Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto’s Thyroiditis

The essential trace element selenium (Se) is needed for the biosynthesis of selenocysteine-containing selenoproteins, including the secreted enzyme glutathione peroxidase 3 (GPX3) and the Se-transporter selenoprotein P (SELENOP). Both are found in blood and thyroid colloid, where they serve protective functions. Serum SELENOP derives mainly from hepatocytes, whereas the kidney contributes most serum GPX3. Studies using transgenic mice indicated that renal GPX3 biosynthesis depends on Se supply by hepatic SELENOP, which is produced in protein variants with varying Se contents. Low Se status is an established risk factor for autoimmune thyroid disease, and thyroid autoimmunity generates novel autoantigens. We hypothesized that natural autoantibodies to SELENOP are prevalent in thyroid patients, impair Se transport, and negatively affect GPX3 biosynthesis. Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto’s thyroiditis as compared with healthy control subjects (6.6% versus 0.3%). Serum samples rich in SELENOP autoantibodies displayed relatively high total Se and SELENOP concentrations in comparison with autoantibody-negative samples ([Se]; 85.3 vs. 77.1 µg/L, p = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, p = 0.001), while GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.

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Differential expression of Fas system apoptotic molecules in peripheral lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis.

Acta Endocrinologica ◽

10.1530/eje-08-0092 ◽

2008 ◽

Vol 158 (6) ◽

pp. 853-859 ◽

Cited By ~ 16

Author(s):

Stelios Fountoulakis ◽

George Vartholomatos ◽

Nikolaos Kolaitis ◽

Stathis Frillingos ◽

George Philippou ◽

...

Keyword(s):

Immune Cells ◽

Hashimoto’S Thyroiditis ◽

Fas Ligand ◽

Differentially Expressed ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Serum Samples ◽

Autoimmune Thyroid ◽

Peripheral Lymphocytes ◽

Soluble Fas

ObjectiveTo examine whether the Fas system apoptotic molecules are differentially expressed in Graves' disease (GD) and Hashimoto's thyroiditis (HT), the two opposite phenotypes of autoimmune thyroid disease (AITD).DesignThe expression of Fas and Fas ligand (FasL) on peripheral CD4 and CD8 lymphocytes, and non-lymphoid immune cells as well as their soluble forms in serum from untreated patients with GD and HT were evaluated.MethodsFlow cytometry was performed for the study of peripheral immune cells from 70 newly diagnosed patients with AITD (55 with HT and 15 with GD) and 20 controls. ELISA was used for the measurement of soluble Fas (sFas) in serum samples from a subgroup of 35 AITD patients.ResultsAn increase in the proportion of CD4 and CD8 cells expressing Fas was found in both GD and HT, albeit with some differences, when compared with controls. Importantly, in GD patients, the intensity of Fas expression on CD4 and CD8 lymphocytes was reduced and sFas levels in serum were simultaneously increased when compared with HT patients and controls.ConclusionsThe Fas system apoptotic molecules appear to be differentially expressed on peripheral lymphocytes in the two opposite phenotypes of AITD.

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Vitamin D Treatment in Patients with Hashimoto’s Thyroiditis may Decrease the Development of Hypothyroidism

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000269 ◽

2016 ◽

Vol 86 (1-2) ◽

pp. 9-17 ◽

Cited By ~ 3

Author(s):

Bekir Ucan ◽

Mustafa Sahin ◽

Muyesser Sayki Arslan ◽

Nujen Colak Bozkurt ◽

Muhammed Kizilgul ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Hashimoto’S Thyroiditis ◽

Healthy Control Group ◽

Hashimoto's Thyroiditis ◽

Control Group ◽

Endocrine Society ◽

Thyroid Autoantibody ◽

Healthy Control ◽

The Mean

Abstract.The relationship between Hashimoto’s thyroiditis and vitamin D has been demonstrated in several studies. The aim of the present study was to evaluate vitamin D concentrations in patients with Hashimoto’s thyroiditis, the effect of vitamin D therapy on the course of disease, and to determine changes in thyroid autoantibody status and cardiovascular risk after vitamin D therapy. We included 75 patients with Hashimoto’s thyroiditis and 43 healthy individuals. Vitamin D deficiency is defined as a 25-hydroxy vitamin D (25(OH)D3) concentration less than 20ng/mL. Vitamin D deficient patients were given 50.000 units of 25(OH)D3 weekly for eight weeks in accordance with the Endocrine Society guidelines. All evaluations were repeated after 2 months of treatment. Patients with Hashimoto’s thyroiditis had significantly lower vitamin D concentrations compared with the controls (9.37±0.69 ng/mL vs 11.95±1.01 ng/mL, p < 0.05, respectively). Thyroid autoantibodies were significantly decreased by vitamin D replacement treatment in patients with euthyroid Hashimoto’s thyroiditis. Also, HDL cholesterol concentrations improved in the euthyroid Hashimoto group after treatment. The mean free thyroxine (fT4) concentrations were 0.89±0.02 ng/dL in patients with Hashimoto’s thyroiditis and 1.07±0.03 ng/dL in the healthy control group (p < 0.001). The mean thyroid volumes were 7.71±0.44 mL in patients with Hashimoto’s thyroiditis and 5.46±0.63 mL in the healthy control group (p < 0.01). Vitamin D deficiency is frequent in Hashimoto’s thyroiditis and treatment of patients with this condition with Vitamin D may slow down the course of development of hypothyroidism and also decrease cardiovascular risks in these patients. Vitamin D measurement and replacement may be critical in these patients.

