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

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 beta-chain TCR transcripts by the nonpalindromic adaptor-PCR/Vbeta-specific PCR and/or Vbeta-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 beta-chain TCR transcripts were identified in these patients. These clonal expansions are statistically significant. These results demonstrate that alphabeta 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

Clonally Expanded Alpha-Chain T-Cell Receptor (TCR) Transcripts are Present in Aneurysmal Lesions of Patients With Abdominal Aortic Aneurysm (AAA)

Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRβGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of β-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αβ TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease

Human abdominal aortic aneurysm (AAA): Evidence for an autoimmune antigen-driven disease

Abdominal aortic aneurism (AAA) is a complex immunological disease with a strong genetic component, and one of the ten leading causes of death of individuals 55-74 years old worldwide. Strong evidence has been accumulated suggesting that AAA is an autoimmune specific antigen-driven disease. Mononuclear cells infiltrating AAA lesions comprised of T and B lymphocytes and other cells expressing early-, intermediate- and late-activation antigens, and the presence of antigen-presenting cells have been documented, demonstrating an ongoing immune response. The three components of the trimolecular complex, T-cell receptor (TCR)/peptide (antigen)/HLA have been identified in AAA, and specifically: (i) clonal expansions of T-cell clones in AAA lesions; (ii) the association of AAA with particular HLA Class I and Class II; and (iii) self or nonself putative AAA-associated antigens. IgG autoantibodies recognizing proteins present in normal aortic tissue have been reported in patients with AAA. Molecular mimicry, defined as the sharing of antigenic epitopes between microorganisms (bacteria, viruses) and self antigens, maybe is responsible for T-cell responses and antibody production in AAA. Also, the frequency and the suppressor activity of CD4 + CD25 + FOXP3+ Tregs and the expression of FOXP3 transcripts and protein have been reported to be significantly impaired in AAA patients vs normal donors

Clonally expanded alpha-chain T-cell receptor (TCR) transcripts are present in aneurysmal lesions of patients with Abdominal Aortic Aneurysm (AAA).

Abdominal aortic aneurysm (AAA) is a life-threatening immunological disease responsible for 1 to 2% of all deaths in 65 year old or older individuals. Although mononuclear cell infiltrates have been demonstrated in AAA lesions and autoimmunity may be responsible for the initiation and account for the propagation of the disease, the information available about the pathogenesis of AAA is limited. To examine whether AAA lesions from patients with AAA contain clonally expanded α-chain TCR transcripts, we amplified by the non-palindromic adaptor-PCR (NPA-PCR)/Vα-specific PCR and/or the Vα-specific PCR these α-chain TCR transcripts. The amplified transcripts were cloned and sequenced. Substantial proportions of identical α-chain TCR transcripts were identified in AAA lesions of 4 of 5 patients, demonstrating that clonally expanded T cells are present in these AAA lesions. These results were statistically significant by the bimodal distribution. Three of 5 of these patients were typed by DNA-based HLA-typing and all three expressed DRB1 alleles containing the DRβGln70 amino acid residue that has been demonstrated to be associated with AAA. All three patients exhibited clonally expanded T cells in AAA lesions. Four of the 5 patients with AAA who exhibited clonal expansions of α-chain TCR transcripts, also exhibited clonal expansions of β-chain TCR transcripts in AAA lesions, as we have demonstrated previously (J Immunol 192:4897, 2014). αβ TCR-expressing T cells infiltrating AAA lesions contain T-cell clones which have undergone proliferation and clonal expansion in vivo in response to as yet unidentified specific antigens that may be self or nonself. These results provide additional evidence supporting the hypothesis that AAA is a specific antigen-driven T-cell autoimmune disease