Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating TH1 Adaptive Immunity
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Author
Hilgendorf, Ingo
Theurl, Igor
Gerhardt, Louisa M. S.
Robbins, Clinton
Weber, Georg
Gonen, Ayelet
Iwamoto, Yoshiko
Degousee, Norbert
Holderried, Tobias
Winter, Carla
Zirlik, Andreas
Lin, Herbert
Sukhova, Galina
Butany, Jagdish
Rubin, Barry
Witztum, Joseph
Libby, Peter
Nahrendorf, Matthias
Weissleder, Ralph
Swirski, Filip
Published Version
https://doi.org/10.1161/CIRCULATIONAHA.113.006381Metadata
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Hilgendorf, Ingo, Igor Theurl, Louisa M.S. Gerhardt, Clinton S. Robbins, Georg F. Weber, Ayelet Gonen, Yoshiko Iwamoto, et al. 2014. “Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating T Helper-1 Adaptive Immunity.” Circulation 129 (16): 1677–87. https://doi.org/10.1161/circulationaha.113.006381.Abstract
Background: Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other's function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor-secreting cells of hitherto unknown function in atherosclerosis. Methods: and Results Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon -producing T helper-1 cells. This IRA B cell-dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins. Conclusions: Granulocyte macrophage colony-stimulating factor-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1-associated milieu that aggravates atherosclerosis.Terms of Use
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