Immune mechanisms in medium and large-vessel vasculitis

Journal name:
Nature Reviews Rheumatology
Volume:
9,
Pages:
731–740
Year published:
DOI:
doi:10.1038/nrrheum.2013.161
Published online

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.

At a glance

Figures

  1. TH1-cell-mediated and TH17-cell-mediated immunity in giant cell arteritis.
    Figure 1: TH1-cell-mediated and TH17-cell-mediated immunity in giant cell arteritis.

    The walls of human arteries are multilayered, with an endothelial barrier in the intima, sheets of VSMCs 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 VSMCs migrate towards the lumen and lay down to form lumen-stenosing intimal hyperplasia. Abbreviations: TH1 (cell), type 1 helper T (cell); TH17 (cell), type 17 helper T (cell); VSMC, vascular smooth muscle cell.

  2. The IL-6-IL-17 cytokine cluster in giant cell arteritis.
    Figure 2: The IL-6–IL-17 cytokine cluster in giant cell arteritis.

    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. Abbreviations: CCL20, CC-chemokine ligand 20; CCR6, CC-chemokine receptor 6; NK cell, natural killer cell; TH17 (cell), type 17 helper T (cell); TREG (cell), regulatory T (cell).

  3. The IL-12-IFN-[gamma] cytokine cluster in giant cell arteritis.
    Figure 3: The IL-12–IFN-γ cytokine cluster in giant cell arteritis.

    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. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; MMP, matrix metalloproteinase; NK cell, natural killer cell; ROS, reactive oxygen species; TH1 (cell), type 1 helper T (cell); TREG (cell), regulatory T (cell); VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

  4. Notch-Notch ligand interactions in vessel wall inflammation.
    Figure 4: Notch–Notch ligand interactions in vessel wall inflammation.

    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 VSMCs. Both CD4+ T cells and VSMC express NOTCH receptors and NOTCH ligands, thus functioning as signal-receiving and signal-sending cells in immunostromal communications. Abbreviations: GCA, giant cell arteritis; VSMC, vascular smooth muscle cell.

Key points

  • Giant cell arteritis (GCA), the most frequent form of large-vessel vasculitis, occurs in a strictly defined tissue context and requires corruption of the immune-privileged tissue niche of the arterial wall
  • Receptors and ligands from the Notch family facilitate information exchange between vascular stromal cells and immune cells, and are critically involved in the development of vasculitis
  • The therapeutic potential of targeting the stromal compartment in vasculitis is currently unexplored
  • Granulomatous inflammation in GCA is characterized by a cytokine cascade, in which the initiating signals are poorly defined, but the many effectors match those encountered in protective immune responses
  • A cytokine cluster involving the IL-6–IL-17 axis is highly active in early and untreated disease, is rapidly suppressed by corticosteroids and is redundant for vasculitis
  • A cytokine cluster centring on the IL-12–IFN-γ axis is more resistant to immunosuppression and reveals pathogenic similarities between allograft arteriosclerosis and GCA

Introduction

Human blood vessels range in diameter from 8 μm to 30,000 μm and span >60,000 miles, making them one of the largest organ systems in the body. Similar to the immune system, blood vessels are distributed widely, ultimately reaching every tissue site, however remote. Blood vessels are the major transit for immune cells, giving innate and adaptive immune cells rapid access to essentially all peripheral tissues as well as to the immune storage sites in lymphoid organs. Given the intimate relationship between the immune and vascular systems, it is surprising that immune-mediated vasculopathies are rare diseases.1, 2, 3, 4 This statement does not hold for atherosclerotic disease, which remains the most frequent cause of death in the Western world. In that context it is intriguing that the understanding of the pathogenesis of atherosclerosis has now undergone a marked change. Previously recognized as a lipid storage disease, atherosclerosis is now emerging as an inflammatory syndrome in which innate and adaptive immune responses participate in every stage of the disease process.5, 6

Classic autoimmune inflammation of medium and large arteries (diameter >2,000 μm) occurs infrequently. Large-vessel vasculitides (LVV) affect the aorta and its major branches and, owing to the vital role of such blood vessels, are characterized by serious clinical complications. When attacked by dysfunctional immunity, medium-sized arteries respond with occlusion of the lumen, and ischaemic damage of dependent organs ensues. The aorta is more likely to develop signs of wall destruction rather than stenotic lesions; manifesting as aneurysm formation, rupture or dissection.7, 8 The pathological hallmark of LVV is chronic inflammatory lesions within the vessel wall, not outside the vessel wall, distinguishing LVV clearly from the small-vessel vasculitides in which inflammation also occurs in the surrounding tissue.

