| Atherosclerosis is a chronic inflammatory disease and its progression is both enhanced and accelerated by immune mechanisms. Oxidized LDL (OxLDL) is an immunodominant antigen in lesions, and elicits prominent cellular and humoral responses. Although the overall impact on atherogenesis of these responses to OxLDL is not defined, immunization of animal models of atherosclerosis with model epitopes of OxLDL, such as MDA-LDL, significantly reduces progression of disease. The primary goal of my studies was to identify mechanisms contributing to the protective effect of immunization with MDA-LDL.; I first characterized the endogenous immune responses in cholesterol-fed LDLR−/− mice, a murine model of atherogenesis. There was a prominent expansion of innate IgM antibodies to OxLDL and specifically, expansion of one immunodominant clone, EO6, that previously was shown to bind to the PC (phosphorylcholine) moiety of oxidized phospholipids of OxLDL. EO6 is identical to the classic innate, natural anti-PC antibody T15, which binds to the PC moiety of the cell wall of S. pneumonia, and affords protection to mice against lethal infection. EO6 blocks the uptake of OxLDL by macrophages and should be atheroprotective. I then showed that immunization of LDLR−/− mice with S. pneumoniae expanded EO6 in vivo, and significantly inhibited atherogenesis.; The endogenous response was also characterized by Th1 adaptive responses specific for another model epitope MDA-LDL, which is not bound by EO6. Th1 responses, mediated by INFγ, are proatherogenic. Exogenous immunization with MDA-LDL also led to protection against atherogenesis, but was associated with a dominant Th2 adaptive response that led to elevated IL-5 levels in plasma. Unexpectedly, there was a prominent expansion of atheroprotective EO6 IgM, which was shown to be specifically mediated by IL-5.; Thus, MDA-LDL immunization leads to a dominant Th2 adaptive response with increased IL-5 levels, which mediates expansion of EO6 IgM. These data define a novel mechanism by which a Th2 adaptive immune response leads to expansion of atheroprotective innate immunity. Thus, my studies define mechanisms by which immunization with epitopes of OxLDL are protective and suggest a novel therapeutic strategy by which PC-based immunization could lead to protection against atherosclerosis. |
