Abstract 30: Localized Immune Response to Oxidized Lipids in ABCG1-/- Mice: A New Model for Lipid-Driven Autoimmunity
Many metabolic diseases, including atherosclerosis, type 2 diabetes, pulmonary alveolar proteinosis (PAP), and obesity, have a chronic inflammatory component involving both innate and adaptive immunity. Mice lacking the ATP binding cassette (ABC) transporter ABCG1, develop chronic inflammation in the lungs, associated with lipid accumulation (cholesterol, cholesterol ester, phospholipid, oxidized lipids) and cholesterol crystal deposition, characteristic of atherosclerotic lesions and PAP. Here we demonstrate that specific lipids, likely oxidized (Ox) phospholipids and/or sterols, elicit a lung-specific immune response in Abcg1-/- mice. Loss of ABCG1 results in increased levels of specific oxysterols, phosphatidylcholines and oxidized phospholipids, including 1-palmitoyl-2-(5’-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), in the lungs. Further, we identify a niche-specific increase in natural antibody (NAb)-secreting B-1 B cells in response to this lipid accumulation that is paralleled by increased titers of IgM, IgA and IgG against oxidation specific epitopes such as those on OxLDL and malondialdehyde-modified LDL (MDA-LDL). Finally, we identify a cytokine/chemokine signature in the lungs of Abcg1-/- mice reflective of increased B cell activation, antibody secretion and homing. Collectively, these data demonstrate that the accumulation of lipids in Abcg1-/- mice induces the specific expansion and localization of B-1 B cells, which secrete NAbs that may help protect against the development of atherosclerosis. Indeed, despite chronic lipid accumulation and inflammation, hyperlipidemic mice lacking ABCG1 develop smaller atherosclerotic lesions compared to controls. These data also suggest that Abcg1-/- mice may represent a new model in which to study the protective functions of B-1 B cells/NAbs, and may provide novel targets for pharmacologic intervention and treatment of disease.
Author Disclosures: A. Baldan: None. A. Gonen: None. C. Choung: None. T. Marquart: None. X. Que: None. C. Diehl: None. J.L. Witztum: None. E.J. Tarling: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.