Inflammatory infiltrates within the wall of the aorta and its major branches often display a distinct microarchitecture and are arranged as granulomatous lesions. Two syndromes account for most cases of LVV, giant cell arteritis (GCA) and Takayasu arteritis.9 Takayasu arteritis preferentially occurs in the aorta and its primary branches, whereas GCA lesions have a tendency to be localized in more peripheral, medium-sized arteries, affecting the third to fifth branches of the aorta.10 The manifestation patterns of both LVV make it clear that vessel size and closely linked structural and functional attributes are key factors in the disease process.11 Which determinants within the wall of the major aortic branches (diameter of 5–30 mm) distinguish that tissue niche from the wall of an arteriole (diameter of 10–30 μm) is currently not understood. Arterial diameter and wall thickness is directly correlated with body size.12, 13 In large human arteries, the thickness of the wall exceeds the effective diffusion distance of oxygen and the medial smooth muscle cell layer, which has the highest metabolic demands, must be supplied from adventitial vessels.14 By contrast, in small animals, the medial layer is thin enough to receive oxygen and nutrient supply solely via diffusion from the main lumen.15 Accordingly, it has been a major challenge to mimic LVV in model organisms that are much smaller than humans. These structural challenges are in addition to concerns that genomic responses in mouse models poorly mimic inflammatory disease in humans.16 On the other hand, access to the aorta of a human for tissue sampling occurs only under extremely restricted clinical conditions and these hurdles have hampered attempts to elucidate the pathogenesis of Takayasu arteritis. The temporal artery, the preferred target of GCA, is easily accessible and is routinely biopsied for diagnostic purposes. Investigations of arterial immune infiltrates, coupled with studies of circulating immune cells, have supported the development of new pathogenic concepts directly relevant for humans. Considerable progress has been made in unravelling the aberrant immune responses underlying LVV over the past decade and we focus this Review on GCA as a rich source of new ideas and understandings. The emerging theme is that of multiple, fundamentally divergent immune pathways contributing to disease, making it unlikely that a single disease instigator causes LVV. Instead, recognition of the critical role of the artery as a player in immunostromal interactions is refocusing the pathogenic concepts, promoting the emergence of the new field of vasculoimmunology.17, 18

The cellular players of GCA

The immunopathology of GCA derives from dysregulated interaction between the vessel wall and the immune system (Figure 1).10 The vessel wall contains endothelial cells, vascular smooth muscle cells (VSMCs), elastic membranes, matrix and fibroblasts. In arteries with a diameter of >2,000 μm, the walls reach such a thickness that a supply network of vasa vasorum is required, such arteries harbour dendritic cells at the interface of the adventitia and the media.19, 20, 21 Despite these vascular dendritic cells (vasDCs), arterial walls are immunoprivileged, able to avoid spontaneous allorecognition.22 In vasculitic lesions, vasDCs undergo activation, increase in number, are distributed throughout the wall and are an absolute requirement to sustain the disease process.23 The immune system sends T cells, mostly CD4+ T cells, and macrophages to the vessel wall niche; these cells enter the wall through the vasa vasorum and penetrate through the tissue space in an adventitial–intimal direction.24 Typically, highly activated macrophages, so-called histiocytes, are arranged in granulomas, with surrounding T cells. B cells are absent from the infiltrates,25 and germinal centre formation is not a feature of LVV. To disrupt the immune privilege of normal human arteries, wall-integrated dendritic cells need to be stimulated. Triggering of receptors recognizing danger signals, such as Toll-like receptors (TLRs), is sufficient to break tissue tolerance and render arteries susceptible to immune attack;26, 27 whether such an event initiates LVV is currently unknown. Both local as well as systemic danger signals could break the immune privilege. As in all autoimmune syndromes of unknown aetiology, infectious agents have been suspected to elicit the granulomatous reaction. A multitude of infectious microorganisms have been proposed to be involved, including a new observation of a Burkholderia-like strain in some tissues.28, 29 Such observations require confirmation in independent studies. The relationship between infectious agents and vascular disease is certainly more complex, as evidenced by a report of diverse oral and gut bacteria (Chryseomonas, Veillonella and Streptococcus) present in all tested atherosclerotic plaque samples.30 Equally probable is the local presence of autoantigens or stress-related proteins that can elicit autoreactivity.31

Figure 1: TH1-cell-mediated and TH17-cell-mediated immunity in giant cell arteritis.
TH1-cell-mediated and TH17-cell-mediated immunity in giant cell arteritis.

The walls of human arteries are multilayered, with an endothelial barrier in the intima, sheets of VSMCs 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 VSMCs migrate towards the lumen and lay down to form lumen-stenosing intimal hyperplasia. Abbreviations: TH1 (cell), type 1 helper T (cell); TH17 (cell), type 17 helper T (cell); VSMC, vascular smooth muscle cell.

