Abstract 14947: JAK/STAT-Signaling in Giant Cell Arteritis
Background: Giant cell arteritis (GCA) is a granulomatous vasculitis that preferentially targets the aorta and its major branches. CD4 T cells and macrophages are key pathogenic drivers and cause luminal occlusion and secondary ischemic organ damage such as blindness, stroke and aortic arch syndrome. TH17 and TH1 cells have previously been implicated in the disease process with TH1 immunity persisting despite chronic corticosteroid-based immunosuppression. The role of cytokine-dependent signaling pathways, particularly JAK/STAT signaling in chronic GCA, is unknown.
Results: To identify signaling pathways involved in chronic vasculitis we screened plasma from GCA patients and temporal artery biopsy samples for evidence of cytokine signaling. Circulating IFN-γ levels were 10-fold higher in GCA patients compared to age-matched controls. IFN-γ and downstream target genes including the signal transducer and activator of transcription (STAT)-1 were abundantly expressed in tissue lesions. To investigate the relevance of STAT-1 signaling, we compared the immunosuppressive effects of corticosteroids and the JAK/STAT-inhibitor tofacitinib (CP-690,550, a potent kinase inhibitor for JAK3 > JAK1 > JAK2) in experimentally induced vasculitis of medium-sized human arteries in a SCID chimera model. Dexamethasone effectively suppressed the activity of vascular dendritic cells (DCs) and inhibited inflammatory cytokines (IL-6, IL-1β) in the vascular lesions. Dexamethasone could not reduce the density of the T cell infiltrates and IFN-γ-producing TH1 cells persisted (P = 0.98). In contrast, the JAK/STAT inhibitor reduced T cell accumulation in the vessel wall and effectively suppressed IFN-γ production (P = 0.03) and signaling. Circulating IFN-γ levels declined by 65% (P = 0.004) following CP-690,550 treatment. A major effect of JAK/STAT inhibition involved a disruption in the supply of vasculitic T cells by retaining them in secondary lymphoid tissues.
Conclusion: IFN-γ-dependent STAT-1 signaling is a key pathogenic pathway in GCA. JAK/STAT signaling regulates the activity of vascular DCs but more importantly T cell trafficking from lymphoid tissues to the blood vessel wall and determines retention of vasculitic T cells in the inflammatory lesions.
- © 2013 by American Heart Association, Inc.