Thyroid Peroxidase Revisited – Whatʼs New?

Godlewska, Marlena; Gawel, Damian; Buckle, Ashley M.; Banga, J. Paul

doi:10.1055/a-1057-9469

Cited by 16 publications

(10 citation statements)

References 70 publications

(98 reference statements)

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“…TPO is also a major thyroid antigen, to which both humoral and cellular immune responses are directed. TPO autoantibodies (TPOAb) occur in almost all HT patients and approximately 75% of individuals with GD, whereas their positivity in euthyroid patients may be the risk factor for future thyroid disorders ( 15 ). They may be involved in autoimmune thyroid cell death via antibody-dependent cytotoxicity cells (ADCC) and C3 complement-mediated cytotoxicity ( 16 ).…”

Section: Thyroid Antigens In Aitdmentioning

confidence: 99%

Cellular and molecular basis of thyroid autoimmunity

Bogusławska

Godlewska

Gajda

et al. 2022

European Thyroid Journal

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Autoimmune thyroid disease (AITD) is the most common human autoimmune disease. The two major clinical manifestations of AITD are Graves’ disease and Hashimoto’s thyroiditis (HT). AITD is characterized by lymphocytic infiltration of the thyroid gland, leading either to follicular cell damage, thyroid gland destruction, and development of hypothyroidism (in HT) or thyroid hyperplasia, induced by thyroid antibodies which activate thyrotropin receptor (TSHR) on thyrocytes, leading to hyperthyroidism. The aim of this review is to present up-to-date picture of the molecular and cellular mechanisms that underlie the pathology of AITD. Based on studies involving patients, animal AITD models, and thyroid cell lines, we discuss the key events leading to the loss of immune tolerance to thyroid autoantigens as well as the signaling cascades leading to the destruction of thyroid gland. Special focus is given on the interplay between the environmental and genetic factors, as well as ncRNAs and microbiome contributing to AITD development. In particular, we describe mechanistic models by which SNPs in genes involved in immune regulation and thyroid function, such as CD40, TSHR, FLT3, and PTPN22, underlie AITD predisposition. The clinical significance of novel diagnostic and prognostic biomarkers based on ncRNAs and microbiome composition is also underscored. Finally, we discuss the possible significance of probiotic supplementation on thyroid function in AITD.

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Section: Thyroid Antigens In Aitdmentioning

confidence: 99%

Cellular and molecular basis of thyroid autoimmunity

Bogusławska

Godlewska

Gajda

et al. 2022

European Thyroid Journal

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“…Thyroid peroxidase (TPO) attaches oxidized iodide to tyrosine residues of thyroglobulin (Tg) producing monoiodotyrosine (MIT) and diiodotyrosine (DIT). Subsequently, TPO couples a MIT and a DIT residue to form triiodothyronine (T3) or two DIT residues to form thyroxine (T4) [ 1 , 106 ].…”

Section: Current Diagnostic and Treatment Strategiesmentioning

confidence: 99%

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Ratajczak

Gawel

Godlewska

2021

IJMS

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Thyroid cancers (TCs) are the most common tumors of the endocrine system and a constant rise in the number of TC cases has been observed for the past few decades. TCs are one of the most frequent tumors in younger adults, especially in women, therefore early diagnosis and effective therapy are especially important. Ultrasonography examination followed by fine needle biopsy have become the gold standard for diagnosis of TCs, as these strategies allow for early-stage detection and aid accurate qualification for further procedures, including surgical treatment. Despite all the advancements in detection and treatment of TCs, constant mortality levels are still observed. Therefore, a novel generation line of targeted treatment strategies is being developed, including personalized therapies with kinase inhibitors. Recent molecular studies on TCs demonstrate that kinase inhibitor-based therapies might be considered as the most promising. In the past decade, new kinase inhibitors with different mechanisms of action have been reported and approved for clinical trials. This review presents an up-to-date picture of new approaches and challenges of inhibitor-based therapies in treatment of TCs, focusing on the latest findings reported over the past two years.

