Toll-like receptors in giant cell arteritis

Abstract

Giant cell arteritis, a primary vasculitis of medium-sized and large arteries, causes vessel occlusion through fast and concentric intimal hyperplasia. Contextual parameters, especially the topography of the arterial wall, have emerged as critical pathogenic elements. Experimental data support the concept that the disease is initiated in the most outer layer of the arterial wall, the adventitia. CD4 T cells are recruited to the adventitia, undergo local activation and subsequently orchestrate macrophage differentiation. T cells and macrophages infiltrate into all wall layers and acquire different effector functions dependent on cues in their immediate microenvironment. The end result is myofibroblastic proliferation, luminal stenosis, and tissue ischemia. Adaptive immune responses in the adventitia are triggered by a population of indigenous dendritic cells (DC) placed at the adventitia-media junction. These arterial DCs have a unique surface receptor profile, including a series of Toll-like receptors (TLR). Responsiveness of such arterial DCs to blood-borne stimuli has been studied in human arteries engrafted into immunodeficient mice. Ligands of TLR4 are able to start maturation of adventitial DCs which fail to leave the peripheral tissue site. Instead, these adventitial DCs produce chemokines, recruit T cells, and support their local activation. These data identify tissue-residing DCs as gatekeepers in vasculitis and support the model that TLR ligands function as instigators of vessel wall inflammation.

Introduction

Giant cell arteritis (GCA) is a granulomatous vasculitis that affects large and medium-sized arteries. The disease manifests primarily in the head, neck, and upper extremities. In most patients, vascular lesions are detectable in the extracranial branches of the carotid arteries, such as the temporal arteries. Vessel wall inflammation in the vertebral arteries, subclavian arteries, and the aorta itself is not unusual. The disease process causes vascular lumen occlusion and subsequent tissue ischemia leading to blindness, jaw claudication, and stroke [1], [2], [3]. Over the last decade, it has become clear that GCA is a T-cell mediated disease. Activation of CD4⁺ T cells occurs in the adventitia of the arterial wall. T cells that reside in the adventitia release IFN-γ and regulate differentiation and function of tissue-infiltrating macrophages [4], [5], [6]. Upon activation, macrophages produce reactive oxygen intermediates [7], [8] and matrix metalloproteinases [9], resulting in the destruction of the elastic laminae and thinning of the media. Macrophages also secrete proinflammatory cytokines and growth factors [7] which drive cell recruitment, proliferation of myofibroblasts [10], and neoangiogenesis [11], eventually causing luminal stenosis. Experimental evidence indicates that selected CD4⁺ T cells undergo clonal expansion in the adventitia, suggesting antigen-driven stimulation. A critical question is which antigen-presenting cells (APC) are involved in initiating T-cell activation. We have been focused on investigating the contributions of different types of APCs to the disease process. We have found that dendritic cells (DC) are present in temporal artery lesions, and evidence is accumulating that these cells have gatekeeper function in vessel wall inflammation [12]. Surprisingly, we found that the adventitia of normal noninflamed temporal arteries harbors a population of DCs. These adventitial DCs are immature and resting and do not release inflammatory mediators. Adoptive transfer experiments performed in temporal artery-SCID mouse chimeras have demonstrated that activation of such adventitial DCs is sufficient to initiate T-cell recruitment and in situ activation [13]. We therefore propose that adventitial DC differentiation is an early and critical event in GCA. In full-blown arteritis, DCs are mature and highly activated, migrate into the media, and release large amounts of chemokines. Depletion of such DCs by antibody therapy specifically disrupts vasculitis [12], [13].

Our current studies center on pathways that trigger adventitial DCs, thereby leading to T-cell recruitment, vessel wall inflammation, and breakdown of tolerance. Guided by the importance of Toll-like receptors (TLR) in the activation and maturation of DCs, we have examined ligands relevant for TLRs 2 and 4 and tested their contribution to the induction of vascular inflammation [13]. Triggering of TLRs 2 and 4 in human arteries by blood-borne stimuli is sufficient to initiate the cascade of events that leads to activation of T cells in the arterial adventitia and subsequent arteritis.