The IL-6–IL-17 cytokine cluster in GCA

IL-6

Two decades ago, the elevation of circulating IL-6 levels was reported in patients with GCA32 and serum levels were correlated with disease activity.33 Later reports assigned IL-6 production to several cell populations in the vessel wall granulomas, except endothelial cells and multinucleated giant cells, and were able to correlate the intensity of the systemic inflammatory response to tissue expression of IL-1β, TNF and IL-6.34 Several clinical aspects of GCA have supported the concept that IL-6 is an important disease mediator. Patients have a combination of vascular and extravascular disease, almost always with a strong component of systemic inflammation. Among clinicians, GCA is considered a prototype of an intense systemic inflammation, often associated with constitutional symptoms (weight loss, fever, anorexia, failure-to-thrive) and it is not unusual for this extravascular component to dominate the clinical presentation of the disease.35 The underlying molecular process is a vigorous acute-phase response, which separates GCA from many other autoimmune syndromes. Biomarkers associated with the acute-phase response are a strongly elevated erythrocyte sedimentation rate (ESR), often reaching 80–100 mm/h, and C-reactive protein levels that are often extremely high.35 Acute-phase proteins are produced by hepatocytes upon stimulation with IL-1–type and IL-6–type cytokines.36 Accordingly, IL-6 levels were reported to be strongly elevated in patients with GCA ~20 years ago.32, 33, 37

IL-6 is a pleiotropic cytokine, with a multiplicity of functions that specializes in the crosstalk between stromal cells and immune cells and ferries information between injured tissues and the immune system.38 Endothelial cells, VSMCs and fibroblasts can release IL-6, but it can also derive from lymphocytes and macrophages, enabling positive feed-forward looping in the amplification of inflammatory reactions. Deriving from vascular cells, including endothelial cells and VSMCs, IL-6 seems to be an important connector between injured vascular walls and immune cells. Besides its systemic effect (activating hepatocytes), IL-6 also shapes the local cytokine environment and orchestrates the patterning of immune reactions; of particular importance is the role of IL-6 as a polarizing cytokine, guiding the differentiation of T cells into selected functional lineages (Figure 2). Specifically, IL-6 is critically involved in promoting the differentiation of the type 17 helper T cell (TH17 cell) lineage, a functional T-cell population first described in 2005.39, 40, 41, 42 Initially, it was believed that a combination of IL-1β, IL-6 and IL-23 was sufficient to direct the differentiation of a T cell into a TH17 cell. It is now clear that naive T cells do not express IL-1R and IL-23R, but these receptors are upregulated when the cells are exposed to TGF-β and IL-6 or IL-21.43, 44 This mechanism assigns a key role to IL-6 in directing T-cell responses.

Figure 2: The IL-6–IL-17 cytokine cluster in giant cell arteritis.
The IL-6-IL-17 cytokine cluster in giant cell arteritis.

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. Abbreviations: CCL20, CC-chemokine ligand 20; CCR6, CC-chemokine receptor 6; NK cell, natural killer cell; TH17 (cell), type 17 helper T (cell); TREG (cell), regulatory T (cell).

TH17 cells

TH17 cells exert their multiple proinflammatory functions through the release of effector cytokines, including IL-17, IL-21, IL-22, CCL20, GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-8 (also known as CXCL8), and IL-26.45, 46 Many of these cytokines have been identified in the inflammatory lesions of GCA. The wide distribution of receptors for the TH17-related cytokines makes it possible for TH17 cells to participate in several layers of injurious immunity that occurs in the vascular wall: IL-21–enhanced differentiation of cytotoxic cells; IL-22–mediated hepatocyte stimulation and acute-phase amplification; IL-17–dependent stimulation of endothelial cells, VSMCs and fibroblasts; IL-17–regulated recruitment of macrophages and neutrophils; CCL20-facilitated recruitment of dendritic cells and T cells (Figure 2).47, 48, 49, 50

Frequencies of TH17 cells, as assessed by flow cytometry, are increased up to 10-fold in the blood of patients with GCA.51, 52, 53 TH17 cells are part of the cellular infiltrates in the arteries. In a study comparing the composition of the vasculitic infiltrates before and after corticosteroid therapy in patients with GCA, immunosuppression caused an intriguing shift in wall-infiltrating T-cell populations.51 Prior to therapy, IL-17–producing T cells were mixed with IFN-γ–producing TH1 cells to create the granulomas. Arteries from treated patients contained few TH17 cells, but were populated by TH1 cells.51 IL-21 has also been reported to appear within vasculitic infiltrates.53 IL-6 and IL-1 are certainly present and TGF-β has been detected in GCA-affected temporal artery biopsy samples.54, 55 In essence, a cluster of TH17-related cytokines participates in the vasculitic reaction.

