Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice

Abstract

Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. Two forms of GCA have been identified: a cranial form involving the medium-caliber temporal artery causing temporal arteritis (TA) and an extracranial form involving the large vessels, mainly the thoracic aorta and its branches. GCA generally affects individuals with a genetic predisposition, but several epigenetic (micro)environmental factors are often critical for the onset of this vasculitis. A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. Cells of the vessel wall cells, including vascular smooth muscle cells (VSMCs) and endothelial cells, actively contribute to vascular remodeling responsible for vascular stenosis and ischemic complications. This review will discuss new insights into the molecular and cellular pathogenetic mechanisms of GCA, as well as the implications of these findings for the development of new diagnostic biomarkers and targeted drugs that could hopefully replace glucocorticoids (GCs), still the backbone of therapy for this vasculitis.

Keywords: adaptive immunity; cytokines; giant cell arteritis; innate immunity; vascular wall cells.

Figure 1

Cellular and molecular pathogenesis of GCA. Cells of the innate and adaptive immune system and the vascular wall contribute to the pathogenesis of GCA. Adventitious dendritic cells are activated by unknown molecules of microbial and/or cellular origin. Dendritic cells in GCA are typically defective in the expression of the immunosuppressive surface molecule PD-L1, as indicated in the figure by the red cross. Dendritic cells produce IL-12, which promotes the differentiation of Th1 cells, and Il-6 and IL-23, which contribute to the differentiation and stabilization of the phenotype of Th17 cells. T lymphocytes are activated by both dendritic cells and B lymphocytes through the presentation of a putative antigen. Th1 cells produce IFN-γ and GM-CSF, while Th17 cells produce IL-17. These cytokines activate M1 and M1 macrophages, which in turn produce MMP-9, IL1-β, and ROS, contributing to media destruction. Some macrophages, unable to kill the phagocytosed material, transform into giant cells. CD4+ and CD8+ Treg cells participate in the inflammatory reaction, being deficient in their immunosuppressive function, as indicated by the stop symbol. CD8+ cytotoxic T cells and neutrophils producing proinflammatory cytokines and NETs play an additional role in the pathogenesis of GCA. At the vascular level, damaged VSMCs produce VEGF, PDGF, endothelin-1, and MMP-2, which promote their differentiation into myofibroblasts. These cells cause thickening of the intima and subsequent vascular stenosis. Many cytokines recognize JAK-associated receptors and amplify the inflammatory cascade through the activation of the JAK/STAT signaling pathway. T and B cells aggregate to form tertiary follicular structures (ATLO), whereas T cells and macrophages are the main components of granulomas. The light-yellow boxes show the main drugs available to date that inhibit the various factors involved in the pathogenesis of GCA, as indicated by the thin arrows. Of these, only tocilizumab has been officially approved for the treatment of this vasculitis.