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The Effect of Ezetimibe/Statin Combination and High-Dose Statin Therapy on Thyroid Autoimmunity in Women with Hashimoto’s Thyroiditis and Cardiovascular Disease: A Pilot Study

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0042-113872 ◽

2016 ◽

Vol 124 (09) ◽

pp. 577-581

Author(s):

R. Krysiak ◽

W. Szkróbka ◽

B. Okopień

Keyword(s):

Cardiovascular Disease ◽

Pilot Study ◽

Statin Therapy ◽

Hashimoto’S Thyroiditis ◽

Thyroid Autoimmunity ◽

Hashimoto's Thyroiditis ◽

High Dose

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Defect of a subpopulation of natural killer immune cells in Graves’ disease and Hashimoto’s thyroiditis: normalizing effect of dehydroepiandrosterone sulfate

Acta Endocrinologica ◽

10.1530/eje.1.01906 ◽

2005 ◽

Vol 152 (5) ◽

pp. 703-712 ◽

Cited By ~ 15

Author(s):

Sebastiano Bruno Solerte ◽

Sara Precerutti ◽

Carmine Gazzaruso ◽

Eleonora Locatelli ◽

Mauro Zamboni ◽

...

Keyword(s):

Nk Cells ◽

Hashimoto’S Thyroiditis ◽

Nk Cell ◽

Secretory Activity ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Tnf Α

Background: The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves’ disease (GD) and Hashimoto’s thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases. Objective: Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect. Design: We studied 13 patients with recent onset Graves’ disease, 11 patients with Hashimoto’s thyroiditis at first diagnosis and 15 age-matched healthy subjects. Methods: NK cells were concentrated at a density of 7.75 × 106 cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16 + /CD56 + cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-β (IFN-β) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-α (TNF-α) from NK cells. Results: Lower spontaneous, IL-2- and IFN-β-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P < 0.001). A decrease in spontaneous and IL-2-modulated TNF-α release from NK cells was also found in both groups of patients (P < 0.001). The co-incubation of NK cells with IL-2/IFN-β + DHEAS at different molar concentrations (from 10−8 to 10−5 M/ml/NK cells) promptly normalized NKCC and TNF-α secretion in GD and HT patients. Conclusions: A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.

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Atorvastatin potentiates the effect of selenomethionine on thyroid autoimmunity in euthyroid women with Hashimoto’s thyroiditis

Current Medical Research and Opinion ◽

10.1080/03007995.2018.1541314 ◽

2018 ◽

Vol 35 (4) ◽

pp. 675-681 ◽

Cited By ~ 1

Author(s):

Robert Krysiak ◽

Witold Szkróbka ◽

Bogusław Okopień

Keyword(s):

Hashimoto’S Thyroiditis ◽

Thyroid Autoimmunity ◽

Hashimoto's Thyroiditis

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Angioedema in a Patient with Autoimmune Thyroiditis – A Case Report

Acta Medica Bulgarica ◽

10.2478/amb-2020-0021 ◽

2020 ◽

Vol 47 (2) ◽

pp. 34-37

Author(s):

S. Dermendzhiev ◽

A. Dzhambov ◽

T. Dermendzhiev

Keyword(s):

Autoimmune Thyroiditis ◽

Hashimoto’S Thyroiditis ◽

Immunoglobulin E ◽

Thyroid Autoimmunity ◽

Hormonal Control ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Normal Range ◽

History Of ◽

One Year

AbstractWe present a case of a 29-year-old Bulgarian woman with autoimmune thyroiditis and recurrent angioedema. The patient presented with a one-year-long history of recurrent angioedema and Hashimoto’s thyroiditis. Physical examination showed oedema surrounded by erythema on the forearms, and erythematous, itchy plaques spreading over her face, neck, chest, abdomen, and extremities. Blood tests showed elevated total immunoglobulin E (IgE). The patient had been diagnosed with Hashimoto’s thyroiditis and hypothyroidism. She had been taking levothyroxine 50 μg/d, resulting in a good hormonal control; however, her anti-thyroid peroxidase (anti-TPO) antibodies were high. She was started on methylprednisolone and antihistamines. In three weeks, we observed a good therapeutic response to the treatment and the lesions remitted. IgE dropped within normal range. Levels of anti-TPO antibodies were persistently high. In conclusion, patients with angioedema should be tested for thyroid autoimmunity. Further delve into the pathogenesis of angioedema in them is warranted in order to explore the possibility of an underlying atopy in those not responding to the standard treatment with levothyroxine.