Besides its role in inducing TH17 differentiation, IL-6 has also been implicated in regulating the induction of anti-inflammatory regulatory T (TREG) cells. Specifically, the developmental pathways leading to the induction of TH17 and TREG cell seem reciprocal, with IL-6, IL-21 and IL-23 blocking the TREG cell-specifying transcription factor forkhead box protein P3 (FOXP3) and instead upregulating the TH17-inducing RORγt (nuclear receptor ROR-γt) transcription factor.56, 57 Accordingly, frequencies of TREG cells have been reported to be reduced in patients with GCA.52, 53 Within the arterial-wall infiltrates, TREG cells were distinctly low in numbers in these two studies,52, 53 whereas in one report FOXP3-expressing cells were described in the tissue.58 As these latter cells co-expressed IL-17, the functional relevance of these cells remains unclear. Thus, IL-6 might have two major effects in LVV; boosting proinflammatory T-cell immunity and paralyzing opposing anti-inflammatory T cells. A similar duality of IL-6 also applies to another immune-dependent vasculopathy, arterial allograft rejection.59, 60

Given that the frequencies of TH17 precursor cells, CD161+CD4+ T cells, have been reported to be similar in patients and healthy individuals as controls,52 the defect in biasing T-cell immunity towards TH17 differentiation seems to be extrinsic to the adaptive immune system. Whether the ageing process and immunosenescence contribute to this deviation of T-cell immunity is currently not known. Given the stringent age cut-off point of GCA—the disease occurs exclusively during the sixth to ninth decade of life—age-related defects in the regulatory control of innate and adaptive immune responses almost certainly have a major pathogenic function.61

The IL-12–IFN-γ cytokine cluster in GCA

Although available evidence suggests that the IL-6–IL-17 cytokine cluster has an important role in early GCA, it might be less important during chronic disease.62 Support for this concept stems from a plethora of clinical observations, such as the persistence of vasculitis despite long-term and high-dose corticosteroid therapy,63 and from evaluations of patients with GCA treated with the IL-6 pathway blocker tocilizumab.64 Unizony et al.64 have reported that a patient treated with tocilizumab had persistent vasculitis of medium-sized and large vessels at autopsy and Xenitidis et al.65 have encountered sustained inflammation of the aortic wall despite tocilizumab treatment in two patients with Takaysu arteritis. Clinical observations have already suggested that LVV might indeed not be a short-term, self-limiting condition but persist over extended periods in a subset or most patients. Aortic aneurysm formation a decade after initial diagnosis and treatment,66 and positivity of temporal artery biopsies in patients on corticosteroids is a suspicious finding, supporting the concept of persistent, chronic smouldering disease that contrasts with the idea of GCA as a self-limiting syndrome.

A study published in 2010 systematically evaluated temporal artery biopsy samples from patients with GCA 3, 6, 9 and 12 months after treatment initiation and confirmed that vasculitis did not go into remission, despite IL-1, IL-6 and IL-17 production being effectively suppressed.51 Whereas untreated arteritic tissues contained a mixture of TH17 and TH1 cells, biopsy and blood samples from treated patients displayed a signature of a TH1-cell response, which was separable from the TH17-cell response (Figure 3). Plasma levels of IFN-γ, essentially nondetectable in healthy age-matched controls, are elevated in untreated patients with GCA and remain elevated after corticosteroid therapy.51 Corticosteroids rapidly control IL-1, IL-6 and IL-23 production, followed by suppression of IL-17 production, both in the blood and in the inflamed arteries.51 Despite this effective immunosuppression, vasculitis persists and continues as a TH1-dependent disease. The cytokine signature associated with chronic disease includes IL-12 and IFN-γ and no longer relies on IL-6, IL-23 and IL-17.67 Our data confirm previous work published in 1997 by Brack et al.68 That study explored the therapeutic effects of corticosteroids in vivo in severe combined immunodeficiency (SCID) mice that had been engrafted with inflamed human temporal arteries to create SCID–human artery chimeras as a model. Even when extremely high doses of corticosteroids were used (dexamethasone 4 mg/kg, equivalent to >1,900 mg prednisolone), the T-cell infiltrates in tissue persisted and tissue IFN-γ expression was barely affected.68 By contrast, the monocyte cytokines IL-1β and IL-6 were highly susceptible to steroid-mediated suppression. Thus, despite the limitations inherent to studies in human tissues, evidence has accumulated that vascular inflammation might indeed persist despite effective IL-6 blockade.

Figure 3: The IL-12–IFN-γ cytokine cluster in giant cell arteritis.
The IL-12-IFN-[gamma] cytokine cluster in giant cell arteritis.

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. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; MMP, matrix metalloproteinase; NK cell, natural killer cell; ROS, reactive oxygen species; TH1 (cell), type 1 helper T (cell); TREG (cell), regulatory T (cell); VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

Effector functions of IFN-γ in GCA

The IL-6–independent, IFN-γ–dependent arm of vasculitic immunity is reminiscent of graft arteriosclerosis (Table 1). Graft arteriosclerosis occurs in transplanted hearts and is the dominant mechanism causing late cardiac allograft failure.69, 70 The disease process is characterized by concentric intimal hyperplasia, which eventually leads to luminal stenosis and allograft ischaemia. Outgrowth of the lumen-obstructing neotissue is driven by a T-cell-dependent and macrophage-dependent immune response that stimulates vascular smooth-muscle-like cells to migrate, replicate and secrete extracellular matrix.71 This process closely mimics events in GCA, in which the clinical complications (blindness, stroke, aortic arch syndrome) are a consequence of luminal occlusion.

