Although, atherosclerosis is not observed without ApoE−/− mutation in mice, this study reports for the first time a systemic activation of the immune system upon an atherogenic diet, with high tissue infiltration of myeloid cell subsets CD45+CD11b+CD11c, CD45+ F4/80+, CD45+ CD11b+Ly6G+ in the spleen, a massive lymphocyte infiltration in the aorta and in the liver, a significant increase in CD4+ and CD8+ positive cells in the aorta and in the hearts, paralleled by increased IL-17, IL-1, IFN-γ, and IL-4 levels in the aorta and heart. The gene discussed is APOE; the disease is atherosclerosis.