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