TA clearly seem to be an autoimmune disease in which cellular immunity plays a major role and humoral immunity participates in a form that still remains to be clarified. In fact, immunohistochemical studies have shown different cell strains involved in the aortoarteritis process, suggesting a critical role in the onset of the disease. Gamma-delta T cells, NK cells, cytotoxic T cells, T-helper cells, and macrophages are some of the cells found in the aortic wall. This process does not seem to start in the endothelium of the aortic wall. The pathogenesis implies the stimulation of an antigen of unknown nature. T cells, NK cells, and ­cytotoxic T cells express and release massive amounts ­perforin (a membrane-disrupting protein) through the recognition of MICA, which is directly placed on the surface of arterial ­vascular cells [14]. This way, the endothelial cells of the vasa vasorum are activated to allow the lymphocytes to gain access to the media and adventitia of the arterial wall [16], thus amplifying the inflammatory response, recruiting ­especially mononuclear cells.

Immature dendritic cells (DCs) are vastly distributed migratory cells in charge of sampling the antigens in the environment. Once activated, the profile of their chemokine receptor is modified, migrating to lymphoid tissues. Here they express a mature chemokine-producing DC profile and costimulatory molecules that interact with antigen-specific T cells.

In giant cell arteritis (also called Horton’s arteritis), DCs are activated and produce chemokines (CCL18, CCL19, and CCL21) that bind the chemokine receptor (CCR7) they express, leading to the entrapment of DC within the vascular wall [17]. The co-localization of DC near T-cells indicates that they are probably involved in the physiopathology of the TA by a similar mechanism.

Study of the cellular composition within the adventitia in Takayasu’s arteritis has shown inflammatory infiltrates ­containing T-cells colocalizing with dendritic cells (DC) [18 19]. This fact is essential in the development and maintenance of inflammation in the vascular wall.

The antigens (of unknown nature) are presented to killer T-cells by an epitope associated with the major histocompatibility complex (MHC) on the activated DCs, which facilitates the cytotoxic reaction present within the vascular wall.

Although the existence of a humoral role is not known, specific immunologic markers for aortoarteritis, rheumatoid factor, and antinuclear antibodies have been identified, supporting the role of an autoimmune component [20, 21] in the establishment of the disease.

The presence of immune complexes in the sera and receptors of lymphocytes has been reported, but the results differ among authors [22].

Anti-aorta antibodies have long been reported in TA ­[23–28], but in the study by Baltazares [29], reactive antibodies against a total human aorta extract were searched for, including their main protein components, elastin, fibronectin, and collagen, but no difference was found compared with controls. However, in the same trial, the immunoblot technique showed an immunoprecipitate of a 45 kDa protein in the sera of TA patients significantly more frequently than in the sera of the control group [29]. In the same line of research, Eichhorn [30] suggested that an antigen to these antibodies was stored within the cytoplasm when they found that healthy cells exposed to sera from patients with TA had a bright, homogeneous, and specific immunofluorescent cytoplasm stain and weak membrane stain.

There are reports about the presence of antiphospholipid antibodies in a significant proportion of patients with TA [31–33], anticardiolipin antibodies and antimonocyte antibodies [34]. These were correlated with disease activity, suggesting a pathogenic role in TA. Finally, alpha-beta T-cells would then infiltrate the arterial wall and specifically recognize one or a few autoantigens presented by a shared epitope associated with a specific MHC on the DCs.

The participation of other proinflammatory mediators, such as interleukin (IL)-6, mainly synthesized by macrophages and T-cells, is also known. Functions of the IL-6 are to activate B-cells, enhance T-cell cytotoxicity [35] and NK cell activity [36], stimulate fibroblast proliferation, and induce acute-phase protein synthesis. Other proinflammatory molecules, such as RANTES chemokine (regulated on activation, normal T-cell-expressed and secreted) and IL-8 cytokine, are potent chemoattractants for most mononuclear cells, including those that constitute the majority of the inflammatory infiltrate of the vascular wall in TA. Interleukin-6 and RANTES can also induce the production of metalloproteinases (MMP) in the matrix from mononuclear cells and smooth muscle cells. These proteolytic enzymes degrade elastin and collagen, which are structural components of the arterial wall [37].

These findings have been reinforced by several studies in patients with TA that showed higher serum concentrations of IL-6 [38], RANTES [39], IL-8 [40], MMP-2, MMP-3, and MMP-9. The levels of these latter two MMPs are correlated with disease activity [41]. However, studies of mRNA of proinflammatory cytokines showed increased gene expression of TNF-alpha, IFN-gamma, IL-2, IL-3, and IL-4 and higher expression of IL-12 mRNA after stimulation of cells with lipopolysaccharide and lower mRNA expression of IL-10 than in controls. These results suggest a chronic ­establishment of the inflammatory response in Takayasu’s arteritis [42].

In conclusion, notwithstanding numerous studies, the physiopathology of TA remains unknown and is probably multifactorial, involving several actors.

The data strongly implicate of autoimmune processes, mainly led by cellular immunity, whose role remains to be elucidated. The 2004 study by Seko et al. linked some of the previously discussed data [43]. Therefore, the model proposed in Fig. 23.2 is valid for the understanding the pathogenesis of the disease. The pathologic sequence may implicate the stimulation from an unknown antigen, triggering the expression of heat shock protein 65 in the aortic wall, which in turn would induce the expression of MICA. Inflammatory cells recognize MICA and secrete perforin, disrupting the endothelial membrane of the vasa vasorum and gaining access to the arterial wall.

