Innate and Adaptive Immunity in Giant Cell Arteritis

Abstract

Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4⁺ T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4⁺ T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8⁺ T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.

Keywords: CD8 Treg; NOTCH; PD-L1; T cell; endothelial cell; exosome; macrophage; vasculitis.

Figure 1

Giant Cell Arteritis in the Temporal Artery. Classic histopathologic and immunophenotypic findings of temporal arteritis in a 78-year old woman presenting with headaches. Panel (A) Transmural arterial inflammation with marked luminal narrowing caused by intimal proliferation which creates a slit-like lumen. Multinucleated giant cells are concentrated in the medial layer (H&E x125) Panel (B) CD68-positive histiocytes accumulating within the medial and adventitial layers of the artery with only scattered histiocytes in the intimal layer (x100). Panel (C): CD4⁺ T cells with a similar pattern of distribution as the CD68⁺ macrophages (x100). Panel (D) Infrequent CD8⁺ T cells within the T cell infiltrates (x100).

Figure 2

Key Pathogenic Steps in Giant Cell Arteritis. 1. The protective shield of the artery wall breaks when immune cells leave the vasa vasorum and invade into the tissue. An essential checkpoint is the digestion of the vascular basal lamina, facilitated by MMP-9-producing monocytes. 2. Vasculitic T cells follow, and macrophages (histocytes) and T cells form granulomatous infiltrates in the adventitia and media. 3. MMP-9-producing macrophages destructs the elastic laminae and eventually, tissue-damaging multinucleated giant cells emerge. 4. T cells encounter DC that lack the immunoinhibitory ligand PD-L1 and enter unopposed and persistent activation. 5. Wall-residing DC provide chemokines and cytokines to enhance immune cell recruitment. 6. Chronically stimulated T cells differentiate into multifunctional effector cells providing an array of effector cytokines. They also acquire tissue residence and replenish the lesion from within. 7. Macrophages are functionally heterogenous, but their functional commitment is directly related to their positioning in the vessel wall. Macrophage products include chemokines and cytokines, tissue-damaging mediators (ROS, MMP-9) as well as growth factors (VEGF, PDGF). 8. Continuously stimulated T cells and macrophages elicit a maladaptive response-to-injury presenting as vessel wall remodeling, with wall vascularization and intimal hyperplasia.

Figure 3

Giant Cell Arteritis in the Aorta. Biopsy sample from surgically removed aortic wall of a patient undergoing emergency aortic repair. (A, B) Hematoxylin and eosin staining showing typical granulomatous inflammation with rings of predominantly lymphocytes and macrophages around necrotic medial tissue (A x60; B x200). (C) CD3⁺ T cells form a collarette of inflammation enclosing the necrotic aortic wall (x100). (D) CD68⁺ histiocytes palisade at the edge of the damaged tissue (x200). (E) CD4⁺ T cells are the dominant T cell subset within the granulomatous infiltrates (x100). (F) Infrequent CD8⁺ T cells in the aortic wall (x100).

Figure 4

Innate Immune Cells in Giant Cell Arteritis. Tissue sections from temporal artery biopsies were stained for the dendritic cell (DC) marker DC-SIGN (A) and the macrophage marker CD68 (B) and visualized by immunofluorescence imaging. Nuclei marked by DAPI. In the healthy artery, the autofluorescent lamina elastica interna separates the media and intima. DC-SIGN⁺ dendritic cells are positioned at the adventitial-medial border. In the vasculitis-affected artery, DC-SIGN⁺ dendritic cells expand in the adventitia. CD68⁺ macrophages are essentially undetectable in the healthy artery but occupy all wall layers of the GCA artery. Int, intima; Med, media; Adv, adventitia. Scale Bar; 50 μm.

Figure 5

Abnormal T cell Activation in GCA. The intensity and duration of adaptive immunity depends on the availability of specific antigen, but also on a mixture of positive (co-stimulatory) and negative (co-inhibitory) signals, that modulate the T cell receptor activation cascade. Patients with GCA have abnormalities in the CD28 co-stimulatory pathway and in the co-inhibitory PD-1/PD-L1 pathway, resulting in sustained and unopposed activation of pathogenic T cells. Under physiologic conditions, CD28 on T cells recognizes CD80/86 on antigen-presenting cells (e.g. dendritic cells; DC), prolonging and intensifying T cell activation. Signaling through this pathway is intensified in GCA. Under physiologic conditions, PD-1 on T cells recognizes PD-L1 on antigen presenting cells (e.g. macrophages; Mac), resulting in dampening of T cell activation. In GCA, PD-L1 is expressed at very low levels, disrupting this negative signal, and boosting T cell effector functions.

Figure 6

Pathogenic role of T cells in GCA. The shift from protective to pathogenic immunity in GCA involves multiple processes. Four major abnormalities have been molecularly defined (1). In GCA patients, CD4+ T cells aberrantly express NOTCH1, which facilitates T cell-endothelial communication, tissue entry and uncontrolled T cell expansion (2). Excess CD28-dependent signaling imprints a metabolic signature that sustains pro-inflammatory T cells (3). Such T cells supply a multitude of effector cytokine to stimulate macrophages and vascular cells (4). A critical feature of disease-promoting CD4⁺ T cells is the ability to establish tissue residency in the vessel wall. Tissue-resident memory CD4⁺ T cells render the lesion autonomous and ensure chronicity of disease.