Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.11.1.8 (thyroid peroxidase)
 3,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of thyrotropin receptor (TSHR) agonist antibodies in the manifestations of Graves' disease (GD) is recognized. There are, however, no convincing reports of TSHR-specific T cells. We have previously cloned T cells specific for thyroglobulin and thyroid peroxidase (TPO) from GD lymphoid infiltrates and used autologous EBV-transformed B cell lines (EBVL) transfected with an expression vector encoding TPO to efficiently detect TPO-specific T cells. Here we used EBVL transfected with TSHR to seek TSHR-specific T cells in the GD infiltrates, after cloning the in vivo activated T cells without antigen. 3 out of 30 clones responded vigorously and reproducibly to EBVL-TSHR, with a mean stimulation index > 7. Their release of IL-2, IL-4, and IL-10 after stimulation with soluble anti-CD3 and phorbol ester was indistinguishable from the other clones from this thyroid. However, they produced relatively little IFN gamma (median IL-4/IFN gamma ratio of 0.80) compared with the other clones (median IL-4/IFN gamma ratio 0.06). Thus, this new potent method of antigen presentation, using autoantigen-transfected EBVL, has permitted the first unequivocal identification of TSHR T cells in GD thyroid, with distinct Th0/Th2 characteristics, unlike previously cloned TPO-responsive cells which have Th1 characteristics.
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PMID:Identification of thyroid stimulating hormone receptor-specific T cells in Graves' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines. 761 99

Intrathyroidal lymphocytes are a source of cytokines thought to stimulate or maintain the immune process within the thyroid in Graves' disease (GD) and Hashimoto's thyroiditis (HT). Quantitative assessment of the cytokine profile may provide important clues as to the Th1/Th2 balance prevailing in these diseases. We analyzed cytokine mRNA expression levels in thyroid tissue samples from 13 patients with GD, 2 with HT, 5 with nontoxic multinodular goiter (NTG), and 4 with thyroid autonomy (nodular = TAnod and perinodular = TAperi tissue) using multispecific competitor fragments with primer sequences for IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, CD25, and CD3 delta-chain mRNA. Patients with GD were subdivided into two groups according to their serum levels of antibodies to thyroperoxidase (anti-TPO; GDhigh > 4000 U/mL, GDlow < or = 200 U/mL). These levels correlated positively with the CD3 delta-chain mRNA levels (r = 0.83) and with the T cell infiltration (r = 0.71) as determined by immunohistochemistry. Patients with GDhigh demonstrated 2- to 4-fold higher IL-4 mRNA levels (as compared to all other investigated groups) and significantly higher IL-10 mRNA levels as compared to HT, GDlow, and TAnod patients. Patients with GDhigh also had significantly higher levels of IFN-gamma, IL-1 beta, IL-8, and CD25 mRNA as compared to GDlow. The highest IFN-gamma, IL-2, and CD25 mRNA levels were found in HT. The lowest mRNA levels of all the investigated groups were detected in TAnod. No significant differences in IL-6 and IL-8 mRNA levels were found between most of the patient groups. In summary, patients with GDhigh showed a shift to a more Th2-driven cytokine pattern. In contrast, the increase mRNA levels of Th1-related cytokines found in HT indicate predominantly T cell-mediated cytotoxic processes.
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PMID:Different cytokine mRNA profiles in Graves' disease, Hashimoto's thyroiditis, and nonautoimmune thyroid disorders determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). 873 79

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100-119 and 625-644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158-176, 207-222, and 343-362/357-376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-gamma], Th1 (secreting IFN-gamma) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-beta and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-gamma was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100-119 and 625-644 of TPO in HT and amino acid residues 158-176, 207-222 and 343-362/357-376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.
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PMID:Thyrotropin-receptor and thyroid peroxidase-specific T cell clones and their cytokine profile in autoimmune thyroid disease. 936 May 22

A human anaplastic thyroid cancer cell line FB-1, derived from a 68-yr-old woman who underwent surgery for anaplastic thyroid cancer, has been established. The spindlelike cells have been proliferating stably for more than 2 yr. Karyotype analysis shows many abnormalities and many marker chromosomes have been observed. Heterotransplant of FB-1 cells into severe combined immunodeficient mice has resulted in rapidly growing tumors classified as anaplastic carcinomas, although 50% have shown areas with a trabecular pattern. FB-1 cells failed to express messenger RNA for thyroglobulin; TSH-receptor; thyroperoxidase, and placental angiogenic growth factor. Conversely, PAX8 and thyroid transcription factor 1, whose expression is thyroid specific, was kept in an FB-1 cell line at a level comparable with that observed in normal thyroid tissue. In addition, the present cell line expressed high levels of messenger RNA for high-mobility group proteins (Y) and -C. The in vitro study revealed that FB-1 cells are able to produce high levels of interleukin (IL)-8 and medium amount of IL-6, whereas no release of IL-1-alpha, IL-1-beta, and IL-4 was observed. No modulation of cell proliferation and DNA synthesis in FB-1 cells has been observed after the addition of exogenous IL-6.
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PMID:Cytokine production by a new undifferentiated human thyroid carcinoma cell line, FB-1. 939 20

