Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context?

Curci, John A.; Thompson, Robert W.

doi:10.1172/jci22309

Cited by 87 publications

(66 citation statements)

References 31 publications

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“…66 Conversely, Th2 type cytokines and chemokines localize in late stages of the human AAA disease. 110 Although our recent study appears to contradict previous results suggesting that IFN-␥ participates critically in AAA development, 111 we emphasize that Th1 cytokines may critically initiate the early accumulation of inflammatory cells. Attenuated production of IFN-␥ (or other Th1 cytokines) may diminish the early stages of atherosclerotic inflammatory cell recruitment, thus modulating subsequent protease activity and attenuating aneurysm formation.…”

Section: Triggers For a Cascade Of Events Leading To Atherosclerosis contrasting

confidence: 85%

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Shimizu

Mitchell

Libby

2006

ATVB

567

478

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Abstract-Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. 1 However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-␥ (IFN-␥) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Key Words: aortic aneurysm Ⅲ atherosclerosis Ⅲ cytokine Ⅲ pathogenesis Ⅲ T-lymphocytes Ⅲ transplantation A ortic aneurysms are permanent and localized aortic dilations defined as having diameters 1.5-times greater than normal (ie, Ͼ3 cm diameter for abdominal aortic aneurysms [AAA]). In comparison, the term aortic ectasia describes localized aortic enlargement Ͻ1.5-times normal diameter. 2 Although most aneurysms remain asymptomatic and undiagnosed, risk of rupture increases dramatically when diameters exceed 5.5 cm. Despite surgical advances, the prognosis of ruptured AAA remains poor, and the overall mortality remains high (80% to 90%). 3 Although surgical or endovascular repair constitutes the major therapeutic options for AAA Ͼ5.5 cm, such invasive procedures provide no therapeutic advantage for AAA Ͻ5.5 cm diameter.Most AAA develop below the renal arteries and end above the bifurcation of the iliac arteries; they typically exhibit a fusiform morphology, with symmetrical circumferential enlargement involving all layers of the aortic wall. Less frequently, aneurysms have a saccular form, with aneurysmal degeneration affecting only part of the aortic circumference. The AAA wall usually becomes laminated with thrombus and its intraluminal diameter often appears relatively normal by angiography. Important histological features of aneurysms include chronic adventitial and medial inflammatory cell infiltration, elastin fragmentation and degeneration, and medial attenuation. Collagen (especially types I and III) in the media and adventitia provides tensile strength to the aortic wall. Collagen synthesis increases during the early stages of aneurysm formation, suggesting a repair process. 4 However, in later stages, collagen degradation exceeds its synthesis (accompanied by excessive degradation of other extracellular matrix macromolecules, notably elastin), ultimately favoring AAA rupture. Indeed, AAA exhibit increased local production of enzymes capable of degrading collagen and elastin extracellular matrix proteins. [5][6][7] In AAA, inflammatory cells (polymorphonuclear neutrophils, T cells, B cells, macrophages, mast c...

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Section: Triggers For a Cascade Of Events Leading To Atherosclerosis contrasting

confidence: 85%

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Shimizu

Mitchell

Libby

2006

ATVB

567

478

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“…We wonder whether the concomitant development of a Th1 response as indicated by the prominent increase in IFN-␥ expression might still have an effect on cells within the aortic graft and thus could trigger aneurysm formation. 27 In our experiments both CD4 ϩ CD28 Ϫ and CD8 ϩ CD28 Ϫ T cells lack the intracellular production of IL-4 analyzed by FACS after stimulation ( Figure 3B and 3E). ϩ CD28 Ϫ T cells.…”

Section: Discussionmentioning

confidence: 46%

High Prevalence of Circulating CD4⁺CD28⁻T-Cells in Patients With Small Abdominal Aortic Aneurysms

