Abstract 11539: Innate Response Activator B Cells Aggravate Atherosclerosis by Stimulating Th1 Adaptive Immunity
Rationale: B cells are a heterogenous population of lymphocytes that engage in atherogenesis. While natural IgM producing B1a cells protect from atherosclerosis, B2 cells are thought to aggrevate plaque formation. Innate response activator (IRA) B cells have recently been described as a distinct GM-CSF-producing cell population in experimental sepsis but their function in atherosclerosis is unknown.
Objective: To determine the role of IRA B cells in atherosclerosis.
Methods and Results: We show that GM-CSF-producing IRA B cells progressively arise in both atherosclerotic LDLR-/- and ApoE-/- mice and preferentially accumulate in secondary lymphoid organs via Myd88-dependent signaling. Mixed bone marrow chimeras lacking B cell-derived GM-CSF develop smaller plaque lesions with fewer macrophages and T effector cells. Mechanistically, IRA B cells promote the generation of IL-12-producing CD11b+ CD8- classical dendritic cells that prime naive CD4+ T cells towards a TH1 response. This manifests in increased IFNγ production in the aorta and in TH1-cell dependent isotype switching of atherosclerosis-related immunoglobulins against oxidized lipoproteins.
Conclusion: This is the first report showing that highly specialized GM-CSF-producing IRA B cells are capable of promoting the generation of mature dendritic cells, which in turn control adaptive immunity. In the context of atherosclerosis IRA B cells thereby foster an antigen-specific TH1-response that promotes macrophage accumulation and plaque formation. IRA B cells represent a previously unknown regulatory node in atherosclerosis-related immunity and a novel candidate for therapeutic intervention.
- © 2013 by American Heart Association, Inc.