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Polymorphisms of IKZF3 Gene and Autoimmune Thyroid Diseases: Associated with Graves’ Disease but Not with Hashimoto’s Thyroiditis

Cellular Physiology and Biochemistry ◽

10.1159/000487870 ◽

2018 ◽

Vol 45 (5) ◽

pp. 1787-1796 ◽

Cited By ~ 8

Author(s):

Ling Li ◽

Xiaolian Ding ◽

Xuan Wang ◽

Qiuming Yao ◽

Xiaoqing Shao ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Zinc Finger Protein ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Control Group ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Significant Difference ◽

Proliferation And Differentiation

Background/Aims: The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs. Methods: We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction. Results: It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator. Conclusion: It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD.

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Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

Endocrine Reviews ◽

10.1210/edrv.31.4.9999 ◽

2010 ◽

Vol 31 (4) ◽

pp. 600-600

Author(s):

Chun-Rong Chen ◽

Sepehr Hamidi ◽

Helen Braley-Mullen ◽

Yuji Nagayama ◽

Catherine Bresee ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Time Course ◽

Thyroid Autoimmunity ◽

Cross Reactivity ◽

Eukaryotic Cells ◽

Human Thyroid ◽

Hashimoto's Thyroiditis ◽

Thyroid Peroxidase ◽

Thyroglobulin Antibodies ◽

Self Tolerance

Abstract Hashimoto’s thyroiditis, a common autoimmune disease, is associated with autoantibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO). TPO, unlike abundant and easily purified Tg, is rarely investigated as an autoantigen in animals. We asked whether antibodies (Abs) develop to both TPO and Tg in thyroiditis in mice that is induced (C57BL/6 and DBA/1 strains) or arises spontaneously (NOD.H-2h4). Screening for TPOAbs was performed by flow cytometry using mouse TPO-expressing eukaryotic cells. Sera were also tested for binding to purified mouse Tg and human TPO. The antibody data were compared with the extent of thyroiditis. Immunization with mouse TPO adenovirus broke self-tolerance to this protein in C57BL/6 mice, but thyroiditis was minimal and TgAbs were absent. In DBA/1 mice with extensive granulomatous thyroiditis induced by Tg immunization, TPOAbs were virtually absent despite high levels of TgAbs. In contrast, antibodies to mouse TPO, with minimal cross-reactivity with human TPO, arose spontaneously in older (7–12 months) NOD.H-2h4 mice. Unexpectedly, TgAbs preceded TPOAbs, a time course paralleled in relatives of probands with juvenile Hashimoto’s thyroiditis. These findings demonstrate a novel aspect of murine and human thyroid autoimmunity, namely breaking B cell self-tolerance occurs first for Tg and subsequently for TPO.

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IRF7 Gene Variations Confer Susceptibility to Autoimmune Thyroid Diseases and Graves’ Ophthalmopathy

International Journal of Endocrinology ◽

10.1155/2019/7429187 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Qiuming Yao ◽

Xiaofei An ◽

Jing Zhang ◽

Kaida Mu ◽

Ling Li ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Susceptibility Gene ◽

Thyroid Diseases ◽

Minor Allele ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Graves Ophthalmopathy ◽

Significant Difference

The objective of this study was to investigate whether IRF7 polymorphisms are associated with autoimmune thyroid diseases (AITDs). We selected three single nucleotide polymorphisms (SNPs) of IRF7, namely, rs1061501, rs1131665, and rs1061502 for genotyping using PCR-based ligase detection reaction (LDR) method in a total of 1659 participants (592 with Graves’ disease, 297 with Hashimoto’s thyroiditis, and 770 healthy controls). Gene-disease and genotype-clinical phenotype associations were evaluated for the three SNPs. Our results showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in AITD patients were both higher than those of the controls (rs1131665: AG genotype: P=0.017, OR=1.968; allele G: P=0.018, OR=1.946; rs1061502: AG genotype: P=0.029, OR=1.866; allele G: P=0.031, OR=1.847). Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in Graves’ disease patients were both higher than those of the controls (rs1131665: AG genotype: P=0.015, OR=2.074; allele G: P=0.016, OR=2.048; rs1061502: AG genotype: P=0.034, OR=1.919; allele G: P=0.035, OR=1.898). Furthermore, the allele G frequency of rs1061501 was associated with Graves’ ophthalmopathy (P=0.035, OR=1.396). No significant difference in IRF7 polymorphisms was found between Hashimoto’s thyroiditis patients and controls. Our study has revealed for the first time that IRF7 is a susceptibility gene for AITD, especially for Graves’ disease and Graves’ ophthalmopathy.

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