title: Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis.
abstract: Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4+T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1lo, whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD-1+effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1+effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Ryu
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Berry
authors.affiliation: Division of Nephrology, University Hospital of Parma, 43100 Parma, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
authors.affiliation: Department of Ophthalmology, Stanford Byers Eye Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Yaping Joyce
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Warrington
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305; cweyand@stanford.edu.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001158:Arteries / Q000378:metabolism* / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D013700:Giant Cell Arteritis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1; T cells; autoimmunity; immune checkpoint; vasculitis