Aneurysmal Lesions of Patients with Abdominal Aortic Aneurysm Contain Clonally Expanded T Cells

Abstract

Abdominal aortic aneurysm (AAA) is a common disease with often life-threatening consequences. This vascular disorder is responsible for 1–2% of all deaths in men aged 65 years or older. Autoimmunity may be responsible for the pathogenesis of AAA. Although it is well documented that infiltrating T cells are essentially always present in AAA lesions, little is known about their role in the initiation and/or progression of the disease. To determine whether T cells infiltrating AAA lesions contain clonally expanded populations of T cells, we amplified β-chain TCR transcripts by the nonpalindromic adaptor–PCR/Vβ-specific PCR and/or Vβ-specific PCR, followed by cloning and sequencing. We report in this article that aortic abdominal aneurysmal lesions from 8 of 10 patients with AAA contained oligoclonal populations of T cells. Multiple identical copies of β-chain TCR transcripts were identified in these patients. These clonal expansions are statistically significant. These results demonstrate that αβ TCR+ T lymphocytes infiltrating aneurysmal lesions of patients with AAA have undergone proliferation and clonal expansion in vivo at the site of the aneurysmal lesion, in response to unidentified self- or nonself Ags. This evidence supports the hypothesis that AAA is a specific Ag–driven T cell disease.

ApoB-100–Related Peptide Vaccine Protects Against Angiotensin II–Induced Aortic Aneurysm Formation and Rupture

“…Interestingly, a recent study has suggested that CD8 þ T cells mediate Th17 polarization by activated CD4 þ T cells (20). In agreement with this report, we show that CD8 þ T cells were required for The clinical relevance of our findings is demonstrated by evidence of T cell clonality in human AA (10,11). Clonality indicates specificity to antigenic immune epitopes.…”

“…The interaction of T cells with antigen-presenting cells, such as macrophages and dendritic cells, thus provide the prime condition for immune activation (9). Clonal expansion of T cells in human AA (10,11) We have demonstrated that immunization with an apolipoprotein B-100 (apoB-100)-related peptide, p210, reduces atherosclerosis in hyperlipidemic apolipoprotein E-deficient (apoE À/À ) mice (12). The antiatherosclerotic effect of p210 vaccine was due to immunomodulation of CD8 þ T cells (12) independent of antibody production (12,13).…”

The pathophysiologic basis of abdominal aortic aneurysm progression: a critical appraisal

“…The abundance of cellular components of the immune system clearly differentiates AAA disease from atherosclerotic disease [103]; an observation that has led to the suggestion that AAA bears characteristics of an immune-driven pathology [35, [104][105][106]]. Yet, as pointed out by Curci and Thompson in 2004, it remains unclear whether (aspects) of the adaptive cellular immune responses are causatively involved in AAA disease, or whether they reflect the chronic inflammation and ongoing tissue degradation [107].…”

Clonal Expansion of T Cells in Abdominal Aortic Aneurysm: A Role for Doxycycline as Drug of Choice?

“…Therefore, we postulate that the primary effect of doxycycline is based on its inhibition of mitochondrial protein synthesis, preventing clonal expansion of T-cells and possibly also other proliferating cells in AAA tissue, thus, indirectly, resulting in a decrease of proinflammatory cytokines, MMP-2 and MMP-9 that otherwise damage the vascular stroma [9,28,41]. Whilst there is no direct experimental evidence available that the observed effects of doxycycline on AAA are based on its inhibition of mitochondrial protein synthesis, the finding of Lu et al [11] that aneurysmal lesions contain clonally expanded T cells combined with our own observations in cancer research that doxycycline results in a proliferation arrests of T cells through its inhibition of mitochondrial protein synthesis [72,73] lends strong support to our hypothesis. The resulting changes in cell type composition of the AAA tissue render quantification of mRNA and primary translation products unreliable.…”