Immunoinhibitory checkpoint deficiency in medium & large vessel vasculitis

Hui Zhang, Ryu Watanabe, Gerald J. Berry, Augusto Vaglio, Yaping Joyce Liao, Kenneth J Warrington, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticle

71 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E970-E979
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number6
DOIs
StatePublished - Feb 7 2017

Keywords

  • Autoimmunity
  • Immune checkpoint
  • PD-1
  • T cells
  • Vasculitis

ASJC Scopus subject areas

  • General

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