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“…These hormones are critical in the regulation of metabolism. TPO is of clinical significance, as it is a target of autoantibodies and autoreactive T cells in autoimmune thyroid diseases (AITD) such as destructive thyroiditis (Hashimoto’s disease) and hyperthyroidism (Grave’s disease) 2, 3 . AITDs are some of the most common autoimmune diseases in the developed world, with Hashimoto’s disease being a strong risk factor for thyroid cancer 4 .…”

Section: Introductionmentioning

confidence: 99%

“…AITDs are some of the most common autoimmune diseases in the developed world, with Hashimoto’s disease being a strong risk factor for thyroid cancer 4 . TPO is suspected to be involved in the pathogenesis of Hashimoto’s thyroiditis (prevalence 300-2980 cases per 100,000 in the Western world), leading to thyrocyte destruction via CD8+ T-cell infiltration resulting in hypothyroidism 1, 3, 5 . This incidence rate can be compared to other autoimmune diseases – for example type 1 diabetes, which has an incidence in the developed world of 310-570 cases per 100,000 patients - demonstrating the immense disease burden caused by AITDs 5 .…”

Section: Introductionmentioning

confidence: 99%

“…The precise mechanism by which these antibodies cause damage is uncertain 2 . Additionally, in some cases AITDs can occur without these autoantibodies being present, and transplacental passage of anti-TPO antibodies does not necessarily cause thyroid damage in the offspring 3, 6, 7 . Despite this, transplacental passage of these autoantibodies can potentially have cognitive effects on the child.…”

Section: Introductionmentioning

confidence: 99%

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Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

Williams

Hoke

et al. 2019

Preprint

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25Thyroid peroxidase (TPO) is a critical membrane-bound enzyme involved in the biosynthesis of 26 multiple thyroid hormones, and is a major autoantigen in autoimmune thyroid diseases such as 27 Graves' disease and Hashimoto's thyroiditis. Here we report the biophysical and structural 28 characterisation of two novel TPO constructs containing only the ectodomain of TPO and lacking the 29 propeptide. Both constructs were enzymatically active and able to bind the patient-derived TR1.9 30 autoantibody. Analytical ultra-centrifugation data suggests that TPO can exist as both a monomer 31 and a dimer. Combined with negative stain electron microscopy and molecular dynamics 32 simulations, these data show that TR1.9 autoantibody preferentially binds the TPO monomer, 33 revealing conformational changes that bring together previously disparate residues into a 34 continuous epitope. In addition to providing plausible structural models of a TPO-autoantibody 35 complex, this study provides validated TPO constructs that will facilitate further characterization, 36 and advances our understanding of the structural, functional and antigenic characteristics of TPO, a 37 molecule behind some of the most common autoimmune diseases. 38 39 40 41 48 (Hashimoto's disease) and hyperthyroidism (Grave's disease) 2,3. AITDs are some of the most 49 common autoimmune diseases in the developed world, with Hashimoto's disease being a strong risk 50 factor for thyroid cancer 4. TPO is suspected to be involved in the pathogenesis of Hashimoto's 51 thyroiditis (prevalence 300-2980 cases per 100,000 in the Western world), leading to thyrocyte 52 destruction via CD8+ T-cell infiltration resulting in hypothyroidism 1,3,5. This incidence rate can be 53 compared to other autoimmune diseases -for example type 1 diabetes, which has an incidence in 54 the developed world of 310-570 cases per 100,000 patients -demonstrating the immense disease 55 burden caused by AITDs 5. The pathogeneses that underlies these autoimmune diseases is complex, 56 however the lack of any tertiary or quaternary structure of TPO complicates matters. The absence of 57 a structure in which to understand binding of anti-TPO antibodies, which are prevalent almost 58 ubiquitously (>95%) in cases of destructive thyroiditis, complicates the understanding of the 59 pathogenesis and nature of the disease. The precise mechanism by which these antibodies cause 60 damage is uncertain 2. Additionally, in some cases AITDs can occur without these autoantibodies 61 being present, and transplacental passage of anti-TPO antibodies does not necessarily cause thyroid 62 damage in the offspring 3,6,7. Despite this, transplacental passage of these autoantibodies can 63 potentially have cognitive effects on the child. In addition, antibodies to thyroglobulin (Tg) and 64 thyroid stimulating hormone receptor have been identified in both conditions, indicating that there 65 may be multiple antigens in AITD pathogenesis 2. 66TPO is a member of the animal heme peroxidase family, which also includes myelope...

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Thyroid Peroxidase Revisited – Whatʼs New?

Cited by 16 publications

References 70 publications

Cellular and molecular basis of thyroid autoimmunity

Cellular and molecular basis of thyroid autoimmunity

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

Structural studies of thyroid peroxidase show the monomer interacting with autoantibodies in thyroid autoimmune disease

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