Auto-Antibody Production During Experimental Atherosclerosis in ApoE-/- Mice

Frontiers in Immunology

Richard Telljohann¹  Edward G. Lakatta¹  Mingyi Wang¹  Jing Zhang¹  Li Zhang¹  Robert W. Maul²  Patricia J. Gearhart²  Juan Alvarez-Gonzalez²  Mark A. Hutchinson²  Han-Sol Park²  Kimberly J. Zanotti² 

[1] Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD, United States;Laboratory of Molecular Biology and Immunology, National Institute on Aging, NIH, Baltimore, MD, United States;

关键词: AID;    atherosclerosis;    B cells;    antibodies;    antigens;   

DOI  :  10.3389/fimmu.2021.695220

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown