Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results-The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-␥ and interleukin (IL)-17 and frequencies of interferon-␥-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1␤, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions-Two Clinical Perspective on p 915Glucocorticoids remain the gold standard of therapy; attempts to introduce steroid-sparing agents, including antitumor necrosis factor blockers, have not been successful. 3,4 Methotrexate may have minor benefits when given over prolonged periods. 5 In a double-blind, placebo-controlled study employing glucocorticoid pulse therapy, patients pulsed at diagnosis had fewer disease flares and discontinued therapy earlier than patients without initial pulse therapy. However, benefits of pulse glucocorticoids were delayed until 12 to 18 months into treatment. 6 Acetylsalicylic acid has a role as adjuvant therapy, partially by inhibiting inflammation and partially through antiplatelet effects. 7,8 Steroid withdrawal after Ͼ2 years of therapy is often accompanied by recurrence of inflammatory markers, and vascular inflammation persists despite glucocorticoid treatment. 9 -11 In essence, despite their prompt, impressive therapeutic effects, glucocorticoids fail to abrogate vasculitis. Improved disease management and avoidance of severe glucocorticoid side effects will require a better understanding of underlying immune abnormalities.Both the innate and adaptive immune system contribute to GCA pathogenesis. 12 Granulomatous inflammatory infiltrates composed of CD4 T cells, activated macrophages, and multinucleated giant cells induce intimal hyperplasia and luminal compromise. 13 In cell-depletion studies, dendritic cells (DCs) have emerged as the predominant antigen-presenting cell. 14,15 DCs are now recognized as an indigenous cell

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Background-Inflammatory vasculopathies, ranging from the vasculitides (Takayasu arteritis, giant cell arteritis, and polyarteritis nodosa) to atherosclerosis, display remarkable target tissue tropisms for selected vascular beds. Molecular mechanisms directing wall inflammation to restricted anatomic sites within the vascular tree are not understood. We have examined the ability of 6 different human macrovessels (aorta and subclavian, carotid, mesenteric, iliac, and temporal arteries) to initiate innate and adaptive immune responses by comparing pathogen-sensing and T-cellstimulatory capacities. Methods and Results-Gene expression analysis for pathogen-sensing Toll-like receptors (TLRs) 1 to 9 showed vessel-specific profiles, with TLR2 and TLR4 ubiquitously present, TLR7 and TLR9 infrequent, and TLR1, TLR3, TLR5, TLR6, and TLR8 expressed in selective patterns. Experiments with vessel walls stripped of the intimal or adventitial layer identified dendritic cells at the media-adventitia junction as the dominant pathogen sensors. In human artery-severe combined immunodeficiency (SCID) mouse chimeras, adoptively transferred human T cells initiated vessel wall inflammation if wall-embedded dendritic cells were conditioned with TLR ligands. Wall-infiltrating T cells displayed vessel-specific activation profiles with differential production of CD40L, lymphotoxin-␣, and interferon-␥. Vascular bed-specific TLR fingerprints were functionally relevant, as exemplified by differential responsiveness of iliac and subclavian vessels to TLR5 but not TLR4 ligands. Conclusions-Populated by indigenous dendritic cells, medium and large human arteries have immune-sensing and T-cell-stimulatory functions. Each vessel in the macrovascular tree exhibits a distinct TLR profile and supports selective T-cell responses, imposing vessel-specific risk for inflammatory vasculopathies.

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