Table 1: Pathogenic pathways in giant cell arteritis and graft arteriosclerosis

Elegant work in a model system of graft arteriosclerosis has established IFN-γ as a key pathogenic factor (Table 1).70, 72 IFN-γ is a powerful cytokine, a prototype of an effector cytokine in anti-pathogen immune responses. The role of IFN-γ in conferring pathogen resistance is nonredundant.73, 74 Binding of the IFN-γ receptor elicits activation of the JAK–STAT signalling pathway, culminating in the activation of the STAT1 transcription factor. STAT1-dependent genes represent a complex programme of immune effector genes, with hundreds of genes amplifying antigen presentation, lymphocyte and macrophage recruitment, proliferation and apoptosis of target cells.75 An important outcome of IFN-γ action is the activation of macrophages, differentiation of TH cells and TREG cells, and the remodelling of stromal cells.76 Accordingly, IFN-γ integrates immune regulatory events with response patterns of the surrounding tissues, optimizing antibacterial and antiviral immunity, but also intensifying tissue damage. In the specialized tissue niche of the vessel wall, IFN-γ triggers migratory and proliferative signalling pathways in VSMC.77 In temporal artery lesions of patients with GCA, tissue levels of IFN-γ have been associated with the following pathologies: luminal compromise by hyperplastic intima,78 formation of a neoangiogenic network of capillaries that support the expanding intimal layer (Figure 3).79 In line with these observations, chronically inflamed arteries of treated patients contain dense infiltrates of IFN-γ-producing TH1 cells. Tissue transcripts for IFN-γ and plasma concentrations of IFN-γ are essentially unaffected by corticosteroid treatment.51

Although the source of tissue IFN-γ is clear, it derives from TH1 effector T cells, the spectrum of IFN-γ–induced processes in the arterial wall is steadily expanding.77 IFN-γ upregulates TLR3, rendering VSMCs susceptible to activation by tissue-endogenous and exogenous danger signals.80 In an elegant study exploring interactions of IFN-γ with other T-cell effector cytokines, such as IL-17, these two cytokines displayed a synergistic interaction with enhanced production of IL-6, CXCL8 and CXCL10.81 These data place IFN-γ at the top of the hierarchy of immune regulators in the mural infiltrates. IFN-γ seems to be particularly important in regulating the dialogue between tissue-infiltrating T cells and VSMCs, as well as endothelial cells. Whereas some VSMCs become migratory and move towards the central lumen, others disappear creating the typical loss of medial layer encountered in GCA-affected arteries.82 IFN-γ can induce apoptosis of VSMCs and thus might well function as a triage signal that separates proliferating and dying VSMCs.83 In its role as an immune amplifier, IFN-γ induces a set of chemokines, including CXCL10 (also known as IP-10), CXCL9 (also known as Mig), CCL5 (also known as RANTES), CXCL11 (also known as ITAC) and CX3CL1. A detailed profiling of GCA lesions for such products has not been performed. However, TH1 cells, in turn, are responsive to CXCR3 and CCR5-binding chemokines,84 establishing a potent reinforcing feedback loop sustaining in situ T-cell activation, differentiation and recruitment, which might be critically involved in the chronicity of medium-vessel and large-vessel vasculitis.

TH1 cell differentiation in GCA

GCA lesions have all the features of a TH1 lesion (Figure 3). IFN-γ–producing T cells are surrounded by highly activated macrophages, committed to either the M1 or the M2 polarization lineage.24, 85 Overexpression of IL-32, an IFN-γ-inducible cytokine has been described in inflamed temporal arteries in patients with GCA.86 Whether TH1 cells are recruited as committed cells or whether they acquire this functional phenotype within the tissue niche is currently unknown. The functional activity of TH1 cells is regulated by IL-12 and this polarizing cytokine has been identified in the plasma of patients with GCA, with plasma levels indistinguishable in untreated and steroid-treated patients.51, 62 The cellular source of IL-12 has not been unequivocally identified, but wall-embedded dendritic cells certainly can serve as a reservoir of IL-12.87 Some information is available on triggers that can induce local release of IL-12 to direct T cells towards the TH1 differentiation pathway. Ligands for TLR4 and TLR5 have been demonstrated in experimental systems to activate arterial-wall-integrated dendritic cells and initiate and promote TH1 cell accumulation.27 VasDCs are equipped with a broad portfolio of pattern-recognition receptors, including TLRs 2–6 and TLR8.20 Whether all of these receptors have a potential role in kickstarting immune activation in the otherwise protected artery wall needs to be examined. Theoretically, different dendritic cells, expressing distinct repertoires of danger receptors, could activate different T-cell response patterns. The separability of TH1 and TH17 immunity in untreated and treated patients with GCA supports the concept that independent axes exist that regulate vasculitic immunity.62

