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J Thorac Cardiovasc Surg 2008;136:922-929
© 2008 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms

^a Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas
^b Department of Cardiovascular Surgery, The University of Texas Medical School at Houston, Houston, Texas
^c Department of Pathology, The University of Texas Medical School at Houston, Houston, Texas
^d Department of Immunology, Baylor College of Medicine, Houston, Texas

Received for publication June 30, 2007; revisions received November 28, 2007; accepted for publication December 18, 2007.

^_* Address for reprints: Dianna M. Milewicz, MD, PhD, The University of Texas Medical School at Houston, 6431 Fanin St, MSB 6.100, Houston, TX 77030. (Email: Dianna.M.Milewicz{at}uth.tmc.edu).

	Abstract

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Objective: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm.

Background: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm.

Methods: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor β-chain variable region gene.

Results: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease.

Conclusion: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

	Introduction

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Aortic aneurysms are classified in terms of their anatomic location and most commonly occur in the infrarenal abdominal aorta (abdominal aortic aneurysm [AAA]) and thoracic aorta (thoracic aortic aneurysm [TAA]). AAAs primarily affect the elderly population and are characterized by atherosclerotic changes with chronic inflammation of the aortic wall. In contrast, TAAs affect a younger population and the pathology present in the aortic wall in these patients is medial degeneration (MD), described as a lesion characterized by the triad of loss of smooth muscle cells, fragmented and diminished number of elastic fibers, and increased accumulation of proteoglycans.¹ Individuals with TAAs are referred for prophylactic surgical repair of the ascending aorta when an aneurysm reaches a diameter greater than 5 cm to prevent the life-threatening complications of aortic dissection or rupture.²

A number of genetic conditions can predispose individuals to the formation of TAAs, most notably Marfan syndrome (MFS).³ MFS is a pleiotropic condition inherited in an autosomal dominant manner that has associated skeletal and ocular manifestations. A defective gene causing MFS, FBN1, encodes for an extracellular matrix protein called "fibrillin-1," a component of the elastic fiber system. The fibrillin-1 deficient mouse, an accepted model of MFS that recapitulates the cardiovascular phenotype, shows MD in the aortic wall that is associated with inflammatory infiltrates before dilatation or dissection.⁴ A second gene for MFS was recently identified as transforming growth factor β receptor type II (TGFBR2).⁵

A genetic predisposition for TAA can also be inherited in an autosomal dominant manner in the absence of any associated syndromic findings. Families with multiple affected members typically demonstrate autosomal dominant inheritance with decreased penetrance and variable expression, indicating that a single defective gene is responsible for the disease.^6,7 Genetic heterogeneity has been demonstrated for familial TAA, and 4 chromosomal loci have been mapped for inherited forms of thoracic aortic disease: TAAD1 on 5q,⁸ TAAD2 on 3p,⁹ TAAD4 on 10q,¹⁰ the FAA1 locus on 11q,¹¹ and a locus of 16p for TAA associated with patent ductus arteriosus.¹² The defective gene at the TAAD2 locus was recently identified as TGFBR2. Mutations in TGFBR2, TGFBR1, ACTA2, and MYH11 have been identified that lead to varied phenotypes associated with TAAs and dissections.^5,13,14 Similar to MFS, the aortas of patients with familial forms of TAA also demonstrate MD.

Previous studies have documented an inflammatory infiltrate in the aortic wall of patients with TAA.^15,16 In aortas of patients undergoing prophylactic repair of TAAs, there were significant increases in the number of CD3+ and CD68+ cells throughout the aortic media and adventitia when compared with control aortas.¹⁵ Other investigators have also documented an inflammatory infiltrate in the aortic wall that was associated with interferon-gamma production production.¹⁶ In this study, we sought to further characterize the inflammatory infiltrate in aortas of patients referred for prophylactic repair of an ascending aortic aneurysm resulting from single gene defects, such as MFS and familial TAA, and sporadic, nonfamilial cases.

	Materials and Methods

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Subjects and Collection of Tissues
All patients gave signed consent to these studies, which were approved by the Institutional Review Board at the University of Texas Health Science Center at Houston. Full aortic segments were collected from patients undergoing elective repair of TAAs (N = 20; 12 male and 8 female, mean age 46.9 ± 16.6 years, range, 21–77 years) ( Table 1). Five patients had MFS (3 male and 2 female, mean age 35.6 ± 11.2 years, range, 25–49 years), 6 unrelated patients had a family history of TAAs (4 male and 2 female, mean age 44.8 ± 18.1 years, range, 21–67 years), and 9 patients had sporadic TAA (5 male and 4 female, mean age 54.6 ± 15.4 years, range, 39–77 years). Control ascending aortas were obtained from 5 individuals at autopsy who died of a cause unrelated to aortic disease and were not septic at the time of death (2 male and 3 female, mean age 57.2 ± 12.5 years, range, 44–74 years). Aortic specimens were immediately transferred to the laboratory in a container with cold Waymouth's MB 752/1 Medium (Invitrogen Corp, Carlsbad, Calif). Each specimen was divided into several parts for histochemistry, protein, and RNA extraction.

