The western-type diet induces anti-HMGB1 autoimmunity in Apoe-/- mice

Background and aims: Anti-HMGB1 autoimmunity plays a role in systemic lupus erythematosus (SLE). Because SLE increases atherosclerosis, we asked whether the same autoimmunity might play a role in atherogenesis. Methods: We looked for the induction of HMGB1-specific B and T cell responses by a western-type diet (WTD) in the Apoe(-/-) mouse model of atherosclerosis. We also determined whether modifying the responses modulates atherosclerosis. Results: In the plasma of male Apoe(-/-) mice fed WTD, the level of anti-HMGB1 antibodies (Abs) was detected at similar to 50 mu g/ml, which was similar to 6 times higher than that in either Apoe(-/-) mice fed a normal chow or Apoe(+/+) mice fed WTD (p <= 0.0005). The Abs were directed largely toward a novel, dominant epitope of HMGB1 named HMW4; accordingly, compared with chow-fed mice, WTD-fed Apoe(-/-) mice had more activated HMW4-reactive B and T cells (p = 0.005 and p = 0.01, respectively). Compared with mock-immunized mice, Apoe(-/-) mice immunized with HMW4 along with an immunogenic adjuvant showed proportional increases in anti-HMW4 IgG and IgM Abs, HMW4-reactive B-1 and B-2 cells, and HMW4-reactive Treg and Teff cells, which was associated with similar to 30% increase in aortic arch lesions (p <= 0.01) by two methods. In contrast, Apoe(-/-) mice immunized with HMW4 using a tolerogenic adjuvant showed preferential increases in anti-HMW4 IgM (over IgG) Abs, HMW4-reactive B-1 (over B-2) cells, and HMW4-specific Treg (over Teff) cells, which was associated with similar to 40% decrease in aortic arch lesions (p <= 0.03). Conclusions: Anti-HMGB1 autoimmunity may potentially play a role in atherogenesis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.