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

Atherosclerosis. 2016 Aug:251:31-38. doi: 10.1016/j.atherosclerosis.2016.05.027. Epub 2016 May 19.

Abstract

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 ∼50 μg/ml, which was ∼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 ∼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 ∼40% decrease in aortic arch lesions (p ≤ 0.03).

Conclusions: Anti-HMGB1 autoimmunity may potentially play a role in atherogenesis.

Keywords: Anti-HMGB1 autoimmunity; Apoe(−/−) mice; Atherosclerosis; Western-type diet.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens / blood
  • Aorta, Thoracic / pathology
  • Atherosclerosis / genetics*
  • Autoimmunity / genetics*
  • B-Lymphocytes / immunology
  • Diet, Western / adverse effects*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • HMGB1 Protein / genetics*
  • Inflammation
  • Lipids / blood
  • Lipids / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE

Substances

  • Antigens
  • Epitopes
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Lipids