Human autoimmune diseases are specific antigen-driven T-cell diseases: identification of the antigens

Platsoucas, Chris D.; Oleszak, Emilia L.

doi:10.1007/s12026-007-0044-9

Cited by 8 publications

(4 citation statements)

References 98 publications

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“…For this reason, the size of the T cell repertoire in the peripheral blood was estimated to be 10 6 different b-chain TCR polypeptides, and each one of them pairs with $25 different a-chain TCR polypeptides (reviewed in Ref. 27). The number of T cell clones is very large and sufficient to recognize all possible antigenic epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial proportions of identical b-chain TCR transcripts were found in these lesions, after PCR amplification followed by cloning of the amplified transcripts and sequencing. Their presence can be explained only by proliferation and clonal expansion in vivo of the corresponding T cell clones in response to specific, as yet unidentified Ag(s) (27). These results strongly suggest that AAA is a specific Ag-driven T cell disease.…”

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confidence: 90%

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

White

Lin

et al. 2014

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 90%

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

White

Lin

et al. 2014

The Journal of Immunology

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“…The TCR repertoire is very large [47–49,69,70] and for this reason the probability is very small to find by chance in an independent sample of T lymphocytes two identical copies of a single α- or β-chain TCR transcript. The only mechanism that can explain the presence of multiple identical copies of a single α- or β-chain TCR transcript in an independent population of T lymphocytes is specific antigen-driven proliferation and clonal expansion (reviewed in [56]). However, during transformation of DH5α- E .…”

Section: Methodsmentioning

confidence: 99%

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

White

Judy

et al. 2019

PLoS ONE

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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.

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“…Roles for B and T lymphocytes have long been recognised in AAA disease [14,15,16]. This has led to the notion that AAA may be a specific antigen-driven T cell disease [17,18] and attempts to characterise the antigens have been published [19]. In a recent review, treatment with the tetracycline antibiotic doxycycline was advocated as a non-invasive therapy for AAA, based on its inhibitory effects on matrix metalloproteinases (MMPs) [10].…”

Section: Doxycycline and Aaamentioning

confidence: 99%

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

Kroon

Taanman

2015

IJMS

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Most reported studies with animal models of abdominal aortic aneurysm (AAA) and several studies with patients have suggested that doxycycline favourably modifies AAA; however, a recent large long-term clinical trial found that doxycycline did not limit aneurysm growth. Thus, there is currently no convincing evidence that doxycycline reduces AAA expansion. Here, we critically review the available experimental and clinical information about the effects of doxycycline when used as a pharmacological treatment for AAA. The view that AAA can be considered an autoimmune disease and the observation that AAA tissue shows clonal expansion of T cells is placed in the light of the well-known inhibition of mitochondrial protein synthesis by doxycycline. In T cell leukaemia animal models, this inhibitory effect of the antibiotic has been shown to impede T cell proliferation, resulting in complete tumour eradication. We suggest that the available evidence of doxycycline action on AAA is erroneously ascribed to its inhibition of matrix metalloproteinases (MMPs) by competitive binding of the zinc ion co-factor. Although competitive binding may explain the inhibition of proteolytic activity, it does not explain the observed decreases of MMP mRNA levels. We propose that the observed effects of doxycycline are secondary to inhibition of mitochondrial protein synthesis. Provided that serum doxycycline levels are kept at adequate levels, the inhibition will result in a proliferation arrest, especially of clonally expanding T cells. This, in turn, leads to the decrease of proinflammatory cytokines that are normally generated by these cells. The drastic change in cell type composition may explain the changes in MMP mRNA and protein levels in the tissue samples.

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Human autoimmune diseases are specific antigen-driven T-cell diseases: identification of the antigens

Cited by 8 publications

References 98 publications

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

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

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

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

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