Etiology
The exact cause remains unknown; however, genetic and environmental factors are thought to contribute to the development of GCA. The condition is probably triggered by an environmental cause in a genetically predisposed person.
Genetic polymorphisms of the human leukocyte antigen (HLA) class II region, specifically HLA-DRB1*04 and DRB1*01 alleles, are associated with susceptibility to GCA.[21]
Several infectious agents have been implicated, but conclusive evidence is lacking. These agents include Mycoplasma pneumoniae, parvovirus B19, parainfluenza virus, Chlamydia pneumoniae, and the varicella-zoster virus.[9]
Pathophysiology
GCA is an immune-mediated vasculitis characterized by granulomatous inflammation in the walls of medium-sized and large arteries.[22][23] The extracranial branches of the carotid artery are preferentially involved, although the aorta and its major branches are often targeted as well. Affected arteries contain inflammatory lesions arranged in granulomas composed of T cells and macrophages.[22] Multinucleated giant cells are present in about 50% of cases, but they are not required to make the diagnosis of GCA.
The initial immune insult is thought to occur in the outer or adventitial layer of the arterial wall.[2] Highly activated resident dendritic cells play a critical role by attracting and presenting antigen to T cells. CD4 T cells enter the artery through the vasa vasorum and, on activation, proliferate and undergo clonal expansion in the vessel wall. T cells release the cytokine interferon gamma, which in turn stimulates tissue-infiltrating macrophages and induces formation of multinucleated giant cells.[2] Macrophages in the adventitia produce the inflammatory cytokines interleukin 1 and interleukin 6, which are responsible for systemic inflammation and the acute-phase response, resulting in elevation of inflammatory markers.[22] In the muscular or medial layer of the artery, macrophages cause tissue damage by releasing matrix metalloproteinases and reactive oxygen species, resulting in oxidative stress.[2] Consequently, the internal elastic lamina, which separates the intimal and medial layers, becomes fragmented. In some patients, interferon gamma promotes the differentiation and fusion of highly activated macrophages to form multinucleated giant cells.[22] Multinucleated giant cells tend to lie at the media-intima border, often close to fragments of the internal elastic lamina.
In response to immunologic injury, the artery releases growth and angiogenic factors (i.e., platelet-derived growth factor and vascular endothelial growth factor) that result in proliferation of myofibroblasts, new vessel formation, and marked thickening of the intimal or inner layer.[2]
This process of intimal expansion and hyperplasia leads to narrowing and occlusion of the vessel lumen, ultimately causing tissue ischemia. Clinical symptoms derive from ischemia in organs such as the eye and brain, leading to blindness and stroke.[24][25][26] Low-grade inflammation has also been demonstrated in temporal artery biopsy specimens from patients with polymyalgia rheumatica but without overt clinical arteritis.[27]
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