Abstract 11539: Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating Th1 Adaptive Immunity

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 understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of GM-CSF-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 high cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived GM-CSF develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classical dendritic cells, which then generate IFN γ -producing T H1 cells. This IRA B cell-dependent T H1 skewing manifests in an IgG1 to IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins. Conclusions— GM-CSF-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T H1 -associated mileu that aggravates atherosclerosis.

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