To study the role of Th0 and Th1 cells in autoimmune thyroid disease, thyroid tissues from patients with Graves' disease (GD), Hashimoto's thyroiditis (HT), and colloid nodular disease were xenografted into SCID mice, followed by ip injection of peripheral blood mononuclear cells (PBMC), T cell lines, and T cell clones (TCC). The antigen-specific TCC reactive to TSH receptor (TSH-R), thyroid peroxidase (TPO), or thyroglobulin (Tg), and their respective peptides, were classified into Th0 (secreting IL-4 and/or IL-5 and IFN-gamma) and Th1 (secreting IFN-gamma) according to their cytokine profile. Engraftment of autologous or HLA-matched allogeneic CD4+ thyroid-specific clones with Th0 or Th1 phenotypes induced the production of total IgG and thyroid-specific autoantibodies by B cells present in xenografted thyroid tissues. TSH-R-specific clones mainly enhanced thyroid-stimulating antibodies (TSAb) production, while clones reactive to TPO and Tg increased the synthesis of TPO and Tg autoantibodies. Total IgG production, but not TSAb, was also stimulated by PBMC and TSH-R lines. TSAb correlated with the viability and hyperplasia of thyroid follicles, but not with the serum T3 levels, which were normal. Thyroid tissue viability was maintained or increased by antigen-specific Th0 clones, and decreased by Th1 clones reactive to TSH-R or TPO. Thyroid lymphocytic infiltration was variable; however, Th0 and Th1 clones from HT patients caused high degree of lymphocytic infiltration compared to the control groups. These results demonstrate for the first time that T cells clones reactive to specific epitopes of TSH-R, TPO, or Tg can generate antibody-mediated and/or cell-mediated responses in the xenografted thyroid tissue microenvironment. Such effects depend on clonal specificity, HLA class II restriction, and cytokine profile of the clone. Th0 clones reactive to TSH-R stimulate both total IgG production and TSAb in SCID mice engrafted with thyroid tissue from GD patients. Th0 and Th1 clones specific for TPO and Tg also function as helper T cells, stimulating total IgG synthesis and autoantibodies against TPO and Tg. Th1 clones may also cause tissue destruction in GD and HT.
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PMID:Evaluating the role of Th0 and Th1 clones in autoimmune thyroid disease by use of Hu-SCID chimeras. 940 Jun 25

We have reported that bcl-2 is expressed in normal human thyroid epithelium and that its expression is down-regulated in undifferentiated thyroid tumors. Production of IL-6 was concomitantly down-regulated in these forms. Based on these observations, we analyzed whether insertion of bcl-2 would reverse the highly malignant phenotype of a thyroid cell line (ARO) derived from an undifferentiated carcinoma. This cell line fails to produce Bcl-2 and IL-6. By infection with a bcl-2 retroviral vector, ARO cells expressing bcl-2 (ARObcl-2) were obtained. Compared with parental cells, expression of bcl-2 was associated with enhancement of growth potential (DNA synthesis, in vitro proliferation rate, anchorage-independent growth in semi-solid media). Chemotaxis and invasive potential in Boyden chambers were also increased. bcl-2-expressing cells showed a reduced response to apoptotic stimuli (low-serum conditions or anti-neoplastic drugs). Large branched colonies were formed in Matrigel from ARObcl-2 cells but not from parental cells. Finally, ARObcl-2 cells showed a decreased latency of tumor appearance when injected into immunodeficient mice. Potentiation of the malignant phenotype of ARO cells by bcl-2 was not ascribed to altered expression of (i) cytokine/growth factors (IL-4, IL-6, IL-8, IL-10, IL-12, TGF-alpha, TGF-beta), (ii) thyroid-specific transcripts (TG, TPO, TSH-R, PIGF, PAX-8) or (iii) genes influencing tumor aggressiveness [VEGF, HMGI (Y), HMGI-C]. Our data indicate that bcl-2 potentiates the malignant phenotype of ARO cells not only by limiting the response to apoptotic stimuli but also by enhancing proliferation and tumor aggressiveness.
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PMID:Potentiation of the malignant phenotype of the undifferentiated ARO thyroid cell line by insertion of the bcl-2 gene. 1036 45

Thyroid-infiltrating lymphocytes spontaneously synthesize IgG class thyroid autoantibodies while blood lymphocytes require activation to produce the same autoantibodies. Surprisingly, the stimulus commonly used to induce autoantibodies by blood lymphocytes, Pokeweed mitogen (PWM), inhibits autoantibody synthesis by thyroid lymphocytes. To address this dichotomy, we investigated the Th1: Th2 cytokine balance in relation to thyroid peroxidase (TPO) autoantibody production in cultures of thyroid, lymph node and blood lymphocytes. The characteristic PWM effect on TPO autoantibody production by thyroid and blood lymphocytes (10 day cultures) was confirmed. Cytokine measurements in these cultures revealed that PWM increased IFN-gamma production by thyroid, lymph node and blood lymphocytes. However, PWM enhanced IL-4 levels in lymphocytes from blood and lymph node but not in thyroid lymphocytes. Moreover, the IL-4: IFN-gamma ratios in short- and long-term cultures were higher for PBMC and lymph node lymphocytes than for thyroid lymphocytes. In summary, PWM shifts the cytokine balance towards Th2 for blood lymphocytes and towards Th1 for thyroid lymphocytes. The shift towards Th1 in the target organ is associated with reduced autoantibody synthesis. Our observations suggest that "immune deviation" towards Th2 as a form of therapy in Graves' disease could project the patient from the frying pan into the fire.
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PMID:Balance of Th1/Th2 cytokines in thyroid autoantibody synthesis in vitro. 1043 89

