**9. Th17 cells in GCA**

Th17 cells play an important role in antimicrobial immunity where they regulate the recruit‐ ment of neutrophils and facilitate protection against extracellular bacteria and fungi. Far beyond their role in host defense, Th17 cells have been implicated in the pathogenesis of several autoimmune and inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. [41]

In untreated GCA patients, the frequency of Th17 cells is 10-fold elevated in the peripheral blood and they accumulate in the vascular infiltrates. [37] In healthy individuals, Th17 cells are infrequent and account for less than 0.3% of the circulating CD4+ T cells. In newly diag‐ nosed GCA patients, an average of 2.2% of circulating CD4+ T cells were found to be IL-17 producers, while in some patients these cells were >5%.

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

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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

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

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

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.

formed in these hemodynamically non-compliant sites of the vasculature. [29]

The outline of GCA immunopathogenesis is displayed in Figure 1.

endothelial dysfunction. [29]

media and the weakening of the arterial wall.

migration and cell-mediated collagen organization. [44]

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

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

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 important in promoting the chronic phase of the disease.
