Abstract
Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated ApoE-/- Aid-/- mice, which are unable to produce IgG antibodies due to the absence of activation-induced deaminase (AID) but maintain high plasma cholesterol due to the absence of apolipoprotein E (APOE). We saw a dramatic decrease in plaque formation in ApoE-/- Aid-/- mice compared to ApoE-/- mice. Rigorous analysis of serum antibodies revealed both ApoE-/- and ApoE-/- Aid-/- mice had substantially elevated titers of IgM antibodies compared to C57BL/6J controls, suggesting a more complex dynamic than previously described. Analysis of antigen specificity demonstrated that ApoE-/- Aid-/- mice had elevated titers of antibodies specific to malondialdehyde-oxidized low density lipoprotein (MDA-oxLDL), which has been shown to block macrophage recruitment into plaques. Conversely, ApoE-/- mice showed low levels of MDA-oxLDL specificity, but had antibodies specific to numerous self-proteins. We provide evidence for a hierarchical order of antibody specificity, where elevated levels of MDA-oxLDL specific IgM antibodies inhibit plaque formation. If the level of MDA-oxLDL specific IgM is insufficient, self-reactive IgM and IgG antibodies are generated against debris within the arterial plaque, resulting in increased inflammation and further plaque expansion.
Highlights
During atherosclerosis, low density lipoproteins are oxidized and activate endothelial cells to release cytokines, which recruit circulating monocytes to invade the arterial wall and uptake oxLDL [1]
To systematically examine the mechanisms of IgM and IgG on atherosclerosis, 12-wk old C57BL/6J, apolipoprotein E (ApoE)-/, and ApoE-/- Aid-/mice were placed on a high-fat diet for 16 additional weeks (Figure S1A)
In our study, B-1 cells were not increased in ApoE-/- mice compared to C57BL/6J mice
Summary
Low density lipoproteins are oxidized (oxLDL) and activate endothelial cells to release cytokines, which recruit circulating monocytes to invade the arterial wall and uptake oxLDL [1]. These inflammatory signals promote the recruitment of other innate and adaptive immune cells to the plaque [2]. The introduction of B-1 cells into B cell-deficient mice decreased plaque and inflammation [6, 7], presumably by secreting IgM antibodies that bind to oxLDL [8]. IgM antibodies could prevent disease by sequestering oxLDL away from macrophages and inhibiting plaque initiation [9,10,11]. B-2 cells express both IgM and IgG, the IgG isotype may bind to atherosclerotic antigens and attach to Fcg receptors on macrophages and vascular smooth muscle cells to increase foam cell development and initiate hyperplasia, respectively [16,17,18,19,20]
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