Disease relevance of TPO

• Monoclonal antibodies specific for human thyroid peroxidase (TPO) were prepared by the hybridoma technique using hyperimmune spleen cells from mice immunized with TPO purified from thyroid glands from patients with Graves' disease [1].
• Taken together, these data indicate that Tg and TPO share common antigenic determinants and that some of those determinants are recognized by autoantibodies in the serum of patients with chronic autoimmune thyroiditis [1].
• TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells [2].
• TPO expression was decreased in thyroid carcinomas, but was normal in cold adenomas; it was increased in toxic adenomas and Graves' thyroid tissues Tg expression was decreased in thyroid carcinomas, but was normal in the other tissues [3].
• TPO transcripts were detected in 7/10 (70%) patients with known metastases of thyroid cancer and in 39 of 110 (36%) patients without metastases (P<0.05), in 15/44 (34%) patients with goitre, in 17/41 (41%) cases with GD and in 4/54 (7.4%) subjects in the control group (P<0.05, controls vs all patients with thyroid disease) [4].
• The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A [5].

Psychiatry related information on TPO

• Some of them, TGPO Ab, are Tg Ab with an interspecies idiotype (Id) reacting with TPO [6].
• For further clarification a prospective follow-up study was performed including 66 female and 14 male total thyroidectomized patients with DTA for the time course of TPO and human thyroglobulin (hTg) in relation to the ablative radioidine therapy (ART) [7].
• The most significant association was however between TPO-antibody positivity (and in particular with high titre and/or with TSH > 4.0 mU/l) and a subgroup of the affective disorders, viz with a rapid cycling of bipolar disorder (18% in cases vs 0% in controls, P < 0.001) [8].
• This study is the first to report age-dependent changes in blood TPO levels throughout child development [9].
• However, reaction times in MSA were longer in all paradigms [10].

High impact information on TPO

• Thyroid peroxidase catalyzes iodination of thyroglobulin and is involved in a second important step, the coupling of the iodotyrosines to form thyroxine or triiodothyronine [11].
• To address this issue, we generated transgenic mice expressing a human T-cell receptor derived from the thyroid-infiltrating T cell of a patient with thyroiditis and specific for a cryptic thyroid-peroxidase epitope [12].
• MSA and EGF receptors on sarcoma virus transformed cells and human fibrosarcoma cells in culture [13].
• We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis [14].
• The molecular biology of thyroid peroxidase: cloning, expression and role as autoantigen in autoimmune thyroid disease [15].

Chemical compound and disease context of TPO

• In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity [2].
• Thyroid peroxidase (TPO) activity determined by a guaiacol assay was 0.411 +/- 0.212 g.u./mg protein in the T3-predominant Graves' disease patients, significantly higher than that in the control Graves' disease patients (0.129 +/- 0.112 g.u./mg protein; P less than 0.01) [16].
• Thyroid peroxidase (TPO), a cell surface glycoprotein, is the major autoantigen in autoimmune thyroiditis in humans [17].
• Intraperitoneal injection of potassium iodide resulted in significant tumor volume reduction in NIS/TPO-modified tumor xenografts without apparent adverse effects in SCID mice [18].
• Anti-TPO Ab significantly decreased in patients with Graves' disease after treatment with methimazole and in those with hypothyroid Hashimoto's thyroiditis or idiopathic myxedema during L-T4 administration [19].

Biological context of TPO

• 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 [20].
• The amino acid sequences of these putative epitopes were located in TPO regions 100-119, 211-223, 261-275, 420-434, 625-644, and 882-901 [21].
• Four human monoclonal TPO autoantibodies, generated using combinatorial immunoglobulin gene libraries and expressed as F(ab), have been used to investigate these properties of TPO autoantibodies [22].
• Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity [23].
• The addition of free DIT (a known coupling enhancer) to the [131I]Tg/TPO incubation increased both the production of T4 and the amount of iodine in the smaller polypeptides [24].

Anatomical context of TPO

• The capacity of EBVL to present transfected Ag was assessed by using EBVL transfected with TPO (EBVL-TPO) to stimulate TPO-specific T cells cloned from autologous thyroid tissue; stimulation indices greater than 100 were consistently obtained, even at low APC:T cell ratios [25].
• The stimulatory capacity of EBVL-TPO was not transferable to untransfected EBVL by cell-free culture supernatant and to only a minor degree by EBVL-TPO-derived cell membrane fragments, indicating that the majority of the TPO presented by the transfected EBVL is endogenously synthesized [25].
• However, as results of TPO-RT-PCR correlate significantly with lymph node status, grading and serum TG measurements in patients with non-metastatic disease, TPO seems to be an interesting molecular marker to look at in follow-up studies [4].
• Our results give the first quantitative evidence that TPO and TG are concentrated in different subcompartments of the endoplasmic reticulum [26].
• On the other hand, gold particles indicating TPO are adjacent to the membranes of the exocytotic pathway [26].