Inflammatory mediators, such as cytokines and chemokines, are released, allowing inflammatory cells to amplify the process and entrap DCs within the arterial wall.

Alpha-beta T-cells would specifically recognize one or a few autoantigens presented by a shared epitope associated with a specific MHC on the DCs. These DC could ­simultaneously cooperate to some extent with the B-cells and determine a humoral immunity mainly consisting of anti-endothelial cell autoantibodies that could trigger complement-dependent cytotoxicity against endothelial cells (though this last pathogenic mechanism remains very controversial). This condition would produce medial destruction of the aortic wall with stenosis, occlusion, or aneurysm formation.

Markers of inflammation, such as C reactive protein levels and the erythrocyte sedimentation rate, are elevated, which may help make the diagnosis, despite being very nonspecific. Multiple studies indicate that C-reactive protein levels and the erythrocyte sedimentation rate are elevated in approximately 70 % of patients in the acute phase and 50 % in the chronic phase of disease [4]. Leukocytosis and anemia may also be present, although, like the other markers, they are very nonspecific variables [48].

For decades, angiography was considered the “gold standard” to confirm the diagnosis of Takayasu’s arteritis (Fig. 23.3). Although this technique can show the location and grade of the stenotic or aneurysmatic lesion [49], it is an invasive method with several limitations (radiation exposure, adverse reactions to contrast media, and arterial damage [50]). Therefore, it will probably be replaced by multiple less invasive techniques that also provide information about changes in the wall, such as ultrasonography, contrast CT scan, and MRI.

Ultrasonographic study can show the stenotic or aneurysmatic lesions and may contribute to the diagnostic process as well as to the evaluation of the grade and progress of the disease [51]. Patients with Takayasu’s arteritis can present an homogeneous, midechoic, circumferential wall thickening with luminal stenosis on carotid echo-Doppler imaging [52]. These findings have been described as pathognomonic of Takayasu’s arteritis and have been called the “macaroni sign” (Fig. 23.4) [53].

The CT scan may have some advantages over angiography, allowing demonstration of the mural changes of the affected vessels, such as wall thickening, calcification, or thrombus, which are not seen with conventional angiography [54], but in order to determine the degree and extension of the damage to the vessels more accurately, the use of magnetic resonance imaging (MRI) may be more helpful than CT scans. MRI has other technical advantages: paramagnetic contrast media rarely cause anaphylactic reactions and are non-nephrotoxic (which can be a determinant in the pediatric patients), ionizing radiation is not used, and soft-tissue differentiation is better [55]. However, some disadvantages of MRI are that it is less available, costs more, and has more technical difficulties than CT scans.

Another diagnostic advantage of MRI compared to the CT scan is an increased sensitivity in detecting mural edema, a finding that is present in almost all acute-phase patients. However, some studies question the use of MRI as a single follow-up imaging technique because of the contradictory findings of disease activity in patients with Takayasu’s arteritis [56].

The use of 18F-FDG PET and enhanced CT has also been described to determine the inflammatory status of the vessels. Parallel studies show that these tests can show the distribution of the inflammation in the aorta, its branches, and the pulmonary artery, suggesting that the 18F-FDG accumulation observed in Takayasu’s arteritis patients directly indicates the inflammation in the vascular wall [57].

Thoracic and abdominal aneurysms are the most common aneurysm presentations in Takayasu’s arteritis [69]. Matsumura showed a markedly high frequency in the thoracic area (29 thoracic and 7 abdominal, respectively) [65]. However, Sueyoshi [13] showed a proportional distribution between the thorax and abdomen (9 and 8 patients, respectively). In 2004, Kieffer et al. in Paris [70] published a series of 27 years’ experience, including 10 thoracic and 23 thoracoabdominal aneurysms. Six patients had associated aneurysms of the proximal aorta.

Aneurysms also occur in the subclavian [71], innominate, and carotid arteries (Regina et al., 1998 [72]), but extracranial carotid aneurysms caused by Takayasu’s arteritis are extremely rare [73]. Tabata et al. [74] reported six cases of extracranial carotid aneurysm among 106 cases in 50 years.

These anatomical presentations may have surgical difficulties in the resection and replacement of the arteries, with a relatively high incidence of stroke. Therefore, decision-making in these cases must be tailored to the individual, depending upon the extent of involvement and the symptoms, and also evaluating the possibility of hybrid intervention with the use of endovascular stent grafts [75] (Fig. 23.6).

Coronary artery involvement in Takayasu’s arteritis was first described by Frovig in 1951, and the first coronary artery bypass grafting was performed by Young [76] in 1973.

Endo et al. [3] in 2003 published their experience in coronary angiography in 130 patients with Takayasu’s arteritis. Thirty-one had coronary artery lesions, and only four had aneurysmal coronary ectasia (Fig. 23.7). In their experience, aneurysms were not treated surgically because they were diffuse and the patients had no angina.

The incidence of coronary lesions complicating Takayasu’s arteritis is relatively low. Nasu [77] in 1976 reported coronary lesions complicating Takayasu’s arteritis in 10.5 % (8/76 autopsy cases). More recently, Amano and Zuzuki [78] reported 45 % of coronary lesions, of which 73 % are occlusive coronary lesions localized around the coronary ostia as a result of the extension of inflammation-induced intimal proliferation and fibrous contraction from the ascending aorta.