| The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, thrombocytopenia, and vasoocclusive manifestations associated with elevated levels of antiphospholipid antibodies (APA). APA may recognize phospholipid-binding proteins or phospholipids alone, phospholipid-protein complexes, or other cryptic antigens. Antibodies of different specificities are usually isolated in APS patients, making it difficult to determine their role in disease.; APA can also crossreact with oxidized low density lipoprotein (oxLDL), an antigen implicated in atherosclerosis. Many APS patients develop atherosclerotic complications, and conversely, individuals with atherosclerosis have increased levels of APA and anti-oxLDL antibodies. Therefore, these two antibody populations may overlap.; We have characterized a panel of monoclonal IgG APA from NZW x BXSB/F1 mice, a mouse model of APS, using both ELISA and surface plasmon resonance. Most of these APA crossreact with both native and oxidized LDL. Likewise, they bind similarly to reduced and oxidized cardiolipin. Therefore, these antibody specificities differ from those previously described in atherosclerotic mice which preferentially bind to oxidized lipids. Additionally, administration of one of these APA to atherosclerosis-prone LDL receptor deficient (LDLR−/−) mice resulted in a 30% reduction in atherosclerosis. Therefore, certain antibodies isolated from an autoimmune mouse may paradoxically protect against atherosclerosis.; Although the role of immune cells in atherogenesis has yet to be clearly elucidated, proinflammatory Th1 responses seem to exacerbate disease. Conversely, atherosclerosis is decreased in LDLR−/− mice that receive IL-10, a Th2 cytokine. IL-4 is another important Th2 cytokine which aids in B cell development and proliferation. To elucidate the effect of IL-4 on atherosclerosis, we have developed a line of atherosclerosis-prone IL4-deficient double knockout mice. Atherosclerosis increased in these double knockout mice, without affecting cholesterol levels. Our analysis also indicated that the role of IL-4 was dependent upon the diet and the cholesterol levels in these mice.; Overall, these data suggest that the antibody response can be manipulated to improve the evolution of atherosclerosis. Future challenges will be to understand the mechanisms responsible for this improvement and to harness them for therapeutic purposes. |
