Large vessel vasculitis (LVV) is characterized by immune-mediated injury of predominantly large vessels. Histopathologic features include mononuclear cell infiltration of the vessel wall that often includes granuloma formation. Within this group of diseases, Takayasu arteritis (TAK) affects younger individuals (younger than 50 years; mean age ~26 years at onset), whereas giant cell arteritis (GCA) is unique to older patients (older than 50 years; mean age ~74 years at onset) (1). Both predominantly affect women. Included within the LVV spectrum is isolated focal aortic disease, which is usually limited to the thoracic aorta. Isolated focal aortic disease is a form of vasculitis within the larger category of single-organ vasculitis (1). Patients with isolated focal aortic disease who do not have histories or features of GCA or TAK at presentation may later develop TAK or GCA, but that is infrequent (2). It has been suggested that GCA (prevalence 1 in 500 in the population older than 50 years) and TAK (annual incidence ~3 per million) may be the same disease with the same etiology, but with phenotypic variations due to immune and substrate senescence that occur with aging (3,4). How and whether isolated focal aortic disease fits into the spectrum of GCA and TAK have not been explored. Limited availability of aorta specimens has been a major deterrent to designing studies that may provide a better understanding of LVV pathogenesis. TAK and GCA are primarily considered Th1 and Th17 cell–mediated diseases (5,6). In both, certain vascular territories are commonly affected (e.g., aorta and aortic arch vessels) and others mostly spared (e.g., arteries distal to the elbows and knees), begging the question of what might be targeted antigens or shared immune vulnerabilities within affected sites (7). Vascular dendritic cells (DCs) are a component of the resident cell population in muscular arteries (6,8). It has been proposed that resident-sentinel DCs within the adventitia–media border of muscular arteries become activated by unknown antigen(s), leading to the recruitment of CD4+ T cells and release of proinflammatory cytokines (8,9). The inflammatory cascade includes endothelial cell activation, recruitment of macrophages and neutrophils, enhanced production of matrix metalloproteinases, and oxidative products that cause extracellular matrix disruption and reorganization (10,11). Previous attempts to identify autoantigens and infectious agents in the temporal arteries of patients with GCA have implicated numerous organisms, including parainfluenza virus type 1 (12), herpes simplex virus (13), parvovirus B19 (14), Varicella zoster virus (15), Chlamydia pneumonia (16), and Mycobacterium tuberculosis (17). In a previous study, microbial fragments present in the giant cells of temporal arteries were isolated and found to contain signatures of multiple bacterial species to which patients produced antibodies (18). Other studies have failed to identify suspected microbial agents in temporal arteries. Our study is unique in addressing the issues of autoantigens within sterile, snapfrozen, thoracic aorta specimens. Within our Heart Vascular Institute, the Center for Aortic Diseases performs thoracic aorta surgeries for >650 patients per year. This has provided opportunities to study specimens from patients with a variety of noninflammatory conditions and LVV. We have explored LVV pathogenesis by asking questions about extractable antigens in the aneurysmal aorta of surgical specimens that may elicit autologous immune responses. The question of antigen reactivity was explored in patients with GCA, TAK, or isolated focal aortic disease, and in disease controls (i.e., patients with thoracic aneurysms who had matrix disorders and no clinical or pathologic evidence of vasculitis). We found that patients with LVV, including GCA, TAK, and isolated focal aortic disease, produce antibodies to select isoforms of 14-3-3 proteins.
