Supplement Article |
OP2. PATHOGENESIS OF GCA AND PMR
Emory University School of Medicine, Atlanta, USA
As artery size increases, a sophisticated wall structure is required to support critical function in oxygen and nutrient transport. Blood supply to the arterial wall itself is provided from the most peripheral layer, the adventitia, which holds a dense system of vasa vasorum. Recent evidence suggests that the adventitia makes additional contributions to securing blood vessel function and health. Specifically, the adventitia is home to an indigenous population of dendritic cells (DCs) that are arranged circumferentially at the adventitia-media border and play an important role in regulating the immunogenicity of the artery.
DCs are powerful antigen-presenting cells that can prime naïve T cells. In order to investigate the function of tissue-residing DCs placed in the adventitia, we implanted medium-sized human arteries into SCID mice and adoptively transferred alloreactive T cells. Adventitial DCs avoided recognition by alloreactive T cells, suggesting that they may have a role in protecting the tissue site from inflammation. Systemic administration of Toll-like receptor ligands, especially ligands specific for TLR2 and TLR4, was sufficient to transform non-stimulatory DCs into highly activated effector cells. Triggered by TLR4 ligands, adventitial DCs released chemokines, attracted T cells, facilitated T-cell stimulation and supported invasion of T cells into the media. We conclude that immune recognition events in the vascular wall are principally regulated through indigenous DCs that are placed at the outskirts of the artery.
In patients with giant cell arteritis (GCA), a granulomatous vasculitis of medium-sized and large arteries, dense networks of DCs occupy the adventitia and media. In vasculitic lesions, DCs produce CCL19 and CCL21, and trap themselves through the expression of CCR7. Activation of CD4 T cells continuously depends upon DC-derived signals as demonstrated by the strong immunosuppressive effects achieved through depletion of activated DCs. DC depletion essentially destroyed the sophisticated organization of the T cell-macrophage infiltrates and disrupted production of the key cytokine IFN-
. In patients with polymyalgia rheumatica (PMR), a forme fruste of GCA lacking vascular infiltrates, the vessel wall DCs are already activated and capable of promoting T-cell stimulation. These data support the model that DCs strategically placed in the adventitia control tissue inflammation in the unique microenvironment of the vessel wall structure and make critical contributions to initiating and maintaining vasculitis.