Trapping of Misdirected Dendritic Cells in the Granulomatous Lesions of Giant Cell Arteritis

Abstract

Immature dendritic cells (DCs) are scattered throughout peripheral tissues and act as sentinels that sample the antigenic environment. After activation, they modify their chemokine receptor profile and migrate toward lymphoid tissues. On arrival, they have matured into chemokine-producing DCs that express co-stimulatory molecules and can prime naive T cells. Normal temporal arteries contain immature DCs that are located at the media-adventitia border. In temporal arteries affected by giant cell arteritis, DCs are highly enriched and activated and have matured into fully differentiated cells producing the chemokines, CCL18, CCL19, and CCL21. In keeping with their advanced maturation, DCs in the granulomatous lesions possess the chemokine receptor, CCR7. CCR7 binds CCL19 and CCL21, causing the highly activated DCs to be trapped in the peripheral tissue site. The co-stimulatory molecule, CD86, which is critical for DC/T-cell interaction, is expressed by a subset of DCs captured in the arterial wall. DC/T-cell interaction does not involve interleukin-12; transcripts for interleukin-12 p40 are absent in the vasculitic infiltrates. We propose that differentiation of DCs and the autocrine and paracrine actions of chemokines in granulomatous lesions misdirect DCs away from their usual journey to lymphoid organs and are critical in maintaining T-cell activation and granuloma formation in giant cell arteritis.

Elastic-Vessel Arteritis in Interleukin-1 Receptor Antagonist–Deficient Mice Involves Effector Th1 Cells and Requires Interleukin-1 Receptor

“…Fainter CD205 ϩ cells are probably macrophages. As in human vessels, 14 dendritic cells (visualized as MHC II ϩ cells) tended to form a ring around the media in the wild-type artery (Figure 5j) and occupied the fibrous tissue of the valve itself. Anti-CD205 antibodies detected no cells in wild-type aortic roots, possibly because CD205 is only upregulated to detectable levels during maturation.…”

“…Trapped dendritic cells have already been implicated in GCA. 11,14 Maturation of dendritic cells can be triggered by a combination of IL-1 and CD40L, 25 which could provide a direct link between IL-1 hyperactivity and the onset of a putative autoimmune state. Chemokine secretion would be expected to mediate the recruitment of more macrophages and effector T cells, as well as immobilize dendritic cells, 22 and we show evidence of CCL2 in the mouse lesions.…”

Role of NADPH Oxidase in Formation and Function of Multinucleated Giant Cells

“…It is also possible that giant cells could be formed through fusion of dendritic cells, which would be promoted by IFN-␥ [161] . Indeed, concentrations of tissue IFN-␥ correlate with the formation of multinucleated giant cells in GCA [162] .…”

Dendritic Cells in Cardiovascular Diseases

“…[37][38][39] It is hypothesized that they contribute to the first critical steps in disease pathogenesis through breakdown of vascular tolerance. In these vasculopathies, resident DCs are located in the adventitia and adventitia-media border, and cDC numbers are seen to increase with disease progression.…”