Clinical observations have also supported the concept of two components of immunopathology in GCA; systemic inflammation mostly associated with IL-6-driven immunity, and vaso-occlusion sustained by a less inflammatory but more tissue-remodelling process. Supportive evidence includes the close association of intimal hyperplasia on biopsy with neuro-ophthalmological complications,88 a reduced frequency of constitutional symptoms in patients with vision loss89, 90 and the stable incidence of visual manifestations despite aggressive management with corticosteroids over the past four decades.91

As in all inflammatory diseases, a multitude of cytokines that do not belong to the IL-12–IFN-γ cluster and the IL-6–IL-17 cluster can be expected to contribute to GCA.85, 86, 92, 93, 94 More mechanistic studies applying pharmacological and genetic knockdown technologies in experimental systems and in clinical trials are required to decipher the role of individual cytokines. Notably, TNF blockade was explored in a well-designed clinical study involving 44 patients with GCA. Although the trial was too small to draw definitive conclusions, the investigators concluded that using infliximab as maintenance therapy was of no benefit and could be harmful.95 A review of clinical trials in GCA has emphasized the urgent need for improved study design and inclusion of larger patient groups to enhance the yield of useful information.96 Going beyond classic cytokine blockade holds great promise as it might provide clues to distinct cellular and molecular pathways in GCA pathogenesis. One such example is the observation in a case series published in 2012 on the efficiency of leflunamide in difficult-to-treat polymyalgia rheumatic and GCA.97

Immunostromal interactions in GCA

Classifying GCA as an autoimmune disease emphasizes the multifaceted and convincing evidence that host-beneficial immunity is misdirected to lead to granuloma formation in the mural layers of medium and large arteries. That paradigm, however, misses the conceptualization of the tissue tropism of the disease and underestimates the stromal milieu as a pathogenic force. According to histomorphology, the secondary and tertiary branches of the aorta might all appear to be similar, but molecular studies have provided a framework to define the selective immunological identity of distinct vascular beds.20 In our opinion, GCA outside of a vascular wall structure is extremely rare and might not be the same disease as classic granulomatous arteritis.98 Within the vasculature, GCA displays a clear preference for certain sites and avoids others. At-risk arteries are the temporal artery, the vertebral artery, the distal subclavian artery, the axillary artery and the aorta. On the other hand, intracerebral arteries, mesenteric arteries and lower extremity arteries are at much lower risk.99 All of these arteries have wall-embedded vasDCs, and should be able to attract and stimulate T cells and macrophages. Functional testing in a humanized mouse model has shown that engrafted human arteries are not recognized by allogeneic T cells, unless the immune privilege of the arterial wall has been broken.22, 100 Injection of lipopolysaccharides that trigger TLR4 on vasDCs is sufficient to render the vessel wall susceptible to immunological attack.27 The ability of human arteries to sense lipopolysaccharides, a bacterial product, emphasizes the potential of the vasculature to fulfil immunological functions. More importantly, each artery participates in this function in a selective way. The pattern of TLRs expressed on the surface of vasDCs changes from vessel to vessel, providing a molecular mechanism as to how different arteries respond to immune stimuli and interact with the adaptive immune system. Carotid, subclavian, mesenteric and femoral arteries derived from the same donor each attract allogeneic T cells, but elicited a different response pattern (C. M. Weyand and J. J. Goronzy, unpublished work). Current studies explore whether the ageing process alters vasDC function to generate age-related susceptibility, as encountered in GCA.101, 102, 103

Given the cellular diversity of a blood vessel wall, it is unlikely that vasDCs are the only cells making contact with the immune system. Rather, it is becoming increasingly clear that the tissue stroma, through its cellular and matrix components defines 'address codes' that determine recruitment, retention and survival of infiltrating immune cells.104, 105 The wall of a temporal artery is normally free of T cells and macrophages. To establish granulomatous lesions, such cells need to be attracted and then retained in the tissue site. Understanding how long wall-residing T cells survive, and whether they recirculate between the disease lesion and secondary lymphoid organs, would be valuable in conceptualizing the dynamics of vasculitic reactions, their durability and the molecular pathways that are promising in the therapy of vasculitis. Disease chronicity requires presence of vasculitic T cells and macrophages over years. Whether this phenomenon requires continuous influx and in situ differentiation would be important to know.

