Evidence for selective accumulation of intrathyroidal T lymphocytes in human autoimmune thyroid disease based on T cell receptor V gene usage.

Davies, Terry F.; Martin, Andreas; Concepcion, Erlinda; Graves, Peter N.; Lahat, Nitza; Cohen, W L; Ben‐Nun, Avraham

doi:10.1172/jci115556

Cited by 81 publications

(50 citation statements)

References 21 publications

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“…The range of families identified in that study was two to six and in most cases a single Va gene predominated. Although some of this apparent restriction may have resulted from culture of ITL with phytohaemagglutinin or IL-2, used to expand certain lymphocyte populations, this cannot be the sole explanation, as restricted usage was also found in non-stimulated cells [18,19]. It is also noteworthy that non-autoimmune thyroid tissue displayed widespread TcR Va gene usage which was ascribed to contaminating blood-borne lymphocytes [ 18], in accord with our present findings using toxic multinodular goitre specimens.…”

Section: Discussionsupporting

confidence: 85%

“…By this approach, usage of a restricted number of Va families was found in areas of demyelination in the brains of patients with multiple sclerosis [17]. More recently, restricted Va but not Vĝ ene usage was identified with this technique in the thyroid lymphocytic infiltrate in patients with Graves' disease and Hashimoto's thyroiditis [18,19]. These results are particularly noteworthy given the diversity of thyroid antigens recognized in both disorders and the heterogeneous response to multiple autoantigenic epitopes even within a single patient [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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No restriction of intrathyroidal T cell receptor Vα families in the thyroid of Graves' disease

McIntosh

Watson

Pickerill

et al. 1993

Clinical and Experimental Immunology

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SUMMARY Recently it has been reported that the intrathyroidal T cells in Graves’disease display restriction in Vα T cell receptor (TcR) gene family usage, although this is not found with TcR Vβ gene families in the same individuals. We have performed a qualitative analysis of TcR Vα family usage in 12 patients with Graves’disease by reverse transcription and polymerase chain reaction (PCR) amplification of RNA extracted from isolated, unstimulated intrathyroidal lymphocytes and from snap‐frozen whole thyroid specimens. No restriction was observed, with 10–15 Vα gene families being amplified in all cases. The pattern of usage was similar to that in peripheral blood lymphocytes derived from normal subjects (n = 3) and from patients with Graves’disease (n = 3), as well as that present in the thyroids of patients with non‐autoimmune toxic multinodular goitre (n= 4). These results indicated that there is no marked restriction of the unselected intrathyroidal T cell population in patients with Graves’disease who have been treated with antithyroid drugs.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

No restriction of intrathyroidal T cell receptor Vα families in the thyroid of Graves' disease

McIntosh

Watson

Pickerill

et al. 1993

Clinical and Experimental Immunology

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“…The accumulation of activated CD4 ϩ T cells in thyroid gland from patients with Graves' disease has been demonstrated (Ishikawa et al, 1987;Ishikawa et al, 1993), and restricted T cell receptor gene usage was recently demonstrated in thyroidal infiltrate from Graves' patients (Davies et al, 1991a;1991b). These data suggest that Ag-specific T cell activation is present in thyroid glands from Graves' patients.…”

Section: Kawakami Et Almentioning

confidence: 73%

CD4+ T Cell-Mediated Cytotoxicity Toward Thyrocytes: The Importance of Fas/Fas Ligand Interaction Inducing Apoptosis of Thyrocytes and the Inhibitory Effect of Thyroid-Stimulating Hormone

Kawakami

Matsuoka

Tsuboi

et al. 2000

Laboratory Investigation

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SUMMARY:The accumulation of activated CD4 ϩ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4 ϩ T cells have been determined in thyroid gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves' disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4 ϩ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular V␤ elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-␥ (IFN-␥)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4 ϩ T cells toward IFN-␥-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4 ϩ T cells cocultured with IFN-␥-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4 ϩ T cells. The cytotoxicity of CD4 ϩ T cells toward IFN-␥-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-␥ in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4 ϩ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL ϩ CD4 ϩ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4 ϩ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL ϩ CD4 ϩ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4 ϩ T cells. (Lab Invest 2000, 80:471-484).

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“…Although MoAbs are becoming available, they still only recognize less than half of the human TCR V/f repertoire. Recently, semi-quantitative methods using the polymerase chain reaction (PCR) have been developed and used to analyse the TCR repertoire of various tissues, including thyroid, brain and synovial fluid [4][5][6][7][8][9][10], A conventional technique to expand T cell populations in vitro is to employ mitogens. including phytohaemagglutinin (PHA).…”

Section: Introductionmentioning

confidence: 99%

The human T cell receptor Vβ repertoire of normal peripheral blood lymphocytes before and after mitogen stimulation

Wong

Hibberd

et al. 1993

Clinical and Experimental Immunology

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SUMMARYMitogenstimulationofTcells/>j(77r(jhasbeenemployedin the analysis ofthe Tcell antigen receptor (TCR) repertoire and as a method of generating T cell lines and clones. It has been suspected for some time that mitogen stimulation may bias the repertoire. We have addressed this problem employing a semi-quantitative technique utilizing the polymerase chain reaction (PCR) and flow cytometry. Using this PC^R method and a panel of primers to 22 V/J subgroups, the V/y repertoire oi both unstimulated and phytohaemagglutinin (PHA)-stimulated peripheral T cells from eight healthy individuals was investigated. The samples were also analysed by flow cytometry using anti-V^2, V/?5 and V/(8 MoAbs, A signifieant increase in the expression of V/!6, V^7.2 and V/ilO,l was found in all eight samples of PHA-stimulated Tcelis compared with unstimulated Tcelis using the PCR method. In contrast, no differences were found between unstimulated and PHA-stimulated T cells by flow cytomeiry. These results question the validity of using mitogen-stiinulated T cells to investigate TCR gene usage.

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Evidence for selective accumulation of intrathyroidal T lymphocytes in human autoimmune thyroid disease based on T cell receptor V gene usage.

Cited by 81 publications

References 21 publications

No restriction of intrathyroidal T cell receptor Vα families in the thyroid of Graves' disease

No restriction of intrathyroidal T cell receptor Vα families in the thyroid of Graves' disease

CD4+ T Cell-Mediated Cytotoxicity Toward Thyrocytes: The Importance of Fas/Fas Ligand Interaction Inducing Apoptosis of Thyrocytes and the Inhibitory Effect of Thyroid-Stimulating Hormone

The human T cell receptor Vβ repertoire of normal peripheral blood lymphocytes before and after mitogen stimulation

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