Anti-CD20 antibody is an established treatment for low-grade non-Hodgkin's lymphoma (NHL). Augmenting the expression of CD20 antigen on the tumor cells may increase the cell kill and therefore increase the effectiveness of the antibody. To study this, we incubated peripheral blood lymphocytes from CLL patients with the following cytokines: EPO, SCF, TNFalpha, TGFbeta, GMCSF, TPO, IL-1, IL-2, IL-3, IL-4, GCSF. CD20 expression was studied by flow cytometry at baseline, 24 and 72 h after exposure to these cytokines. Upregulation of CD20 antigen expression was observed with IL-4, TNFalpha and GMCSF.
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PMID:Effects of cytokines on CD20 antigen expression on tumor cells from patients with chronic lymphocytic leukemia. 1120 84

AKR/N mice injected with fibroblasts expressing MHC class II (RT4.15HP cells) and the TSH receptor (TSHR) develop antibodies similar to those in Graves' disease. We were unable to analyse the subclass of these antibodies because of unexpectedly high non-specific binding by ELISA or flow cytometry. The non-specific binding reflected generalized immune activation which occurred even when the fibroblasts did not express the TSHR. However, the IgG subclasses were determined for thyroid peroxidase (TPO) antibodies induced using TPO-expressing RT4.14HP cells and found to be IgG2a > IgG1. This Thl pattern is consistent with spontaneous secretion of interferon-gamma (but not IL-4 or IL-10) by splenocytes from injected mice. The Th1 bias was related to fibroblast injection because conventional immunization of the same mouse strain with purified TPO and adjuvant induced a Th2 response (IgG1 >> IgG2a). Further, untransfected fibroblasts themselves induced powerful, non-specific proliferative responses when used as antigen-presenting cells (APC) in vitro. Flow cytometry revealed that the RT4.15HP fibroblasts (and TSHR- and TPO-transfected derivatives) expressed B7-1. Unexpected constitutive expression of this key molecule may bypass the requirement for up-regulation of other costimulatory molecules involved in T cell stimulation. Our data support the concept that RT4.15HP fibroblasts present the TSHR (or TPO), at least for initiating the immune response. However, the accompanying generalized immune stimulation creates difficulties for analysis of TSHR-specific T and B lymphocytes. On the other hand, extension of the model to TPO, an easier antigen to study, will facilitate analysis of murine T cell responses likely to resemble those in human thyroid autoimmunity.
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PMID:Cytokines, IgG subclasses and costimulation in a mouse model of thyroid autoimmunity induced by injection of fibroblasts co-expressing MHC class II and thyroid autoantigens. 1109 Dec 71

We tried to efficiently generate human dendritic cells (DCs) from CD34+ peripheral blood hematopoietic progenitor cells mobilized by high-dose chemotherapy and subsequent administration of granulocyte colony-stimulating factor, using a liquid suspension culture system. Among various combinations, the combination of c-kit ligand, flt-3 ligand, c-mpl ligand (TPO), and interleukin (IL)-4 most potently generated the number of CD1a+CD14- DCs in cultures containing granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha). The delayed addition of IL-4 on day 6 of culture gave rise to an additional increase in the yield of CD1a+CD14-DCs that were characterized by the expression of HLA-ABC, HLA-DR, CD80, CD86, and CD83. The majority of the sorted CD1a-CD14+ cells derived from 6-day culture of CD34+ cells gave rise to CD1a+CD14- DCs and CD1a-CD14+ macrophages on day 12 of culture in the presence and absence of IL-4, respectively. These findings suggest that IL-4 promotes the differentiation of CD1a- CD14+ cells derived from mobilized CD34+ peripheral blood hematopoietic progenitors to CD1a+ CD14- DCs. The majority of these DCs expressed CD68 but not the Langerhans-associated granule antigen, a finding that suggests they emerge through the monocyte differentiation pathway. The addition of TPO and IL-4 to cultures did not affect the potential of DCs to stimulate the primary allogeneic T-cell response. These findings demonstrated that the combination of c-kit ligand plus flt-3 ligand plus TPO with GM-CSF plus TNF-alpha, followed by IL-4, is useful for ex vivo generation of human DCs from mobilized CD34+ peripheral blood progenitors.
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PMID:Efficient ex vivo generation of human dendritic cells from mobilized CD34+ peripheral blood progenitors. 1172 65


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