Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 16, Pages E2030-E2038Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1421227112
Keywords
B cells; atherosclerosis; inflammasome
Categories
Funding
- Swedish Research Council
- Magnus Bergvall Foundation
- Swedish Medical Society
- Swedish Rheumatic foundation
- King Gustav V 80-year Foundation
- Torsten Soderberg foundation
- Apotekare Hedbergs foundation
- Cardiovascular Research Programme
- Swedish Heart and Lung Foundation
- Hesselman foundation
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The B-cell response in atherosclerosis is directed toward oxidation-specific epitopes such as phosphorylcholine (PC) that arise during disease-driven oxidation of self-antigens. PC-bearing antigens have been used to induce atheroprotective antibodies against modified low-density lipoproteins (oxLDL), leading to plaque reduction. Previous studies have found that B-cell transfer from aged atherosclerotic mice confers protection to young mice, but the mechanism is unknown. Here, we dissected the atheroprotective response in the spleen and found an ongoing germinal center reaction, accumulation of antibody-forming cells, and inflammasome activation in apolipoprotein E-deficient mice (Apoe(-/-)). Specific B-cell clone expansion involved the heavy chain variable region (Vh) 5 and Vh7 B-cell receptor families that harbor anti-PC reactivity. oxLDL also accumulated in the spleen. To investigate whether protection could be induced by self-antigens alone, we injected apoptotic cells that carry the same oxidation-specific epitopes as oxLDL. This treatment reduced serum cholesterol and inhibited the development of atherosclerosis in a B-cell-dependent manner. Thus, we conclude that the spleen harbors a protective B-cell response that is initiated in atherosclerosis through sterile inflammation. These data highlight the importance of the spleen in atherosclerosis-associated immunity.
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