AUTHOR=Hutchinson Mark A. , Park Han-Sol , Zanotti Kimberly J. , Alvarez-Gonzalez Juan , Zhang Jing , Zhang Li , Telljohann Richard , Wang Mingyi , Lakatta Edward G. , Gearhart Patricia J. , Maul Robert W. TITLE=Auto-Antibody Production During Experimental Atherosclerosis in ApoE-/- Mice JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.695220 DOI=10.3389/fimmu.2021.695220 ISSN=1664-3224 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.