Background/Purpose: HLA-DRB1 alleles are associated with various autoimmune and inflammatory conditions, including rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus, diabetes and atherosclerotic cardiovascular disease. In rheumatoid arthritis, patients expressing HLA-DRB1 have a high risk for cardiovascular mortality. This study aimed to create and characterize a novel animal model to better understand the role of HLA-DRB1 in the pathogenesis of atherosclerosis.

Methods: Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with an established mouse model of atherosclerosis, low density lipoprotein receptor knock-out (Ldlr-/-) mice. DR4tgLdlr-/- (n=48), Ldlr-/- (n=24), DR4tg (n=24), and C57Bl/6 (B6) background (n=24) mice were fed a high fat, high cholesterol (HFHC) or regular diet (RD) for 12 weeks. Serum lipoproteins were measured using a colorimetric assay. C-reactive protein (CRP), anti-cyclic citrullinated protein/peptide antibodies2 (anti-CCP2) and oxidized LDL (OxLDL) were measured using ELISA. Atherosclerosis in whole aortas was assessed using the lipid stain, Sudan IV. The presence of citrulline in atherosclerotic plaque from aortic sinus sections was determined by immunohistochemistry. Mice were monitored for arthritis by measuring knee and ankle swelling and by histopathology.

Results: DR4tgLdlr-/- had a similar degree of atherosclerotic plaque burden compared to Ldlr-/-, despite having lower sera low-density lipoprotein cholesterol (LDL-C) levels; p=0.0056. Levels of the more pro-atherogenic lipoprotein, OxLDL was higher in DR4tgLdlr-/- than Ldlr-/-mice; p=0.0017. Male Ldlr-/- mice had worse atherosclerosis than females, but there were no sex differences in DR4tgLdlr-/-. CRP was elevated in all mice fed a HFHC diet, most pronounced for DR4tgLdlr-/-; p=0.0009. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis. None of the mice developed antibodies to citrullinated antigens or spontaneous inflammatory arthritis.

Conclusion: HLA-DRB1 expression in a mouse model of atherosclerosis resulted in an elevation of oxidized LDL and a reduction in the male bias for atherosclerosis, mimicking what is observed in rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-animal-model-for-investigating-the-effect-of-hla-drb1-on-atherosclerosis/