Acute Loss of Apolipoprotein E Triggers an Autoimmune Response That Accelerates Atherosclerosis

Monica Centa, Kajsa E Prokopec, Manasa G Garimella, Katrin Habir, Lisa Hofste, Julian M Stark, Albert Dahdah, Chris A Tibbitt, Konstantinos A Polyzos, Anton Gisterå, Daniel K Johansson, Nobuyo N Maeda, Göran K Hansson, Daniel F J Ketelhuth, Jonathan M Coquet, Christoph J Binder, Mikael C I Karlsson, Stephen Malin

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe-/- mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.

Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number8
Pages (from-to)e145-e158
ISSN1079-5642
DOIs
Publication statusPublished - Aug 2018
Externally publishedYes

Keywords

  • apolipoproteins E
  • atherosclerosis
  • hyperlipidemias
  • inflammation
  • metabolic syndrome

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