Pathogenesis of giant cell arteritis: More than just an inflammatory condition?

Abstract

Giant cell arteritis (GCA) is characterized by intimal hyperplasia and luminal obstruction leading to ischemic manifestations involving extra-cranial branches of carotid arteries and aorta. Histopathological lesions involve all layers of the arterial wall and are associated with multinucleated giant cells, fragmented internal elastic lamina and polymorphic cellular infiltrates, including T lymphocytes and macrophages. The pathophysiology of GCA is still poorly understood. After dendritic cell activation, CD4⁺ T lymphocytes, T helper 1 (Th1) cells, produce interferon γ and modulate macrophage activation and functions, and Th17 cells produce interleukin 17 (IL-17), which can induce cytokine production by macrophages and fibroblasts. Macrophages in the adventitia produce pro-inflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor α. These cytokines promote arterial wall and systemic inflammation. Questions remain regarding the nature of the antigen(s) triggering dendritic cell activation and the mechanisms underlying vascular remodeling. Here we review recent advances in the pathogenesis of GCA, with emphasis on the interactions between cells of the immune system and components of the vessel wall, including vascular smooth muscle cells and endothelial cells, leading to vascular remodeling. Finally, we propose new areas of investigation that could help understand the triggering factors and key pathogenic events in GCA.

Introduction

Giant cell arteritis (GCA) is a large-vessel vasculitis. This condition occurs exclusively in patients older than 50 years, mainly among people older than 70 years [1]. Women are affected in two-thirds of the cases. Most of the epidemiologic studies have focused on the incidence of GCA, estimated to be 10–29/100 000 at-risk persons and increasing with advancing age [1], [2]. The prevalence of GCA in people over 50 years old has been reported to vary between 278/100 000 in Olmsted County, Minnesota, USA [3], 25/100 000 in Germany [4], and 1.47/100 000 in Japan [5].

GCA specifically involves the aorta and external carotid arteries and their branches, with intimal hyperplasia and luminal obstruction leading to ischemic manifestations such as temporal headaches, jaw claudication, scalp tenderness and temporal artery involvement [6], [7]. Visual loss, which may occur as a consequence of acute anterior ischemic optic neuritis, central retinal artery occlusion or retro-bulbar optic neuritis, represents the most severe complication [8], [9]. In about 50% of patients with GCA, polymyalgia rheumatica develops and is responsible for hip and shoulder inflammation [10]. Most patients with GCA present signs of systemic inflammation, including weight loss, fatigue and fever, together with increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level [11]. No specific biological marker of GCA has been identified, and the diagnosis is usually established by temporal artery biopsy (TAB) [12]. Corticosteroids are the mainstay of GCA treatment [13], [14]. Histopathological lesions involve the 3 layers of the arterial wall and are associated with multinucleated giant cells resulting from the fusion of macrophages, fragmented internal elastic lamina and polymorphic cellular infiltrates, including T lymphocytes (TLs) and macrophages [15]. Several studies provided evidence that adventitial dendritric cells (DCs) are activated by an unknown stimulus that might be a microbial antigen (viral or bacterial) or an autoantigen [16]. These DCs, once activated, selectively activate antigen-specific TLs, which release interferon γ (IFN-γ) and regulate macrophage function and differentiation. Macrophages produce interleukin 1 (IL-1), IL-6 and tumor necrosis factor α (TNF-α); promote inflammation in the arterial wall; and initiate vascular remodeling through the release of cytokines, growth factors, reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), which contribute to tissue injury and intimal hyperplasia [17]. However, the key mechanisms involved in vascular remodeling that lead to luminal occlusion remain unidentified in GCA. Among other factors contributing to vascular remodeling, endothelial cells (ECs), under the influence of cytokines or growth factors produced by macrophages, might also promote neoangiogenesis. In addition, newly formed ECs are involved in local inflammation by producing pro-inflammatory cytokines and expressing adhesion molecules that allow for the recruitment of TLs [18]. Finally, despite the lack of data regarding the implication of humoral immunity in GCA, several studies provided evidence of autoantibodies in CGA [19], [20].

In this review, we provide an overview of recent breakthroughs in the pathogenesis of GCA and emphasize interactions between the main components of the immune system and the different compartments of the vessel wall, including ECs and vascular smooth muscle cells (VSMCs) that may lead to vascular remodeling.