The immunopathology of giant cell arteritis: diagnostic and therapeutic implications

Abstract

Giant cell arteritis (GCA) is an important cause of preventable blindness, most commonly due to anterior ischemic optic neuropathy. Ischemic tissue injury is the end result of a process that begins within the walls of susceptible arteries in which local dendritic cells (DCs) recruit and activate CD4 T cells that, in turn, direct the activity of effector macrophages. In response to the immune attack, the blood vessel forms lumen-stenosing intima. Multiple cascades of excessive T-cell reactivity contribute to the autoimmune features of giant cell arteritis with TH1 and TH17 immunity responsible for the early phase and TH1 immunity promoting chronic-smoldering inflammation. These cascades are only partially overlapping, supporting the concept that a multitude of instigators induce and sustain vascular inflammation. The artery actively participates in the abnormal immune response through endogenous immune sentinels, so-called vascular DCs embedded in the adventitia. Advancing age, the strongest of all risk factors for GCA, contributes to both, the dysfunction of the immune system and the vascular system. Expansion of the therapeutic armamentarium for GCA needs to focus on approaches that mitigate the impact of the aging artery and adapt to the needs of the immunosenescent host.

FIG. 1

Immunopathways in giant cell arteritis (GCA). A. Early GCA. Initial steps in the immune pathogenesis of GCA center on the adventitia. Resident vascular dendritic cells (vasDC) are triggered by danger signals to recruit and acti- vate CD4 T cells. T cells committed to the TH1 lineage release their marker cytokine IFN-γ, whereas T cells committed to the TH17 lineage secret IL-17. Both T-cell lineages participate in the evolving granulomatous inflammation. B. Chronic GCA. Chronic GCA is dominated by TH1 immunity. TH17 cells are explicitly sensitive to corticosteroid therapy and are eliminated from the vascular infiltrates in treated patients. Through the secretion of IFN-γ, vasculitic T cells attract, activate, and guide macrophages. Granulomatous infiltrates move into the media and intima. The vessel wall responds to the immune injury with the formation of hyper- plastic intima that compromises the lumen and leading to ischemic complications. TH, T helper cell; macro, macro- phage; IL, interleukin; INF, interferon; VSMC, vascular smooth muscle cells; IEL, internal elastic lamina; DC, dendritic cells.

FIG. 2

Vasculitic macrophages in giant cell arteritis (GCA). A multitude of macrophages contributes to the inflammatory infiltrates in GCA. Location within the vascular wall layers is associated with functional specialization. Adventitial macrophages produce proinflammatory cytokines (e.g., interleukin [IL]-6, IL-1). Macrophages caught in the media drive matrix and fiber destruction by the release of metal-loproteinases and expose the tissue to reactive oxygen and nitrogen species. Macrophages recruited to the intima provide growth factors (PDGF, VEGF, FGF) needed to support myofibroblast outgrowth and the development of a capillary system to supply oxygen, metabolites and cells for expanding intima. bFGF, Basic fibroblast growth factor; IEL, internal elastic lamina; MMP, matrix metalloproteinases; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.