The Impact of ID3 on Natural Immunity in Atherosclerosis

Coronary artery disease remains the leading cause of death worldwide. The underlying cause of coronary artery disease, atherosclerosis, is the formation of plaques in the arterial wall that can rupture, resulting in heart attacks and stroke. The pathogenesis of atherosclerosis can initiate early in childhood with the deposition of lipoproteins in the wall, leading to the activation of vessel wall cells and innate and adaptive immune responses. Current therapy directed toward lowering pathogenic lipoproteins in the circulation have reduced morbidity and mortality. However, disease burden remains high, suggesting that additional approaches are needed. Therapies targeting inflammation have emerged as the next frontier and anti-inflammatory agents are in clinical trials to reduce cardiovascular events. As such, understanding the complex cellular and molecular mechanisms in the immune pathogenesis of atherosclerosis may help identify those who will benefit from immune-modulatory therapeutic approaches.
Inhibitor of DNA binding-3 (Id3) is a transcription factor protein that has been reported to be important in murine and human atherosclerosis. Id3-deficient atherogenic (Id3-/-Apoe-/-) mice display early onset atherosclerosis. Compared to control mice, Id3-/-Apoe-/- mice contain fewer proliferating B-1a B cells, an immune cell that is a subset of B cells and can protect from atherosclerosis through the secretion of natural IgM antibodies. Additionally, Id3-/-Apoe-/- mice contained lower amounts of a natural IgM antibody, E06, in the circulation compared to control mice. The generation of a B cell specific, Id3-deficient mouse revealed that these effects were not due to the loss of Id3 in B cells. Instead, Id3-/-Apoe-/- mice contained lower amounts of interleukin-5 (IL-5), a cytokine important for B-1a B cell proliferation and natural IgM antibody production. Furthermore, reduced amounts of IL-5 was detected in natural helper cells isolated from Id3-/-Apoe-/- mice compared to control mice. Lastly, proliferating B-1a B cells and IL-5 producing natural helper cells were identified in the aorta and surrounding tissue. Data provides evidence for a novel role for Id3 in promoting IL-5 production by natural helper cells and subsequent proliferation of B-1a B cells.
Prior studies suggest that another mechanism for protection from atherosclerosis in Id3-deficient mice might be due to the loss of Id3 in B cells. To determine if the loss of Id3 in B cells exacerbates atherosclerosis, B cell specific, Id3-deficient and littermate control mice were placed on a Western diet to induce atherosclerosis. Surprisingly, B cell specific, Id3-deficient mice displayed attenuated atherosclerosis compared to controls. B cell specific, Id3-deficient mice also contained a greater number of B-1b B cells and larger amounts of a natural IgM antibody, T15-Id IgM, in the circulation compared to control mice after Western diet. Atherosclerotic plaques of B cell specific, Id3-deficient mice had fewer apoptotic cells and less macrophage content. These associations suggest that B-1b B cells may protect from atherosclerosis; a hypothesis that has yet to be tested.