Immune mechanisms in medium and large-vessel vasculitis

Abstract

Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal, type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts, which engage in an interaction with T cells and macrophages to, ultimately, cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, have been identified in vasculitic lesions. Two dominant cytokine clusters--the IL-6-IL-17 axis and the IL-12-IFN-γ axis--have been linked to disease activity. These two clusters seem to serve different roles in the vasculitic process. The IL-6-IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12-IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the Notch receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive immunosuppression.

Figure 1

The walls of human arteries are multi-layered, with an endothelial barrier in the intima, sheets of vascular smooth muscle cells in the media and the vasa vasorum network in the adventitia. Endogenous vascular dendritic cells populate the adventitia (left) and are responsible for the recruitment of T cells and macrophages into the tissue niche. In early and untreated vasculitis, IFN-γ–producing Th1 cells and IL-17-secreting Th17 cells are abundant, surrounded by macrophages (middle). Corticosteroid therapy diminishes Th17 cells but cannot clear Th1 cells from the vascular lesions (right). Dysregulated VSMC migrate towards the lumen and lay down to form lumen-stenosing intimal hyperplasia.

Figure 2

IL-1β, IL-6, IL-23 and IL-21 shift T cell differentiation towards the Th17 lineage. Th17 cells produce a plethora of cytokines that regulate local and systemic inflammatory effects in GCA.

Figure 3

IL-12 is a major inducer of Th1 cells which release the highly potent cytokine IFN-γ into the microenvironment. IFN-γ controls macrophages activation and regulates disease-relevant functions of endothelial cells and vascular smooth muscle cells in vasculitis.

Figure 4

CD4 T cells from patients with GCA spontaneously express the NOTCH1 receptor, enabling them to engage dendritic cells and macrophages, but more importantly, to exchange information with endothelial cells and vascular smooth muscle cells. Both, CD4 T cells and VSMC express NOTCH receptors and NOTCH ligands, thus functioning as signal-receiving and signal-sending cells in immuno-stromal communications.