Immune checkpoint dysfunction in large and medium vessel vasculitis

被引:91
作者
Watanabe, Ryu [1 ]
Zhang, Hui [1 ]
Berry, Gerald [2 ]
Goronzy, Jorg J. [1 ]
Weyand, Cornelia M. [1 ]
机构
[1] Stanford Univ, Div Immunol & Rheumatol, Dept Med, Sch Med, CCSR Bldg,Rm 2225,Mail Code 5166,269 Campus Dr W, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2017年 / 312卷 / 05期
基金
美国国家卫生研究院;
关键词
dendritic cell; giant cell arteritis; immune checkpoint; programmed cell death protein-1; programmed cell death ligand-1; GIANT-CELL ARTERITIS; DENDRITIC CELLS; POLYMYALGIA-RHEUMATICA; T-CELLS; PD-L1; ACTIVATION; BLOCKADE; MACROPHAGES; DISRUPTION; MECHANISMS;
D O I
10.1152/ajpheart.00024.2017
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-gamma, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.
引用
收藏
页码:H1052 / H1059
页数:8
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