Associations of TPO with chemical compounds

• To examine the coupling process, Tg was chemically iodinated, excess I- removed, and the samples treated with TPO and a H2O2-generating system in the absence of iodide [24].
• Thyroxine production also increased with TPO treatment [24].
• MPO displayed very significant coupling activity, and, like TPO, this activity was stimulated by a low concentration of free diiodotyrosine (1 microM) [27].
• The level of THOX2 mRNA was increased by cAMP in these cells and it was decreased in the thyroids of rats treated with the antithyroid drug methimazole, unlike the TPO and NIS mRNAs [28].
• TPO-2, an alternatively spliced form of TPO, lacks the essential asparagine (Asn 579) [29].

Physical interactions of TPO

• The existence in TPO of still another domain presenting a significant homology with a putative heme-binding region of cytochrome C oxidase polypeptide I raises the possibility that a mitochondrial gene module has contributed a piece to the evolution of a typical nuclear mosaic gene [30].
• Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent trans-activation of a thyroid peroxidase promoter luciferase reporter gene [31].
• We used immunoprecipitation of recombinant human TPO constructs to determine if localized autoantibody binding sites exist in this autoantigen [32].
• The binding of anti-exon 10 peptide antibodies to the immunodepleted TPO-1 fraction was considerably diminished in comparison to binding of polyclonal anti-TPO, suggesting the presence of small amounts (< 10%) of TPO-2 expressed as a protein in thyroid cells [33].

Enzymatic interactions of TPO

• In contrast, both monoclonal and polyclonal autoantibodies recognized TPO with the juxtamembrane EGF-like domain deleted equally as well as the wild-type TPO on the cell surface [34].

Regulatory relationships of TPO

• Human monoclonal autoantibodies against the immunodominant region on thyroid peroxidase: lack of cross-reactivity with related peroxidases or thyroglobulin and inability to inhibit thyroid peroxidase enzymatic activity [22].
• Localization of the thyroid peroxidase autoantibody immunodominant region to a junctional region containing portions of the domains homologous to complement control protein and myeloperoxidase [34].
• IFN-gamma inhibited TSH-stimulated TPO mRNA in a dose dependent manner (0.01-10U/mL) [35].
• Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer [36].
• In conclusion (1) AMLR reactivity of CD4+ cells from GD and HT was impaired, (2) however, CD4+ cells from both GD and HT were significantly more induced by TPO compared to N, and (3) this induction depends, in part, on the in vivo thyroid status [37].

Other interactions of TPO

• Type I interferons modulate the expression of thyroid peroxidase, sodium/iodide symporter, and thyroglobulin genes in primary human thyrocyte cultures [38].
• The presence of 0.1 N Cl- or Br- shifted the pH optimum for MPO to about 5.4 but had little or no effect on TPO- or LPO-catalyzed iodination [27].
• After 1 min of incubation in a system containing goiter thyroglobulin, I-, and H2O2, the pH optimum of MPO-catalyzed iodination was markedly acidic (approximately 4.0), compared to LPO (approximately 5.4) and TPO (approximately 6.6) [27].
• Analysis of the expression of the differentiation markers in all patients showed a significant correlation among Tg, TPO and NIS [39].
• An inverse correlation was found between TPO and PCNA expression, but TG, which persisted at high levels in several actively growing follicular carcinomas, did not appear directly linked to cellular proliferation [40].

Analytical, diagnostic and therapeutic context of TPO

• TPO was immunoprecipitated by anti-Tg autoantibodies isolated by Tg affinity chromatography [1].
• TPO mRNA expression was analysed in peripheral blood by nested RT-PCR [4].
• An evaluation of the relative concentrations of TG and TPO in different subcellular compartments was carried out in stimulated human follicular cells using thin-frozen sections and the immunogold technique [26].
• By Northern blotting, the thyroid peroxidase gene (TPO) was strictly expressed in the thyroid [41].
• Using the TPO preparation as an antigen, an ELISA was performed on 10 serum samples and immunoblot assays were performed on 50 canine sera [42].

References