Duftner

Seiler²,

Klein-Weigel³

et al. 2005

ATVB

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Objective-To assess the possible role of proinflammatory CD28Ϫ T cells in abdominal aortic aneurysms (AAAs). Animal studies and human tissue studies suggest a role for interferon (IFN)-␥-producing T cells in the development and progression of AAAs. Methods and Results-Fluorescence-activated cells sorter analysis of peripheral blood samples and measurement of AAA size using sonography were performed in 101 AAA patients and 38 healthy controls. Key Words: aortic disease Ⅲ aneurysms Ⅲ leukocytes Ⅲ immune system Ⅲ human A bdominal aortic aneurysm (AAA) is a common disease with a prevalence of 3% of individuals aged 60 years and older and is a potentially lethal disorder causing Ϸ15 000 deaths annually in the United States. 1 Recent human tissue studies and animal models have led now to a paradigm shift in the pathogenetic concept of AAAs. Rather than a simple degenerative process, the majority of AAAs has proven to be a complex and dynamic remodeling process. In brief, studies of human AAA tissues have identified extensive inflammatory infiltrates in both the media and the adventitia, 2 leading to an increased expression of proinflammatory cytokines and C-reactive protein (CRP) in aneurysmal tissue. [3][4][5] The presence of vascular-associated lymphoid tissue (VALT) with lymphoid follicles and lymph node-like structures in the adventitia of AAAs suggests a role for immunocompetent and antigen presenting cells not only in atherosclerosis 6 but also in AAA disease. 2 The role for T cells has been further supported by immunogenetic findings with associations between AAA and human leukocyte antigen class II molecules. 7 Infiltration of the adventitia usually occurs together with medial thinning. This inflammatory process triggers the production of metalloproteinases and apoptosis of medial smooth muscle cells thus explaining the disruption of the orderly lamellar structure in aortic aneurysms.Recently, a subgroup of proinflammatory T cells has been identified in patients with immune-mediated disorders including rheumatoid arthritis, 8 -9 ankylosing spondylitis, 10 multiple sclerosis, 11 Wegener granulomatosis, 12 and unstable angina, 13 which lack the costimulatory molecule CD28 on their surface and are considered as markers for chronic inflammation and early aging. 14 Under these circumstances the CD28 Ϫ T cells are part of the CD4 ϩ as well as the CD8 ϩ T cell compartment, persist over years, and include most of the oligoclonally expanded T cells. Phenotypically, CD4 ϩ CD28 Ϫ T cells from rheumatoid arthritis and ankylosing spondylitis patients and CD8 ϩ CD28 Ϫ T cells from aged persons, rheumatoid arthritis, and melanoma patients share the expression of various natural killer (NK) cell receptors and lack the expression of the lymphocyte marker CD7. 9,15-16 Functionally these T cells are capable to release large amounts of interferon (IFN)-␥, perforin, and granzyme B, providing them with the possibility to lyse target cells. 17 In the pathogenesis of coronary arteriosclerosis, the critical role of IFN-␥ was alread...

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“…The mechanisms driving diameter expansion of already-formed AAAs are poorly documented, 28 largely because it is difficult to reproduce further diameter increase in animal models of already-developed AAAs. As a working hypothesis, it can be accepted that the interplay between infiltrating T lymphocytes 29,30 and macrophages 31,32 results in an aggravation of matrix injury by proteases and ultimately in diameter increase. Neoepitopes exposed by ongoing matrix degradation 33 and xenogenic proteins 34 are proposed as stimuli perpetuating wall inflammation and destruction.…”

Section: Inhibition Of Wall Destructionmentioning

confidence: 99%

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms

et al. 2005

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Background-The cell response to transforming growth factor-␤1 (TGF-␤1), a multipotent cytokine with healing potential, varies according to tissue context. We have evaluated the ability of TGF-␤1 overexpression by endovascular gene therapy to stabilize abdominal aortic aneurysms (AAAs) already injured by inflammation and proteolysis. Methods and Results-Active TGF-␤1 overexpression was obtained in already-developed experimental AAAs in rats after endovascular delivery of an adenoviral construct encoding for a mutated form of active simian TGF-␤1 and in an explant model using human atherosclerotic AAA fragments incubated with recombinant active TGF-␤1. Transient exogenous TGF-␤1 overexpression by endovascular gene delivery was followed by induction of endogenous rat TGF-␤1. Overexpression of active TGF-␤1 in experimental AAAs was associated with diameter stabilization, preservation of medial elastin, decreased infiltration of monocyte-macrophages and T lymphocytes, and a decrease in matrix metalloproteinase-2 and -9, which was also observed in the explant model, in both thrombus and wall. In parallel with downregulation of the destructive process, active TGF-␤1 overexpression triggered endoluminal reconstruction, replacing the thrombus by a vascular smooth muscle cell-, collagen-, and elastin-rich intima. Conclusions-Local TGF-␤1 self-induction after transient exogenous overexpression reprograms dilated aortas altered by inflammation and proteolysis and restores their ability to withstand arterial pressure without further dilation. This first demonstration of stabilization of expanding AAAs by delivery of a single multipotent self-promoting gene supports the view that endovascular gene therapy should be considered for treatment of aneurysms.

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Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context?

Cited by 87 publications

References 31 publications

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

High Prevalence of Circulating CD4⁺CD28⁻T-Cells in Patients With Small Abdominal Aortic Aneurysms

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms

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Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context?

Cited by 87 publications

References 31 publications

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

High Prevalence of Circulating CD4+CD28−T-Cells in Patients With Small Abdominal Aortic Aneurysms

Overexpression of Transforming Growth Factor-β1 Stabilizes Already-Formed Aortic Aneurysms

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High Prevalence of Circulating CD4⁺CD28⁻T-Cells in Patients With Small Abdominal Aortic Aneurysms