Innate Immunity plays a fundamental role in atherogenesis and our work has provided an improved understanding of this by demonstrating that "oxidation-specific epitopes" (OSE), which are generated on oxidatively damaged molecular complexes, such as OxLDL and apoptotic cells, are major targets of innate pattern recognition receptors, such as lgM Natural Antibodies (NAbs). During the first cycle, we demonstrated that 20-30% of all lgM NAbs bind to OSE in both mice and humans, and we proposed that lgM OSE-NAbs have been conserved to provide homeostasis to the many OSE generated in both health and disease. Considerable data support an atheroprotective role for lgM in murine models and lgM titers in humans are inversely related to cardiovascular disease (CVD). In the renewal, we will focus on understanding the role of NAbs in mice and humans, and define the mechanisms that regulate 8-1 cells that generate NAbs.
Specific Aim 1 will define the repertoire and prevalence of OSE NAbs in mice and humans. We will generate a B-1 cell derived database of lgM NAb heavy chain variable (IGHV) CDR3 sequences and their relative expression in both humans and mice. We will then sort OSE-B-1 cells to annotate OSE NAbs, and will examine their relative expression under experimental models of inflammation and atherosclerosis in mice, and in epidemiological studies in humans.
Specific Aim 2 will define the roles of OSE NAbs and B-1 cells in inflammation and atherogenesis. Using transgenic mice expressing OSE antibodies, we will seek to define the mechanisms by which OSE-Abs influence inflammation and atherosclerosis. Because these NAbs target prevalent oxidized lipids in atherosclerotic lesions, these studies should define the importance of these oxidized moieties in mediating inflammation and atherogenesis.
Specific aim 3 will test the hypothesis that vital functions of B-1 cells, such as proliferation and secretion of NAbs are positively regulated by TLRs, while the nuclear receptors GRand LXR negatively regulate B-1 cells. We will determine the impact of these immune modulators on transcriptional regulation of B-1 cells in comparison to B-2 cells and macrophages, to provide an improved understanding of the integrated responses to these immune cell regulators. These studies should yield new insights into the important role that innate immunity plays in inflammation and atherosclerosis, and may lead to novel diagnostic and therapeutic approaches for CVD.

Public Health Relevance

The proposed studies will be of significance in improving our understanding of how immune mechanisms provide protection against oxidative stress that occurs in both health and disease. This information may lead to novel diagnostic and therapeutic applications for humans with inflammatory diseases and atherosclerosis.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Fan, Weiwei; Evans, Ronald (2015) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol 33:49-54
Tsimikas, Sotirios; Duff, Gordon W; Berger, Peter B et al. (2014) Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 63:1724-34
Gonen, Ayelet; Hansen, Lotte F; Turner, William W et al. (2014) Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine. J Lipid Res 55:2137-55
Baldan, Angel; Gonen, Ayelet; Choung, Christina et al. (2014) ABCG1 is required for pulmonary B-1 B cell and natural antibody homeostasis. J Immunol 193:5637-48
Daniel, Bence; Nagy, Gergely; Hah, Nasun et al. (2014) The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages. Genes Dev 28:1562-77
Hilgendorf, Ingo; Theurl, Igor; Gerhardt, Louisa M S et al. (2014) Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129:1677-87
d'Uscio, Livius V; He, Tongrong; Santhanam, Anantha Vijay R et al. (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene. Am J Physiol Heart Circ Physiol 306:H1001-10
Hong, Suk-Hyun; Ahmadian, Maryam; Yu, Ruth T et al. (2014) Nuclear receptors and metabolism: from feast to famine. Diabetologia 57:860-7
Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam et al. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513:436-9
Zhao, Xuan; Cho, Han; Yu, Ruth T et al. (2014) Nuclear receptors rock around the clock. EMBO Rep 15:518-28

Showing the most recent 10 out of 51 publications