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Review
. 2013 Jan;123(1):27-36.
doi: 10.1172/JCI63108. Epub 2013 Jan 2.

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Andrew H Lichtman  1 , Christoph J Binder, Sotirios Tsimikas, Joseph L Witztum
Affiliations
Review

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Andrew H Lichtman et al. J Clin Invest. 2013 Jan.

Abstract

Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

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Figures

Figure 1
Figure 1. Theoretical events in initiation and effector phases of a proatherogenic T cell response.
Modified self-proteins generated in early atherosclerotic lesions (or systemically), such as the oxidatively modified apoB-100 component of LDL, are processed by DCs and presented as peptide/MHC complexes to naive T cells in secondary lymphoid tissues, leading to T cell clonal expansion and differentiation into effector T cells, such as Th1 or Th17 cells. The effector T cells migrate into arterial lesions, where resident macrophages or DCs present the same peptide-MHC antigens, leading to effector T cell activation and expression of pro-inflammatory effector molecules, such as secreted IFN-γ and IL-17 and membrane-bound CD40 ligand. These molecules promote lesion growth and/or destabilization.
Figure 2
Figure 2. Costimulatory and coinhibitory molecules and their receptors.
Costimulatory molecules, expressed on APCs, engage receptors on T cells concurrent with antigen recognition and induce signals that are required for naive T cell activation or that enhance effector/memory T cell responses. Coinhibitory receptors (CTLA-4 and PD-1) are expressed on activated T cells and, upon binding ligands on APCs, inhibit T cell responses. The major costimulatory and coinhibitory molecules, which belong to the B7/CD28 families or TNF/TNFR superfamilies, are shown in the table.
Figure 3
Figure 3. Translational applications of OSE Abs.
(A) E06 to oxidized phospholipid (oxPL) can be used to measure oxPL/apoB in human plasma as a biomarker of CVD. Because most oxPL is bound by Lp(A) lipoproteins, the assay primarily reflects the oxPL content on the most atherogenic Lp(A) particles (154). The 10-year predictive value of oxPL/apoB in death, myocardial infarction (MI), and stroke in the prospectively followed Bruneck population, which represents a general community, is shown (155). Groups 1, 2, and 3 represent the top, middle, and bottom tertiles, respectively. (B) Molecular imaging of murine atherosclerosis using MDA2, a malondialdehyde-specific monoclonal Ab. Nanoparticles consisting of micelles containing manganese (Mn) and MDA2 can increase relaxivity through binding to extracellular oxLDL, internalization into macrophages, and intracellular release as free Mn, thus becoming an indirect OSE-dependent macrophage-targeting agent. Noninvasive magnetic resonance imaging of OSEs is accomplished by injection of these nanoparticles and imaging of the abdominal aorta in cholesterol-fed Apoe–/– mice. Note the lack of signal at the preinjection scan and the strong signal (white contrast) in the 48-hour scan (156). Arrow indicates lesions in the abdominal aorta. (C) Therapeutic use of the human OSE Ab IK17 (as a scFv) to inhibit atherosclerosis. High-plasma titers of IK17 scFv were achieved in cholesterol-fed Ldlr–/–Rag1–/– mice via adenoviral-mediated hepatic expression, leading to a 46% reduction in en face atherosclerosis, compared with that in control mice treated with an adenovirus–enhanced green fluorescent protein vector (92). Importantly, peritoneal macrophages isolated from Adv-IK17-scFv–treated mice had decreased lipid accumulation, consistent with the ability of IK17 to inhibit oxLDL uptake by macrophages. Images reprinted with permission from Biomarkers in Medicine (154), Arteriosclerosis, Thrombosis, and Vascular Biology (155), and Journal of the American College of Cardiology (156).
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