**Immunopathophysiology of Large Vessel Involvement in Giant Cell Arteritis — Implications on Disease Phenotype and Response to Treatment**

Panagiota Boura, Konstantinos Tselios, Ioannis Gkougkourelas and Alexandros Sarantopoulos

Additional information is available at the end of the chapter

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

**1. Introduction**

tosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int

[72] Podojil JR, Miller SD. Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunol Rev

[73] Kälsch AI, Soboletzki M, Schmitt WH, van der Woude FJ, Hochhaus A, Yard BA, Birck R. Imatinib mesylate, a new kid on the block for the treatment of anti-neutro‐ phil cytoplasmic autoantibodies-associated vasculitis? Clin Exp Immunol

[74] Bontscho J, Schreiber A, Manz RA, Schneider W, Luft FC, Kettritz R. Myeloperoxi‐ dase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cyto‐ plasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol 2011;22(2):

[75] Negi VS, Elluru S, Siberil S, Graff-Dubois S, Mouthon L, Kazatchkine MD, Lacroix-Desmazes S, Bayry J, Kaveri SV. Intravenous immunoglobulin: an update on the clin‐

[76] Lapraik C, Watts R, Bacon P, Carruthers D, Chakravarty K, D'Cruz D, Guillevin L, Harper L, Jayne D, Luqmani R, Mooney J, Scott D.BSR and BHPR Standards, Guide‐ lines and Audit Working Group. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford) 2007;46(10):

[77] Leong H, Stachnik J, Bonk ME, Matuszewski KA.Unlabeled uses of intravenous im‐

[78] Yu Z, Lennon VA.Mechanism of intravenous immune globulin therapy in antibody-

ical use and mechanisms of action. J Clin Immunol 2007;27(3):233-245.

mune globulin. Am J Health Syst Pharm 2008;65(19):1815-1824.

mediated autoimmune diseases. N Engl J Med 1999;340(3):227-228.

2004;65:1440–8.

92 Updates in the Diagnosis and Treatment of Vasculitis

2009;229(1):337-55.

2008;3:391-8.

336-48.

1615-1626.

Giant cell arteritis (GCA) or temporal arteritis or Horton's disease is classified amongst the primary large-vessel vasculitides, according to the 2012 revision of the Chapel-Hill classifica‐ tion criteria. The disease develops almost exclusively in patients older than 50 years (preva‐ lence of 1 in 500 individuals in this age spectrum) and represents the most common vasculitis in Western countries. [1] Incidence rates are progressively increased and estimated to range between 10-30 new cases per 100000 persons beyond the age of 50, while the highest frequency is reported in Scandinavian and North American populations. [2]

The disease affects, mainly, the large- and medium-sized extracranial branches of the carotid artery and, classical clinical features, such as headache, jaw claudication, scalp tenderness and visual impairment, are closely related to this marked cranial tropism of GCA. [3]

On a histopathological basis, GCA involves all layers of the arterial wall, including the adventitia. Inflammatory lesions consist of activated T cells, dendritic cells (DCs) and macro‐ phages. These lesions are believed to be the histopathologic hallmark of GCA and are charac‐ terized by a predominance of mononuclear infiltrates or granulomas, usually with multinucleated giant cells. [4]

Besides the inflammation of the carotid branches, involvement of the great arteries, such as the aorta and its main tributaries, was initially recognized in the late 1930s and reported sporadically thereafter in necropsy or histopathologic studies of surgically resected tissues. [5,

6] The prevalence of aortic inflammation, in unselected patients with GCA, has not been fully estimated, although in a systematic necropsy study of 13 patients, large artery involvement was demonstrated in over 90% of them. [7] In more recent studies, an increased prevalence of aortic aneurysm (compared to the general population), was observed in GCA patients. [8]

**4. Environmental factors**

infectious agents. [20]

**5. The immune system in GCA**

defined components of the arterial wall.

distinct pathophysiological mechanisms. [22]

**6. Innate immunity abnormalities in GCA**

(PAMPs) and damage associated molecular patterns (DAMPs).

Several experimental studies, using DNA analysis, have shown a possible relation of GCA with certain infectious agents, such as the human papilloma virus (HPV) [17], *Chlamydia spp,* herpes viruses and PARVO B19 among others. [18] Older epidemiological studies have also demonstrated that increased incidence of GCA was observed in close relation to two inde‐ pendent epidemics of *Mycoplasma pneumoniae* infection. [19] However, not all studies con‐ firmed these associations and GCA initiation is not definitely considered to be triggered by

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

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Although evidence regarding the genetic background of GCA and the possible influence of external factors, such as viruses and bacteria, have not elucidated disease pathogenesis, it is now well understood that the immune system plays a central role in the disease process. GCA is a complex systematic disorder and it is believed to represent the result of the breakdown of immunologic tolerance, resulting from interactions between the immune system and poorly

A single triggering factor, initiating the inflammatory process, has not been yet identified. The initial insult may lead to a foreign-body giant cell attack on calcified internal elastic membrane in arteries and calcified atrophic parts of the medium layer of the aorta. [21] The prerequisite

Recent studies have raised the possibility that, in GCA, both the innate and the adaptive arms of the immune system are activated and may lead to vessel wall injury through, at least two,

Immune responses are initiated by the recognition of foreign molecular structures, such as invading pathogens, by the antigen presenting cells (APCs) of the innate immune system. Tissue macrophages and dendritic cells (DCs) represent the main classes of professional APCs and are characterized by the membrane expression of germ-line receptors (pattern recognition receptors, PRRs). These receptors are able to recognize specific molecular patterns of exoge‐ nous and/or endogenous foreign proteins, known as pathogen associated molecular patterns

Upon recognition of a certain PAMP or DAMP, dendritic cells become differentiated and activated and produce cytokines, which are able to recruit neutrophils and macrophages,

for a calcified artery explains why GCA almost exclusively occurs in older people.

Retrospective surveys, over extended time periods (20-50 years), confirmed that aortic aneurysm occurs in 9.5-22.5% of these patients and, particularly, in the first 5 years of follow up. [9, 10] These findings indicate that large vessel involvement in GCA may be more frequent than anticipated. Based on these data, a recent prospective study from Prieto-Gonzalez et al, using non-invasive techniques (CT angiography), concluded that large vessel vasculitis occurs in two thirds of patients with GCA, while aortic dilatation is already present in 15% of them at the time of diagnosis. [11]

Large vessel involvement represents a significant cause of death in GCA and it may be asymptomatic and lead to aortic dissection and/or rupture. [12] These findings underline the importance of elucidating the pathophysiologic basis of the disease, in which the immune system seems to play a central role.

In this chapter, a thorough review of the current evidence for disease immunopathophysiol‐ ogy, in regard to disease phenotype and response to treatment, is presented.
