**10. The final common pathway: Mechanisms of arterial wall destruction in GCA**

After the expansion of the Th1 and Th17 cells, the production of their related cytokines is capable to drive the inflammatory reaction in the vessel wall. IFN-γ induces macrophages towards their effector functions, mainly, the formation of multinucleated giant cells and granulomatous inflammation. [29] Granuloma formation may lead to lumen stenosis and, thus to the ischemic complications of GCA. It is interesting that PMR patients share some clinical features with GCA, although they do not develop ischemic complications. [3] This is possibly related to the lack of IFN-γ from resected arteries of PMR patients. [22] Unsuppressed actions of IFN-γ on macrophages could explain why patients, under corticosteroid treatment, may still develop devastating occlusive vasculitis.

The pro-inflammatory environment, shaped by IL-1, IL-6, IL-17, IL-23 and IFN-γ, promotes the infiltration of the arterial wall adventitia by activated monocytes and neutrophils, via the vasa vasorum. The endothelial cells of these small capillaries in the vessel wall upregulate the expression of certain adhesion molecules, which attract and restrain inflammatory cells. Within the vessel wall, altered macrophage function enhances IFN-γ production (through IL-12 release) and the subsequent recruitment of additional macrophages and lymphocytes, thus creating a vicious cycle. Intimal macrophages also express nitric oxide (NO) synthetase, which augments the capillary permeability and peroxynitrite, which has been associated with endothelial dysfunction. [29]

nosed GCA patients, an average of 2.2% of circulating CD4+ T cells were found to be IL-17

In contrast to the Th1 lineage, Th17 cells displayed a totally different sensitivity to corticoste‐ roid therapy. Prednisone therapies led to a fast and, almost, complete reduction of both circulating and lesional Th17 cells, as, in treated patients, only 0.4% of the circulating CD4+ T cells were capable of producing IL-17. [38] Taking into account that the systemic manifestations of GCA, such as fever and PMR, are the most responsive to steroid therapy and coincide with the normalization of Th17 cells, it can be speculated that these features are pathophysiologi‐ cally related to the Th17 response. In addition, corticosteroid therapy was shown to suppress

The specific circumstances under which the Th17 response is amplified are not well under‐ stood, but studies, in untreated patients, showed that circulating monocytes (primed by IFNγ) produce significant amounts of Th17-polarizing cytokines, such as IL-6 and IL-23. Of note,

Latest studies showed that Th17 cells posses a substantial plasticity and they are able to transform into Th1 cells and release IFN-γ. [22] It is possible that, at least partially, Th17 represent the precursor cells that will progress to Th1 cells in a chronic disease process. On the other hand, one could expect that the successful suppression of Th17 cells (after steroid therapy) would eventually lead to the reduction of the Th1 cells, but this was not confirmed in experimental studies. Furthermore, there is evidence that there may be a small proportion of CD4+ T cells that are able to secrete both IL-17 and IFN-γ. The presence of these double producers was confirmed in atherosclerosis, although in GCA, these cells behave like the Th17 cells, in terms of steroid responsiveness. [22, 42] These findings suggest that these cells are not

**10. The final common pathway: Mechanisms of arterial wall destruction in**

After the expansion of the Th1 and Th17 cells, the production of their related cytokines is capable to drive the inflammatory reaction in the vessel wall. IFN-γ induces macrophages towards their effector functions, mainly, the formation of multinucleated giant cells and granulomatous inflammation. [29] Granuloma formation may lead to lumen stenosis and, thus to the ischemic complications of GCA. It is interesting that PMR patients share some clinical features with GCA, although they do not develop ischemic complications. [3] This is possibly related to the lack of IFN-γ from resected arteries of PMR patients. [22] Unsuppressed actions of IFN-γ on macrophages could explain why patients, under corticosteroid treatment, may

The pro-inflammatory environment, shaped by IL-1, IL-6, IL-17, IL-23 and IFN-γ, promotes the infiltration of the arterial wall adventitia by activated monocytes and neutrophils, via the vasa vasorum. The endothelial cells of these small capillaries in the vessel wall upregulate the

IL-6 may represent a reliable biomarker for assessing disease activity over time.

producers, while in some patients these cells were >5%.

important in promoting the chronic phase of the disease.

still develop devastating occlusive vasculitis.

the entire IL-1 – IL-6 – IL-17 axis. [38]

100 Updates in the Diagnosis and Treatment of Vasculitis

**GCA**

Additionally, reactive oxygen species (ROS) are secreted by macrophages into the surrounding tissues and degrade the proteins of the extracellular matrix. Oxygen-derived free radicals and their metabolites promote tissue injury through multiple mechanisms, the most important being oxidation of membrane lipids, resulting in structural disintegration and cell death. Reactive oxygen intermediates are not only directly cytotoxic; they can also alter cellular function by disrupting intracellular signaling cascades. The net result is the degradation of the media and the weakening of the arterial wall.

