/beta2GPI complexes were internalized by macrophages via IgG anti-beta2GPI antibody-mediated phagocytosis. In contrast, IgM anti-oxLDL antibodies derived from hyperlipidemic mice reduced the incidence of atherosclerosis. The distribution patterns of IgG and IgM anti-oxLDL antibodies in patients suggest the different roles of these antibodies.

The predictive value (PV) and association of 4 antiphospholipid antibodies with clinical manifestations of the antiphospholipid syndrome (APS) were evaluated in 90 patients with systemic lupus erythematosus (SLE) and 100 with APS. Patients with APS were classified into arterial thrombosis, venous thrombosis, and pregnancy morbidity subgroups. IgG, IgM, and IgA anticardiolipin (aCL), antiphosphatidylserine (aPS), anti-beta 2-glycoprotein I (anti-B2GPI), and antiprothrombin (aPT) antibodies were determined by enzyme-linked immunosorbent assay. Individually, anti-B2GPI and aPS antibodies had the strongest PV for APS (86.4%-94.1%; P < .001) in patients with SLE. The PV for APS reached 100% when 2 or more antibodies were present. Similarly, anti-B2GPI and aPS antibodies had a stronger PV and association for arterial thrombosis (87%-95%; P < .001) compared with venous thrombosis (80%-92%; P = .01). Weak PV and association with pregnancy morbidity were seen with all antibodies. These results suggest an important pathogenic role of anti-B2GPI antibodies in arterial thrombosis. In addition, anti-B2GPI and aPS antibodies seem to provide the best diagnostic value for the laboratory assessment of APS.