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Immune Checkpoint Dysfunction in Medium and Large Vessel Vasculitis.

Immune Checkpoint Dysfunction in Medium and Large Vessel Vasculitis.
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Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM,


Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM, (click to view)

Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM,

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American journal of physiology. Heart and circulatory physiology 2017 03 17() ajpheart.00024.2017 doi 10.1152/ajpheart.00024.2017

Abstract

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T-cells, macrophages and dendritic cells build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response-to-injury. Pathologic 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 suggest a more generalized defect in the threshold setting of such T-cells, rendering them hyperreactive. Under physiologic 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 dendritic cells fail to express the immunoinhibitory ligand PD-L1, leaving lesional T-cells unchecked. Consequently, PD-1(+) CD4 T-cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (IFN-γ, IL-17, IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the PD-1 immune checkpoint in GCA, promoting unopposed T-cell immunity, contrasts with checkpoint hyperactivity in cancer patients, in whom excessive PD-L1 expression paralyzes the function of anti-tumor T-cells. Excessive checkpoint activity is the principle underlying cancer immune evasion and is therapeutically targetted by immunotherpay with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anti-cancer T-cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

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