Inflammation and immunity in diseases of the arterial tree: players and layers

Abstract

The hypothesis that immunity and inflammation participate in the pathogenesis of vascular diseases has now gained widespread recognition and stimulated work around the globe. Broadening knowledge has extended the recognition of the role of immune and inflammatory mechanisms to all of the layers of the artery, to all levels of the arterial tree, and implicated virtually all arms, cellular players, and effector molecules and pathways involved in these crucial host defenses, that turn against us in disease. We provide here a guide to a compendium series of articles that aimed to look forward and broaden the traditional focus of immunopathogenesis of arterial disease, with the goal of integrating the players and the layers involved. Although the field has advanced remarkably, much remains to be done, and this commentary also aims to highlight some of the gaps that future research should strive to close on the participation of inflammation and immunity in arterial diseases.

Keywords: aneurysm; atherosclerosis; lymph nodes; lymphocytes; vasculitis.

Figure 1. The immune and inflammatory diseases affect all levels of the arterial tree and smaller vessels

Atherosclerosis typically affects the large and medium arteries, as exemplified in this diagram by the plaque in the right coronary artery. Aneurysmal disease can affect the thoracic or infrarenal abdominal aorta as depicted in this drawing. Large and medium artery vasculitides include Takayasu and giant cell arteritis. Medium sized artery vasculitides include Kawasaki disease and polyarteritis nodosa. The small vessel vasculitides include those associated with anti-neutrophil cytoplasmic antibodies (ANCA) that recognize antigens of polymorphonuclear leukocyte such as proteinase-3 or myeloperoxidase. The ANCA-associated vasculitides include microscopic polyangiitis, granulomatosis with polyangiitis previously known as Wegener’s granulomatosis, and Churg-Strauss syndrome. Henoch-Schönlein purpura also affects smaller vessels. Immune complex vasculitides also typically affect smaller vessels. Some vasculitides affect arteries of various sizes including Behçet’s disease, relapsing polychondritis, and Cogen’s arteritis. (Illustration Credit: Ben Smith)

Figure 2. The immune and inflammatory responses involve all layers of arteries

The diagram depicts an atherosclerotic plaque as a prototypical inflammatory lesion in arteries. The intima, the usual focus in atherosclerosis research, covered by the endothelial monolayer, generally includes a fibrous cap overlying a central, lipid-rich “necrotic core”. The intima contains multiple cellular “players” including smooth muscle cells, macrophages, and T lymphocytes, among other cells involved in the innate and adaptive immune responses as described in the text. The intima may also contain a rich microvasculature that provides a portal for the entry and potential egress of leukocytes involved in immune and inflammatory responses. The internal elastic lamina (IEL) separates the intima from the media. Underneath atherosclerotic plaques, the IEL often undergoes fragmentation as depicted by the break in the dark line separating the intima from the media. The tunica media contains primarily smooth muscle cells and extracellular matrix. Indoleamine dioxygenase (IDO) produced by smooth muscle cells contributes to the immunoprivilege of the intima as described in the text. The media typically thins underlying atherosclerotic plaques. The media can grow outward during atherogenesis accommodating the growth of the plaque in an abluminal direction, a form of geometrical remodeling known as compensatory enlargement. The external elastic lamina separates the media from the adventitia. Previously often overlooked, the adventitia hosts a hotbed of immune and inflammatory activity. It furnishes the vasa vasorum that give rise to the plaque microvasculature. Lymphatic vessels provide channels for trafficking of immune cells and drain to local lymph nodes, a site of generation of immune responses to antigens implicated in arterial diseases. Organized tertiary lymphoid structures also localize in the adventitia. Dendritic cells patrol this and other regions of the plaque sampling antigens and presenting them to T lymphocytes, a vascular site of the afferent limb of adaptive immunity. Mast cells in the adventitia may also participate in arterial diseases. T cells, B cells, and plasma cells also inhabit this outermost layer of the artery wall. Nerve endings in the aventitia can secrete mediators that modulate vascular function. (Illustration Credit: Ben Smith).