**8. Th1 cells in GCA**

Nevertheless, independently of the mode of the initial stimulation, DCs become activated and subsequently produce cytokines with redundant and pleiotropic actions. In inflamed temporal arteries, DCs secrete pro-inflammatory cytokines, mainly IL-2, IL-6 and IFN-γ, which, in turn, mediate the recruitment of inflammatory cells, inhibition of cell migration, enhancement of T cell proliferation and stimulation of T and B cells. [32] The net result is further amplification

The differentiation and activation of DCs (following stimulation via their TLRs) induces the subsequent recruitment of T cells into the vessel wall. Indeed, several studies on activation patterns and inflammatory mediators in GCA, have confirmed that the progression of the immune response is totally dependent on CD4+ T cells. [33] These cells are able to orchestrate the stimulation of macrophages that lead to vessel response to injury, resulting in luminal

Upon antigen recognition, CD4+ T cells are activated and differentiated into effector and memory T cells, while the antigen-specific subpopulation is 10 to 100-fold expanded. Under physiological conditions, only a few antigen-specific memory T cells are capable to persist indefinitely and provide life-long protection against pathogens. In parallel, these memory cells comprise the main barrier against the elimination of T-cell mediated autoimmune responses.

In GCA, several efforts to recognize a single antigen that may initiate the pathogenic specific immune response have not been fruitful. [20] In accordance, attempts to isolate the T cell clone, which is responsible for the vascular pathology in the disease, have suggested more hetero‐ geneity than expected. Studies focusing on T cell receptor V genes in the arterial wall and the peripheral blood of GCA patients have arrived at the conclusion that the T cell repertoire is significantly biased. [34, 35] Sequence analysis of the CD4+ T cells isolated from the inflamed temporal arteries has strongly supported local T cell activation and expansion of only a few selected T cell specificities. Notably, T cells isolated from the right and left temporal arteries

More recent studies confirmed that multiple T cell lineages contribute to the disease process. Histopathologic analyses from temporal arteries, both prior to therapy and on therapy, convincingly proved that two cell lineages, Th1 and Th17, infiltrate the vessel wall prior to therapy. [37] The concurrent presence of the two T cell lineages coincided closely with the stimulation of two distinct immune axes, an IL-12-IFN-γ axis and an IL-1-IL-23 axis. It seems that different APC signals are able to recruit either the IFN-γ-dependent or the IL-17-depend‐ ent arm of the adaptive immunity, thus raising the possibility that more than one instigator is

of the immune response, through positive feedback loops.

98 Updates in the Diagnosis and Treatment of Vasculitis

**7. Adaptive immunity abnormalities in GCA**

stenosis or wall destruction and aneurysm formation.

of the same patient utilized identical T cell receptors. [36]

involved in GCA. [21]

Th1 cells represent the dominant cell population in the intramural lesions and the periphery of patients with untreated GCA. [37] These cells produce IFN-γ, as their signature cytokine, which, physiologically, has a critical role against viral and intracellular bacterial infections. Once called macrophage activating factor, IFN-γ target macrophages and provide a substantial pro-inflammatory environment.

IFN-γ committed T cells are considered to account for >20% of circulating CD4+ T cells, an almost 100% increase compared to age-matched healthy controls. [38] Corticosteroid therapy cannot affect the expansion of this subpopulation, indicating continuous signaling from the respective DCs. The underlying mechanism of this resistance involves the triggering of APCs that continue to release IL-12. Actually, both in the blood and the temporal arteries of GCA patients, IL-12 production continued unabated during the chronic phase of the disease in treated patients. [38]

At the tissue level, cytokine profiling in GCA temporal arteries has demonstrated robust expression of IFN-γ and an association with a defined disease phenotype. [32] In particular, high tissue IFN-γ levels are typical for patients with ischaemic complications, implicating its crucial participation in the process leading to luminal occlusion. Pathophysiological studies have correlated increased IFN-γ levels with the production of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), which are molecules implicated in the intimal response that leads to lumen stenosis. [39, 40] VEGF may, in turn, promote IFN-γ production, thus leading to a vicious cycle of inflammation and structural stenosis. [39]

It is currently unknown which aspects of the granulomatous inflammation depend upon IFNγ. The ability of this cytokine to activate monocytes and macrophages certainly has a role in promoting the differentiation of lesional histiocytes. However, the profound differences in the clinical presentation of treated and untreated GCA patients suggest that IFN-γ is less relevant to the systemic manifestations of the disease and, instead, the major mediator of vessel wall destruction. [21]
