Lymphocytes and the adventitial immune response in atherosclerosis

Abstract

Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.

Figures

Figure 1. Movat’s stain of a cross section of a 24 week old Ldlr−/− mouse fed a Western diet for 16 weeks

As indicated by the small arrow, there is thinning of the media and breakdown of the internal and external elastic lamina in the setting of advanced atherosclerotic plaque. The large arrow points to an advanced atherosclerotic lesion that has breached the internal elastic lamina, media, and external elastic lamina with evidence of necrotic core and cholesterol crystals within the adventitia. This breach enables emigration of intimal macrophages, dendritic cells, and lymphocytes to the adventitia and compromises the barrier status of the media. There is compensatory thickening of the adventitia in this region which likely serves to contain the breached media.

Figure 2. Fluorescent microscopy (10X) of a cross-section from the aortic root of a 24 week old Ldlr−/− mouse fed Western diet for 16 weeks

Macrophages appear red (anti-Mac-2), T lymphocytes appear green (anti-CD3), and nuclei appear blue (DAPI). The overlay RGB image clearly demonstrates the intima, media, and adventitia with the presence of an atherosclerotic plaque containing macrophages and T lymphocytes. Adjacent to the coronary artery (CA) is an area with T lymphocytes as well as an area of adventitial macrophages.

Figure 3. Proposed model of immune system activity in the adventitia

Small medial conduits, as demonstrated by Gräbner and colleagues, may enable soluble antigens, cytokines, growth factors, and chemokines to traffic between the intima and the adventitia. Chemokines and cytokines passing through these conduits may aid in the recruitment of leukocytes to the growing atherosclerotic plaque via the vasa vasorum. Additionally, growth factors secreted by cells within the growing plaque may stimulate neovascularization from the adventitial vasa vasorum. As shown in Figure 1, the media underlying advanced atherosclerotic plaques may be breached, compromising the barrier status of the media. In this model, cells can then cross the media and present antigen to helper T lymphocytes. The helper T lymphocytes (negatively regulated by Fox3p+ T reg lymphocytes) then stimulate B lymphocytes to undergo clonal expansion, isotype switching, and affinity maturation (asterisk). B lymphocytes with low affinity for antigen presented on follicular dendritic cells may undergo apoptosis and be removed by tingible body macrophages via efferocytosis. The B lymphocytes selected through high affinity interaction with antigen presented on follicular dendritic cells may undergo differentiation into memory B lymphocytes and plasma cells that may produce IgM or IgG autoantibodies locally or traffick to lymph nodes.