Abstract 21: Loss of Abcg1 Drives the Site-selective Expansion of B-1 B Cells and Secretion of Atheroprotective Natural Antibodies, in Response to Local Accumulation of Specific Oxidized Lipids
The oxidation of LDL, a key event in the pathogenesis of atherosclerosis, generates multiple oxidation-specific neo-epitopes (OSE). These epitopes are recognized by natural germ line IgM antibodies that are secreted by B-1 B cells. Mice lacking the ATP binding cassette (ABC) transporter, ABCG1, develop chronic inflammation in the lungs, associated with the accumulation of lipid (cholesterol, cholesterol ester, phospholipid)-filled cells and cholesterol crystal deposition, which are also characteristic of atherosclerotic lesions. However, hyperlipidemic mice lacking ABCG1 develop smaller atherosclerotic lesions compared to controls. We previously attributed this decrease to increased apoptosis of macrophages within the atherosclerotic lesions of mice lacking ABCG1. We now demonstrate that the lungs of Abcg1-/- mice have increased levels of specific oxidized phospholipids species. Here we show that there is a significant increase in B cell number in the lungs, but not the spleens, of Abcg1-/- mice. Subsequent comparison of B cell subtypes revealed that B-1 B cells, which secrete natural antibodies (NAbs), are significantly expanded in the pleural cavity of Abcg1-/- mice, compared to wild type mice. In addition, we show that the lungs and plasma of Abcg1-/- mice have increased titers of NAbs to OSE, and increased mRNA transcript levels for the known hypervariable (VH) CDR3 region of the atheroprotective EO6/T15 NAb. These data are consistent with an antigen-specific enhanced local production of NAbs in the pleural cavity. These findings suggest that the accumulation of lipids resulting from loss of ABCG1 induces the specific expansion of B-1 B cells, which secrete NAbs that may help protect against the development of atherosclerosis. 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.
- © 2013 by American Heart Association, Inc.