T-cell Receptor β-Chain Variable Region Gene Expression by Real-time Polymerase Chain Reaction Analysis
Total RNA was extracted from aortic tissue and peripheral blood mononuclear cells using the RNeasy Mini kit (Qiagen Valencia, Calif). cDNA was synthesized with Superscript II Reverse Transcriptase (Invitrogen, Carlsbad, Calif). T-cell receptor β-chain variable region (TCR BV) and TCR BJ gene expression was analyzed by real-time quantitative polymerase chain reaction (PCR). Real-time PCR was performed in 96-well optical PCR plates with SYBR-Green PCR Master Mix (Applied Biosystems, Foster City, Calif) on an ABI 7000 Sequence Detection System (Applied Biosystems) following published protocols.^17,18 Reactions were performed in duplicate.

Statistics Analysis
To test whether there were significant differences in the number of positive inflammatory cell staining in the aortas between controls and patients with MFS, familial thoracic aortic aneurysm (FTAA), and TAA, exact Wilcoxon rank-sum tests were performed. Multiple comparison corrections were made using Bonferroni corrections (significance levels were corrected for multiple comparisons by dividing them by the number of multiple comparisons). Linear regression analyses were conducted to investigate the association between the number of positive cells and the age at surgery.

	Results

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Characterization of the Inflammatory Cells in Thoracic Aortic Aneurysms of Patients with Marfan Syndrome, Familial Thoracic Aortic Aneurysm, and Sporadic Thoracic Aortic Aneurysm Referred for Prophylactic Surgical Repair
Immunohistochemistry was performed using monoclonal antibodies directed against markers for T and B lymphocytes and macrophages to characterize the cells present in the aneurysm wall in patients undergoing prophylactic repair of an ascending aortic aneurysm. CD3+ T cells were clearly observed throughout the sections of aortic media and adventitia of all patients with aneurysms but not in the control aortas ( Figure 1, CD3 staining), and confirmed by immunostaining with a monoclonal antibody to CD45 (data not shown). Further characterization indicated that CD4+ and CD8+ T cells were both present in the aortas (Figure 1, CD4 and CD8 staining). CD20 immunostaining detected a few B lymphocytes in the TAAs but no cells in control aortas (Figure 1, CD20 staining). Staining with macrophage-specific antibody indicated that all aneurysm tissue sections contained CD68+ macrophages that were frequently present diffusely in the media and adventitia of the aortas from patients but were rarely found in control aortas (Figure 1, CD68 staining).

View larger version (120K): [in this window] [in a new window]   Figure 1. Immunohistochemistry for markers of immune cells in the media and adventitia of aortas from controls and patients with MFS, FTAA, and TAA. The marker recognized by the antibody used for immunohistochemistry, the segment of the aorta photographed, and the magnification are on the left. The cause of the aneurysm is on the top. The orientation in the photographs is the lumen of the aorta at the bottom and the adventitia at the top. Color was developed with DAB for peroxidase (brown) or Fast Red for alkaline phosphatase (red). Magnification 200x for panels except CD3 adventitia staining. MFS, Marfan syndrome; FTAA, familial thoracic aortic aneurysm; TAA, thoracic aortic aneurysm.

View larger version (23K): [in this window] [in a new window]   Figure 2. Morphometric quantization of lymphocytes, subpopulations of T cells, and macrophages in ascending aortas of controls and patients with MFS, FTAA, and TAA. After immunohistochemistry of aortic tissue, CD3, CD4, CD8, CD20, and CD68-positive cells in the media in 10 contiguous high-power fields (magnification 400x) were counted by 2 independent observers. In the aortas of patients with MFS, FTAA, and TAA, there was a significant increase in the number of CD3+, CD4+, CD8+, CD20+, and CD68+ cells when compared with control aortas (* P < .01). MFS, Marfan syndrome; FTAA, familial thoracic aortic aneurysm; TAA, thoracic aortic aneurysm.

