Cause of Giant Cell Arteritis
Etiology and Pathogenesis
Giant cell arteritis is a disease of unknown etiology that develops in genetically predisposed individuals over age 50, triggered by unidentified environmental factors that activate dendritic cells in the arterial wall, initiating an autoimmune cascade. 1, 2
The exact cause of GCA has not been clearly identified, but the current understanding points to a multifactorial process:
Genetic and Environmental Factors
Genetic predisposition plays a significant role, with the highest incidence observed in populations of Northern European descent, particularly in Scandinavian nations and Minnesota, suggesting hereditary susceptibility. 3, 4
Environmental triggers remain unidentified but are thought to interact with genetic factors to initiate disease in susceptible individuals. 1, 2
Age-related factors are critical, as advancing age represents the strongest risk factor for GCA, contributing to both immune system dysfunction (immunosenescence) and vascular system abnormalities. 5
Immunopathologic Mechanism
The disease process unfolds through a specific sequence:
Dendritic cell activation occurs first, with vascular dendritic cells embedded in the adventitia of normal arteries becoming activated and matured by unknown triggers. 1, 5
T-cell recruitment and activation follows, as activated dendritic cells produce chemokines that recruit CD4+ T cells, which then proliferate and polarize into Th1 and Th17 cells producing IFN-γ and IL-17. 1
Macrophage differentiation occurs when monocytes are recruited and differentiate into macrophages, which form multinucleated giant cells (the histological hallmark) when persistently exposed to IFN-γ. 6, 1
Vascular remodeling results from immune cells and vascular smooth muscle cells triggering arterial wall destruction, leading to intimal hyperplasia and progressive arterial lumen occlusion responsible for ischemic symptoms. 6, 1
Key Pathophysiologic Features
The inflammatory process is characterized by arterial wall thickening with narrowed lumen, mononuclear inflammatory cell infiltration with media invasion, and the presence of multinucleated giant cells. 6, 7
Both innate and adaptive immune systems contribute to granuloma formation and the development of arterial tertiary follicular organs. 2
Vascular smooth muscle cells and endothelial cells actively participate in the pathologic process, not merely serving as passive targets. 1, 2