Vascular damage in giant cell arteritis

Abstract

Immune-mediated damage to medium-sized arteries results in wall remodeling with intimal hyperplasia, luminal stenosis and tissue ischemia. In the case of the aorta, vasculitis may result in dissection, aneurysm or rupture. The response-to-injury program of the blood vessel is a concerted action between the immune system and wall-resident cells, involving the release of growth and angiogenic factors from macrophages and giant cells and the migration and hyperproliferation of vascular smooth muscle cells. Innate immune cells, specifically, dendritic cells (DC) positioned in the vessel wall, have been implicated in the earliest steps of vasculitis. Pathogen-derived molecular patterns are capable of activating vascular DC and initiating adaptive immune responses. The pattern of the emerging vessel wall inflammation is ultimately determined by the initial insult. Ligands to toll-like receptor (TLR) 4, such as lipopolysaccharides, facilitate the recruitment of CD4 T cells that invade deep into the wall and distribute in a panarteritic pattern. Conversely, ligands for TLR5 condition vascular DC to support perivasculitic infiltrates. In essence, both innate and adaptive immune reactions collaborate to render the arterial wall susceptible to inflammatory damage. Unique features of the tissue microenvironment, including specialized DC, shape the course of the inflammatory response. Differences in vascular damage pattern encountered in different patients may relate to distinct instigators of vasculitis.

Figure 1

Innate and adaptive immune responses lead to vascular damage in GCA. Tissue injury of the vascular wall in GCA is the cumulative effect of a cascade of immune events. Early steps relate to the functioning of the innate immune system with danger signals triggering artery-intrinsic DC. Induction of adaptive immune responses creates granulomatous infiltrates with tissue-injurious potential. The vascular wall responds with a remodeling program that is maladaptive and endangers the supply of blood and nutrients to dependent organs.

Figure 2

Vascular DC shape the arrangement and composition of T-cell responses in the arterial wall. Triggering of wall-embedded DC by different TLR ligands results in distinct architectures of vessel wall inflammation. TLR4 ligands induce the release of CCL20, the preferred recruitment of CCR6^þ T cells and the establishment of wall-penetrating inflammation. TLR5 agonists facilitate T-cell recruitment with T cells clustering in the adventitia, assembling a perivascular infiltrate.

Figure 3

Immune cells and vessel wall cells collaborate in mediating vascular damage in GCA. Vascular DC are an indigenous cell population in the artery’s wall and respond to danger signals by recruiting T cells and macrophages. Macrophages secrete ROI, enzymes, and growth factors. ECs participate in cell recruitment and neoangiogenesis, supporting the remodeling of the wall structure. Vascular smooth muscle cells proliferate and migrate to form the hyperplastic and lumen-obstructive intima but also contribute to wall damage by secreting tissue-injurious enzymes and imposing oxidative stress.