View larger version (74K): [in this window] [in a new window]   Figure 3. Increased expression of leukocyte adhesion molecules, ICAM-1, and VCAM-1 in the vasa vasorum in the adventitia of patients with MFS and FTAA. Immunohistochemistry revealed positive immunostaining for ICAM-1 and VCAM-1 in the vasa vasorum from patients with MFS and FTAA. Magnification 400x. MFS, Marfan syndrome; FTAA, familial thoracic aortic aneurysm; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule.

View larger version (13K): [in this window] [in a new window]   Figure 4. Inverse correlation between the age of patients at the time of prophylactic repair of the aorta and the number of T lymphocytes (CD3+ staining) and macrophages (CD68+ staining) in the aortic media of patients. CD3+ cells (A) and CD68+ cells (B) were counted in 10 contiguous high-power fields of the aortic media of TAAs from 19 patients with MFS, FTAA, and sporadic TAA.

Clonality of the overexpressed BV22 and BV25 of T cells derived from selected aortic specimens by TCRBJ gene use was also examined. The TCRBJ profile of BV22 and BV25 was analyzed by using BV22 or BV25 forward primers and reverse primers for 13 BJ genes with real-time PCR. Both BV22 and BV25 genes exhibited heterogeneous TCRBJ gene profiles in aortic specimens derived from controls and patients with TAA. These analyses revealed that no BJ genes were preferentially used in the context of the overexpressed BV22 and BV25 (data not shown).

The clonality of the T-cell receptors suggested that the T lymphocytes may be replicating in response to specific antigens presented by activated dendritic cells. Staining of the aneurysm aortas with a marker of activated dendritic cells, CD83, showed rare CD83+ cells located at the adventitial/medial border, whereas CD83+ cells were not found in control aortas (Figure 1, CD83).

	Discussion

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An inflammatory component in MD, composed primarily of T cells and macrophages, was identified in TAAs resulting from single gene disorders, MFS, and familial TAA, and nongenetic, sporadic cases of TAA. More inflammatory cells were present in the aortas of patients with single gene defects than in patients with sporadic TAAs. The T-cell–associated vasculitis of the vasa vasorum and the increased expression of leukocyte adhesion molecules by the endothelial cells of the vasa vasorum suggest that a pathway for T-cell migration into the media is from the adventitia. The number of both inflammatory T lymphocytes and macrophages in the aortic media negatively correlated with patients' age at referral for prophylactic surgical repair, thus raising the possibility that the inflammatory infiltrate may contribute to disease progression. Alternatively, the inflammatory infiltrate could correlate with the aortic dilatation and corresponding pathologic changes, but not contribute to the disease progression. In contrast, there was no correlation between the size of the aorta and the number of inflammatory cells, implying that the inflammatory infiltrate did not simply result from irritation of the tissues from the progressive enlargement of the aorta. It is interesting to note that recent studies have suggested that dysregulation in TGF-β signaling contributes to aortic disease in both MFS and familial TAA caused by TGFBR2 mutations.^19,20 TGF-β signaling plays a critical role in controlling T-cell homeostasis and is required to prevent undesirable self-targeted responses, suggesting that TGF-β dysregulation may contribute to the aortic T-cell immune response.²¹

Tang and colleagues¹⁶ also observed that leukocyte infiltration increased in the media of aortas with TAAs compared with control aortas. They suggested dividing TAAs into 2 subgroups, bland and infiltrated aneurysms, on the basis of whether leukocytes infiltrate into the inner half of aortic media. T and B lymphocytes were significantly increased in the aortas with infiltrated aneurysms compared with those of bland aneurysms and controls. Macrophages were significantly increased in the aortic media with infiltrated aneurysms compared with those of bland aneurysms and controls. Although insufficient information is provided to determine the clinical cause of infiltrated and bland TAAs, it may be that the infiltrative aneurysms came from patients with a genetic cause to their aneurysms and the bland aneurysms were from patients with sporadic TAAs.

There are similarities between the characteristics of the inflammatory infiltrate present in TAAs and the inflammatory infiltrate described in giant-cell arteritis and Takayasu's arteritis. These disorders demonstrate a similar cellular immune response involving T cells, primarily CD4+ cells and macrophages, without evidence of an autoantibody component contributing to the pathology.²² Histology studies indicate that T cells enter tissue with activation of endothelial cells in the vasa vasorum and not through the intimal endothelium. Furthermore, a limited T-cell receptor repertoire has been shown to infiltrate the aortic tissue in Takayasu's arteritis, suggesting that an aortic tissue antigen presented in the cleft of certain major histocompatibility complex molecules in the aortic tissue was targeted by the T cells.²³ Restricted use of T-cell receptors on the T cells was also identified in TAAs, specifically TCRBV18, TCRBV22, and TCRBV25. Although the direct link between dendritic cell function and T-cell activation remains unclear in the TAA tissue, the presence of activated dendritic cells capable of presenting antigen in the adventitia of TAAs but not in the control aortas provides further support that a tissue antigen is targeted by the T cells.

