Effector mechanisms of immunity in atherosclerosis

Atherosclerosis is a disease of the medium and large sized arterial vessels, characterized by cholesterol deposition, inflammation and fibrosis. Low-density lipoprotein (LDL) particles carrying cholesterol are trapped within the arterial wall. LDL has been shown to be a candidate antigen for immune responses associated with atherosclerosis and elicits both innate as well as adaptive immune responses. These studies have used different mouse models to unravel immune mechanisms involved in the progression and protection of disease, and can lead to new therapeutic opportunities.

To explore the role of dendritic cells (DCs) in atherogenesis, in the context of an atherosclerosis-related antigen, we injected hypercholesterolemic Apoe-/- mice with malondialdehyde (MDA)-LDL pulsed DCs. This cell transfer induced immune responses specific for components of LDL that augmented local inflammation in the vessel wall and accelerated growth of atherosclerotic lesions. This study shows that DCs presenting the autoantigen LDL can augment atherogenesis.

DCs can be conditioned into a tolerogenic state by immunomodulatory mediators. HuB100tgxLdlr-/- mice were injected with DCs that had been made tolerogenic by treatment with IL-10 and loaded with the protein moiety of LDL, apolipoprotein B100 (ApoB100). One single injection led to a significant reduction of atherosclerotic plaque burden in the aorta with decreased lesional as well as systemic inflammation. This DC therapy diminished the autoreactive T cell response to ApoB100, showing that tolerogenic DC presenting the protein part of LDL can attenuate atherosclerosis.

Animals that are immunized with LDL together with adjuvant are protected against atherosclerosis, but the underlying mechanisms remain unknown. Rag2-/-/Apoe-/- mice, lacking functional T as well as B cells, and B cell-deficient μMT/Apoe-/- mice were immunized with homologous oxLDL. Adaptive immunity was shown to be obligatory for immunization-induced atheroprotection while humoral immunity was dispensable.

Degradation of extracellular matrix (ECM) in the vessel wall is central to inflammatory vascular diseases. SerpinA3 is an inhibitor of several immune cell-derived proteases involved in this process. SerpinA3 expression was detected in human atherosclerotic lesion, while its expression was decreased in human aortic abdominal aneurysm (AAA). Overexpression of the murine orthologue serpinA3n had no effect on atherosclerotic lesion size in Apoe-/- mice, but inhibited CaCl2-induced aneurysm formation.

In conclusion, we have studied the role of effector mechanisms of different immune cells in the pathological process of atherosclerosis. Some of the findings may have applications in the clinic, as novel therapeutic targets for cardiovascular disease. In brief, we found that LDL or components thereof displayed by immunogenic DCs aggravate atherosclerosis, while their presentation by tolerogenic DCs ameliorates disease. Protective immunization is dependent on adaptive, but no humoral immunity and serpinA3 plays a role in inflammatory vascular disease.

List of scientific papers

I. Hjerpe C, Johansson D, Hermansson A, Hansson GK, Zhou X. Dendritic cells pulsed with malondialdehyde modified low density lipoprotein aggravate atherosclerosis in Apoe-/- mice. Atherosclerosis. 2010 Apr;209(2):436-41.
https://doi.org/10.1016/j.atherosclerosis.2009.10.003

II. Hermansson A, Johansson D, Ketelhuth DFJ, Andersson J, Zhou X, Hansson GK. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation. 2011 Mar 15;123(10):1083-91.
https://doi.org/10.1161/CIRCULATIONAHA.110.973222

III. Johansson D, Hjerpe C, Robertson AK, Arnal JF, Hansson GK, Zhou X. Adaptive immunity is obligatory but humoral immunity is dispensable for immunization-induced atheroprotection. [Submitted]

IV. Wågsäter D, Johansson D, Fontaine V, Vorkapic E, Bäcklund A, Razuvaev A, Mäyränpää MI, Hjerpe C, Caidahl K, Hamsten A, Franco-Cereceda A, Wilbertz J, Swedenborg J, Zhou X, Eriksson P. Serine protease inhibitor A3 in atherosclerosis and aneurysm disease. [Submitted]