Notch–Notch ligand interactions in GCA

A study has begun to shed light on possible communication pathways that connect T cells, VSMCs and endothelial cells (Figure 4). Inflamed temporal arteries from patients with GCA contain a strong gene expression signal for Notch receptors and ligands.106 The Notch signalling pathway is well known for its pivotal role in the development of vertebrate organ systems, including development of vascular structures.107 Also, >50% of T-cell acute lymphoblastic leukaemias have activating point mutations in the NOTCH1 receptor, implicating Notch receptors in T-cell proliferation and survival.108 In healthy arteries, multiple Notch receptors, Notch ligands and their downstream signalling targets regulate VSMC differentiation, plasticity and phenotype switching and facilitate VSMC–endothelial cell communication.109 In T cells from patients with GCA, NOTCH1 receptor expression levels are 20-fold increased, enabling these T cells to interact with ligand-expressing dendritic cells, VSMCs and endothelial cells.106 Therapeutic blockade of Notch–Notch ligand interactions effectively suppresses experimentally induced vasculitis,106 emphasizing the disease relevance of this cellular communication pathway. Disruption of Notch signalling blocks T-cell retention and effector differentiation, and downregulates proinflammatory networks in vessel wall lesions during early and established disease.106 Notably, VSMCs and endothelial cells can express both Notch receptors and their ligands.110 Vice versa, CD4+ T cells can express NOTCH1 receptors, but also Jagged2 (a Notch ligand).111 Thus, VSMCs can serve as signal-sending and as signal-receiving cells. The results of the Notch blockade experiments emphasize that such communication fluxes are relevant in vasculitis. Treatment of humanized mouse chimeras engrafted with human arteries revealed that disruption of Notch signalling effectively suppressed both T-cell and macrophage functions.106 Density of tissue-infiltrating T cells declined in the absence of Notch signalling, suggesting a role of the VSMC environment in providing survival signals for T cells. Chimeras treated with an enzyme blocker disrupting Notch signalling produced only low levels of IL-17, whereas tissue IFN-γ levels were more resistant to this form of immunosuppression. One possible explanation is that VSMC selectively communicate with different T-cell lineages and thus are a major shaping force in orchestrating vasculitis.112

Figure 4: Notch–Notch ligand interactions in vessel wall inflammation.
Notch-Notch ligand interactions in vessel wall inflammation.

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 VSMCs. Both CD4+ T cells and VSMC express NOTCH receptors and NOTCH ligands, thus functioning as signal-receiving and signal-sending cells in immunostromal communications. Abbreviations: GCA, giant cell arteritis; VSMC, vascular smooth muscle cell.

Role of extracellular matrix

An integral part of the vessel-wall microenvironment is the extracellular matrix, generally produced by stromal cells. Although little is known about the composition of matrix in different human arteries, an emerging field in immunology addresses how stromal cells regulate recruitment, retention and clearance of immune-competent cells in a tissue niche and how such stromal cells impose regulatory control over host-protective and host-injurious immune responses. The carbohydrate-binding protein galectin-1A, produced by stromal cells and deposited into the extracellular matrix, has been implicated in a potent immunoregulatory circuit. Galectin-1A has been described to initiate IL-27–mediated immunosuppressive functions in human dendritic cells,113 giving rise to the novel concept that stromal-cell populations are signal-sending cells that deviate differentiation of dendritic cells. As demonstrated in chimera experiments, human medium-sized arteries are primarily immunoprivileged, despite being occupied by potent vasDCs. An environment-imposed skewing of dendritic cells towards a regulatory phenotype would provide an adaptable mechanism to protect vital arteries from immune attack. Stromal cells in lymphoid organs modulate the function of dendritic cells and T cells through a variety of mechanisms, including production of IL-10, TGF-β and nitric oxide.114 Given the aggressiveness of dendritic cell and T-cell function in GCA-affected arteries, failure of such mechanisms would need to be proposed. More sophisticated experimental systems are required to explore whether vasculitic lesions in GCA result from the inability of the stroma to inhibit localized immunity. The potency of microenvironment-dependent pathways in controlling tissue inflammation is now recognized for the kidney and the lung,115, 116 emphasizing that affected organ structures are not just innocent bystanders but active participants in dysfunctional immune responses. Two other matrix proteins involved in immune modulation are fibronectin and syndecan.117 Syndecan, a heparan sulphate proteoglycan, displays protective functions in abdominal aortic aneurysm formation and acts through regulating T-cell and macrophage accumulation.118

Role of endothelial cells

Important constituents of blood-vessel walls are endothelial cells, which are the first vessel components to interact with immune cells infiltrating into the wall layers. Endothelial cells participate in immune responses in a number of inflammatory conditions and are certainly involved when pathogenic immunity unfolds in the vessel wall.69 Evidence for active recognition of endothelial cells in GCA derives from elegant studies demonstrating that patients build anti-endothelial-cell antibodies, including those reacting against vinculin, lamin A/C, voltage-dependent anion-selective channel protein 2, and annexin V.119 Régent and colleagues120 are actively pursuing the concept that such antibodies have tissue-damaging functions. Evidence for activation of endothelial cells in GCA-affected arteries has come from studies describing the expression of endothelin-1 and endothelin receptors.121

In summary, stromal cells in the vascular wall, together with the matrix proteins they produce, can profoundly influence inflammatory events. Under physiological conditions, the arterial wall is somewhat unattainable for the immune system. A breakdown of such protective measures enables recruitment of innate and adaptive immune cells that then form organized microarchitectures in this tissue microenvironment. The intensity and direction of the inflammatory response depends on the immune system, possible recognition of antigen in the tissue site, but, to a large extent, on the immunostromal interactions between resident vascular cells and immune effectors.