Once activated, CD4+ T cells can polarize into T-helper type I (Th1) or 2 (Th2) cells, which in turn control the inflammatory cascades in different diseases. A recent study of transmural inflammation of TAAs indicated that the Th1-type or proinflammatory process is the dominant immune response occurring in aneurysms. The up-regulation of interferon-gamma significantly correlated with both outward vascular remodeling and intimal expansion of TAAs.¹⁶ Th1 responses favor effective clearance of intracellular pathogens and play crucial roles in the pathophysiology of organ-specific autoimmune diseases. Autoimmune encephalomyelitis²⁴ and thyroiditis²⁵ are two good examples that autoimmune diseases are initiated by Th1-mediated responses. The prominent autoimmune cause of multiple sclerosis is also considered to be the aberrant activation of interferon-gamma–producing Th1 cells that recognize self-peptides of the myelin sheath. The restricted uses of TCRBV and infiltration of predominant Th1-type cells in TAA lesions suggest that a Th1-mediated proinflammatory response could be a mechanism that contributes to the pathogenesis of TAA.

The results of our study parallel the results of a novel mouse model of TAAs, the interleukin-1 receptor antagonist deficient mouse (interleukin-1-Ra-/-).²⁶ An inflammatory aortitis of the ascending aorta develops in the deficient mice that is not present in wild-type mice, involving the medial infiltration of T lymphocytes and macrophages. Furthermore, peripheral T cells from the interleukin-1-Ra-/- mouse cause aortic aneurysms in nu/nu mice, suggesting that activated or memory T cells are generated and involved in the development of the ascending aortic disease. As in giant cell and Takayasu's arteritis, the pathogenic antigens in the aorta in this mouse model require further investigation.

In our study, no preferential use of BJ gene was selected in the context of overexpressed BV22 and BV25 in the majority of TAA aortas, leading to an alternative possibility that a superantigen-driven stimulation of Vβ22 and Vβ25-positive T cells in the aortic tissues of patients with TAA may be one of the major mechanisms contributing to the initial immune response in the aortic tissue. Mitogens, superantigens, and nominal antigens use distinct mechanisms to activate T cells and induce proliferation. Mitogens and nominal antigens induce a polyclonal proliferation of T cells independently of the TCRBV family expressed. In contrast, stimulation of certain superantigens, such as toxic shock syndrome toxin-1, is based on the TCR BV family and independent of complementary determining region 3 sequence. The T-cell response to superantigens is oligoclonal and restricted in terms of complementary determining region 3.

The phenotype and biological activity of invading T cells and macrophages in TAAs should be further characterized before drawing conclusions on their relevance to the disease process. The limited access to aortic tissue in humans impedes assessing the role of the inflammatory infiltrate in disease progression. Despite these limitations, our study results suggest that an immune-mediated aortitis may contribute to the pathogenesis of TAAs and that a spectrum of aortic disease processes from Takayasu's arteritis to TAA formation involve inflammatory infiltrates in the aortic media. Further investigations are needed to verify the role of this inflammatory infiltrate in the progressive molecular pathology of TAAs.

	Figure E1

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TCR BV gene distribution profiles in the aortas of controls and patients with MFS, FTAA, TAA, and sporadic TAA, and in peripheral blood mononuclear cells of patients with MFS and TAA. TCR BV gene expression was analyzed quantitatively using RNA from aortic tissue and peripheral blood mononuclear cells by real-time PCR using specific primers for 25 BV genes. BV gene distribution is presented as the mean percentage expression of each BV gene relative to BC expression on the y axis. MFS, Marfan syndrome; FTAA, familial thoracic aortic aneurysm; TAA, thoracic aortic aneurysm; CTL, control; PBMC, peripheral blood mononuclear cell.

	Acknowledgments

 
The authors are grateful to the patient and their physicians involved in this study and to Dr Craig T. Bason for referring a patient for this study.

	Footnotes

 
This work was supported by the National Institutes of Health R01HL62594 and P50HL083794 (D. M. M.), R01HL59249 and RO1HL69509 (Y. J. G.), the Doris Duke Foundation (D. M. M), and General Clinical Research Center (MO1RR02558).

^_* Drs He and Guo contributed equally to this work.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Wei Sun Anthony L. Estrera Hazim J. Safi Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by He, R. Articles by Milewicz, D. M. Search for Related Content PubMed Articles by He, R. Articles by Milewicz, D. M. Related Collections Great vessels