Additionally, metalloproteases (MMPs) that are released by macrophages and vascular smooth muscle cells are associated with matrix degeneration, intimal hyperplasia and luminal narrowing. In particular, matrix metalloproteases MMP-2 and MMP-9, which possess gelati‐ nase activity, have both been detected in the infiltrates of the arterial wall in patients with GCA. [43] Due to their ability to destroy elastin, MMP-2 and MMP-9 have been suggested to play a primary role in the internal elastic lamina degradation, a characteristic pathologic finding in GCA. These metalloproteases are able to differentially regulate vascular smooth muscle cell migration and cell-mediated collagen organization. [44]

In parallel, the inflammatory milieu provokes the apoptosis of smooth muscle cells, which are primarily responsible for the compliance of the arterial wall. Aneurysms can eventually be formed in these hemodynamically non-compliant sites of the vasculature. [29]

Although the pathophysiologic mechanism underlying aneurysm formation in GCA is well understood, the pathophysiologic basis of lumen stenosis is not equally clear. It has been shown that IFN-γ may produce endothelial hyperplasia and subsequent narrowing of the vascular lumen. [22] Interestingly, it was demonstrated that the extent of platelet-derived growth factor (PDGF) production, in the vascular lesions, correlates with the degree of luminal occlusion and the severity of the ischaemic manifestations. [40] In accordance, VEGF derived from activated macrophages deregulate the endothelial functions. Eventually, anatomical alterations will ensue, leading to the remodeling of inflamed arteries. The physiologic basis of these findings may rely on the increased needs of the hyperplastic arterial wall in means of oxygen and nutrients. Neoangiogenesis, provoked by these factors, may supply the needed nutrients in the hyperplastic wall but, also, effectively supports the destructive inflammatory reaction. [45] Nonetheless, thrombotic occlusions are rare complications of giant cell arteritis.

The outline of GCA immunopathogenesis is displayed in Figure 1.

Secondly, biochemical modifications in vessel wall extracellular structures, such as the disorganization of the elastic fibers, render the vessel wall extremely compliant. Vascular smooth muscle cells decrease in number and function. The media becomes thinner and deposition of calcium is not unusual. Beyond the alterations observed in biomechanical parameters, the "old" artery seems to provide a distinct micro-environment that potentially increases the risk for the formation of a novel spectrum of neoantigens and the persistence of

Immunopathophysiology of Large Vessel Involvement in Giant Cell Arteritis...

http://dx.doi.org/10.5772/55222

103

**12. Clinical phenotype and response to treatment are dependent on**

Aneurysm formation in GCA is reported in 3% of the patients with 3 months disease duration and 18-27 % of patients with 6 months duration. [49, 50] Cumulatively, the relative risk for

Disease diagnosis is straightforward in typical cases with headache, temporal tenderness, non palpable temporal arteries, jaw claudication and systemic symptoms (fever, malaise, weight loss) in an individual beyond 50 years of age. Unfortunately, a considerable proportion of patients presents with minor or no symptoms from the cranial arteries, which is presumably

Temporal artery biopsy represents the diagnostic gold standard, as its sensitivity is reported to exceed 85%. It should be mentioned that negative biopsy does not exclude GCA, as the lesions are skipped and long tissue specimens (>20mm) are required. Common causes of false negative results are the incomplete technique (sampling error) and the lack of sensitive pathologic criteria. Thus, in highly suspected cases, a second, contralateral, biopsy is recom‐ mended. Recent studies suggest ultrasonography-guided biopsy to precisely locate the patchy

Another advanced technique to detect vascular inflammatory sites is FDG-PET (fluorodeox‐ yglucose positron emission tomography) imaging, which is currently incorporated in diag‐

Immune system abnormalities play a critical role in GCA pathogenesis and are able to drive, not only clinical phenotype, but, also, response to treatment. DCs have been shown to initiate the immune response, as the number of myeloid DCs significantly increases in the adventitia of affected arteries and they appear to be activated via ligation of their TLR-4 (LPS) or TLR-5 (flagellin). [31] Stimulation of DCs via these TLRs induces the subsequent recruitment of T cells into the vessel wall, where they undergo local proliferation and activation. T cells produce pro-inflammatory cytokines to regulate the functions of macrophages, vascular smooth muscle cells and endothelial cells, while they were proved to belong to either Th1 or Th17 lineage. [22] Th17 cells secrete IL-17 and provide the early immune response in GCA, where these cells are reported to be 10-fold elevated in initial phases. Furthermore, in untreated patients, circulating monocytes (primed by IFN-γ) produce significant amounts of Th17-polarizing cytokines, such

inflammatory reactions. [48]

aneurysm formation is estimated to be 17.3. [51]

lesions of vessel wall inflammation. [52]

**pathophysiology**

the hallmark of GCA.

nostic algorithms. [53]

**Figure 1.** The immunopathophysiologic basis of giant cell arteritis. 1. In normal arteries, immature DCs, in the adventi‐ tia-media border, are the immune sentinels of the vessel wall. 2. In GCA, their maturation and activation (by an un‐ known instigator) leads to the recruitment of CD4+ T cells into the vessel wall. 3. CD4+ T cells are able to differentiate into either the Th17 arm of the immune response, which is responsible for the systemic manifestations of the disease, or the Th1 arm. 4. Th1 cells along with IFN-γ are able to drive the activation of macrophages, the formation of granulo‐ ma and the destruction of the structural integrity of the vessel wall via the secretion of MMPs and ROS.