Conclusions

The walls of medium and large arteries are multilayered structures built by endothelial cell, VSMCs, fibroblasts, elastic membranes and matrix proteins. Dedicated microvessels, the vasa vasorum, provide access for inflammatory cells. Interconnected dendritic cells, placed in the vicinity of the vasa vasorum, guard this life-essential structure and have a critical role in initiating and sustaining vessel-wall inflammation. The immunopathogenesis of GCA is defined by a cytokine cascade in which the initiators are ill-defined. Much progress has been made in identifying the effectors, essentially a mixture of cytokines released by differentiated CD4+ T cells, macrophages and resident vascular cells. Two major cytokine clusters have been associated with arterial wall injury, but are also identifiable in the peripheral blood, raising the intriguing possibility that inflammatory cells recirculate from the vasculitic lesions and become accessible in the periphery. The IL-6–IL-17 cytokine cluster seems to have a redundant role in vasculitis and is highly sensitive to corticosteroid-mediated suppression. By contrast, the IL-12–IFN-γ cluster has been linked to persistent vasculitis and is resistant to standard therapy in the clinical setting, supporting shared pathogenic mechanisms in GCA and allograft atherosclerosis. Interdependence of the two cytokine clusters is insufficiently understood, but mechanistic similarities with allograft atherosclerosis in which vascular remodelling and luminal stenosis occurs in the absence of intense systemic inflammation suggests relative independence of the IL-12–IFN-γ cluster. Growing information on the molecular interactions that define the tissue microenvironment of GCA sheds light on the immunostromal interactions between vascular cells and leucocytes that determine recruitment, retention and survival of inflammatory cells and thus control chronicity of vasculitis. Expanding pathogenic concepts in GCA beyond a simplified view of aberrant antigen recognition in a tissue site considerably widens the spectrum of therapeutic possibilities (Box 1).

Box 1: Pathogenesis-based GCA therapeutic strategies

Currently used

• Suppression of the IL-6–IL-17 cytokine cluster (corticosteroids)

• Untargeted T-cell suppression

Unexplored

• Suppression of the IL-12–IFN-γ cytokine cluster

• Inhibition of immunostromal interactions

• Suppression of dendritic cell stimulation and/or function

• Suppression of endothelial function

• Suppression of VSMC function

Abbreviations: GCA, giant cell arteritis; VSMC, vascular smooth muscle cell.

Review criteria

We searched PubMed for the search terms “giant cell arteritis”, “large vessel vasculitis”, “Takayasu arteritis”, “Takayasu's arteritis”, “polymyalgia rheumatic”, “temporal arteritis”, “arteritis” and “vasculitis”. Publications from the past 10 years were analysed for pathogenic studies. If appropriate to support scientific concepts, older publications were included. Case reports were not included, unless providing unique insights into pathogenic pathways. The date of the last search was 22 June 2013.

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Acknowledgements

The authors would like to acknowledge support from grants from the NIH (R01 EY011916, P01 HL058000, U19 AI057266 and U19 AI090019) and the Govenar Discovery Fund (C. M. Weyand).

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Affiliations

  1. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CCSR Building Room 2225, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305-5166, USA.

    • Cornelia M. Weyand &
    • Jörg J. Goronzy

Contributions

Both authors made equal contributions to all aspects of this manuscript.

Competing interests statement

The authors declare no competing interests.

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Author details

  • Cornelia M. Weyand

    Cornelia M. Weyand, MD, PhD is the Chief of the Division of Immunology and Rheumatology at the Stanford School of Medicine, Stanford University, USA. Her clinical expertise is in the management of patients with vasculitis. Her research has focused on the immune pathogenesis of vascular disease, with a special interest in innate and adaptive immunity in giant cell arteritis. Her research team has described dendritic cells residing in the adventitia of medium and large human arteries, has explored their function in immunosurveillance and has uncovered their role in triggering vasculitis. More recent work has examined receptor-ligand pairs in immunostromal interactions and their contribution to the tissue tropism of vasculitis.

  • Jörg J. Goronzy

    Jörg J. Goronzy, MD, PhD is a Professor of Medicine at the Stanford School of Medicine, Stanford University, USA. His work has examined how the human immune system ages and how the immunosenescence process is related to the morbidities of ageing. Together with his research team, he has defined the role of phosphatases in impairing T-cell immunity in the elderly and has described mechanisms of immune deviation that sustain the senescence-associated phenotype of aged T cells. His clinical interest lies in the improvement of vaccine responses in the elderly and in immune-mediated inflammation in the ageing host.

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