Th17 and Th1 T-Cell Responses in Giant Cell Arteritis (original) (raw)

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 pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-␥-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA. (Circulation. 2010;121:906-915.) Key Words: glucocorticoids Ⅲ inflammation Ⅲ interferons Ⅲ interleukin-17 Ⅲ Th1 cells Ⅲ vasculitis G iant cell arteritis (GCA) is a systemic vasculitis with 2 disease components: vessel wall inflammation inducing arterial stenosis/occlusion and a systemic inflammation leading to polymyalgias, anemia, failure to thrive, and malaise. 1 Prototypical vessel wall inflammation preferentially affects the upper extremity and extracranial branches of the aorta, causing blindness, stroke, aortic arch syndrome, aortic aneurysm, or dissection. 1,2 Clinical Perspective on p 915 Glucocorticoids 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. How