Hashimoto's thyroiditis: An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation.
Ralli Massimo,Angeletti Diletta,Fiore Marco,D'Aguanno Vittorio,Lambiase Alessandro,Artico Marco,de Vincentiis Marco,Greco Antonio
Autoimmunity reviews
Hashimoto's thyroiditis, characterized by thyroid-specific autoantibodies, is one of the commonest autoimmune disorders. Although the exact etiology has not been fully elucidated, Hashimoto's thyroiditis is related to an interaction among genetic elements, environmental factors and epigenetic influences. Cellular and humoral immunity play a key role in the development of the disease; thus, a T and B cells inflammatory infiltration is frequently found. Histopathologic features of the disease include lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, and parenchymal atrophy. Moreover, the occurrence of large follicular cells and oxyphilic or Askanazy cells is frequently associated to Hashimoto's thyroiditis. Clinically, Hashimoto's thyroiditis is characterized mainly by systemic manifestations due to the damage of the thyroid gland, developing a primary hypothyroidism. Diagnosis of Hashimoto's thyroiditis is clinical and based on clinical characteristics, positivity to serum antibodies against thyroid antigens (thyroid peroxidase and thyroglobulin), and lymphocytic infiltration on cytological examination. The mainstream of treatment is based on the management of the hypothyroidism with a substitution therapy. A relationship between Hashimoto's thyroiditis and a possible malignant transformation has been proposed in several studies and involves immunological/hormonal pathogenic links although specific correlation is still debated and needs to be further investigated with prospective studies.
10.1016/j.autrev.2020.102649
Molecular Mechanisms in Autoimmune Thyroid Disease.
Cells
The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto's thyroiditis). Hashimoto's thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases. This review summarizes the most common genetic, epigenetic, and environmental mechanisms involved in autoimmune thyroid disease.
10.3390/cells12060918
The Effect of Selenomethionine on Thyroid Autoimmunity in Euthyroid Men With Hashimoto Thyroiditis and Testosterone Deficiency.
Krysiak Robert,Kowalcze Karolina,Okopień Bogusław
Journal of clinical pharmacology
Hashimoto (autoimmune) thyroiditis develops much less frequently in men than in women, suggesting that androgens have a protective effect against thyroid autoimmunity. The current study was aimed at investigating whether the effect of selenomethionine on thyroid antibody titers and thyroid function tests in euthyroid men with autoimmune thyroid disease depends on testosterone levels. The study population consisted of 2 age-matched, weight-matched, and thyroid antibody titer-matched groups of euthyroid men with Hashimoto thyroiditis and testosterone deficiency: 18 patients receiving intramuscular testosterone enanthate (100 mg once weekly) and 19 testosterone-naive men. All subjects were than treated with selenomethionine (200 µg daily) for 6 months. Serum titers of thyroid antibodies, thyrotropin, free thyroid hormones, and testosterone as well as calculated parameters of thyroid homeostasis were assessed at the beginning and at the end of the study. At baseline, except for testosterone, there were no differences between the 2 treatment arms in thyroid antibody titers, serum hormone levels, or values of all calculated indices. Although selenomethionine reduced thyroid peroxidase and thyroglobulin antibody titers in both treatment arms, these effects were stronger in testosterone-treated than in testosterone-untreated men. Only in men receiving testosterone, selenomethionine altered the free thyroxine/free triiodothyronine ratio, testosterone levels, and structure parameter interference approach-GT and structure parameter interference approach-GD. Selenomethionine-induced changes in thyroid antibody titers correlated with the effect of treatment on structure parameter interference approach-GT and testosterone. The obtained results suggest that testosterone determines the strength of selenomethionine action in euthyroid men with autoimmune thyroiditis.
10.1002/jcph.1447
Selenium supplementation in the management of thyroid autoimmunity during pregnancy: results of the "SERENA study", a randomized, double-blind, placebo-controlled trial.
Mantovani G,Isidori A M,Moretti C,Di Dato C,Greco E,Ciolli P,Bonomi M,Petrone L,Fumarola A,Campagna G,Vannucchi G,Di Sante S,Pozza C,Faggiano A,Lenzi A,Giannetta E
Endocrine
PURPOSE:Selenium is frequently in nutraceuticals for pregnancy, given its role on fertility and thyroid metabolism. However, most evidence rise from non-controlled studies. We aimed to evaluate the protective effect of selenium against thyroid autoimmunity during and after pregnancy. METHODS:A multicenter, randomized, double-blind, placebo-controlled trial was performed and promoted by the Young Italian Endocrinologists Group (EnGioI)-Italian Society of Endocrinology. Forty-five women with thyroiditis in pregnancy were enrolled and randomly assigned to L-selenomethionine (L-Se-Met) 83 mcg/day or placebo (PLB) and evaluated at 10 ± 2 (T1), 36 ± 2 weeks of gestation (T2) and 6 months after delivery (postpartum, PP). RESULTS:We measured a significant reduction of autoantibodies after pregnancy in L-Se-Met group [at PP: TgAb 19.86 (11.59-52.60), p < 0.01; TPOAb 255.00 (79.00-292.00), p < 0.01], and an antibodies titer's rebound in PLB group (TgAb 151.03 ± 182.9, p < 0.01; TPOAb 441.28 ± 512.18, p < 0.01). A significant increase in selenemia was measured in L-Se-Met group at T2 (91.33 ± 25.49; p < 0.01) and PP (93.55 ± 23.53; p = 0.02). Two miscarriage occurred in PLB. No differences were found in thyroid volume, echogenicity, quality of life, maternal/fetal complications. CONCLUSIONS:SERENA study demonstrated a beneficial effect of L-Se-Met supplementation on autoantibody titer during pregnancy and on postpartum thyroiditis recurrence.
10.1007/s12020-019-01958-1
Serum Selenium Status and Its Interrelationship with Serum Biomarkers of Thyroid Function and Antioxidant Defense in Hashimoto's Thyroiditis.
Rostami Rahim,Nourooz-Zadeh Sarmad,Mohammadi Afshin,Khalkhali Hamid Reza,Ferns Gordon,Nourooz-Zadeh Jaffar
Antioxidants (Basel, Switzerland)
Selenium (Se) deficiency has been implicated in the pathogenesis of Hashimoto's thyroiditis (HT), although the available evidence is limited. The present study aimed to explore the interrelationships between serum Se status with measures of thyroid function and antioxidant defense in new cases of HT patients with hypoechogenic thyroid. HT patients ( = 49) and matched controls ( = 50) were recruited. Selenium, thyroid hormone panel, thyroid volume (TVol), glutathione (GSH), glutathione peroxidase3 (GPx3) activity, urinary iodine concentration (UIC), and urinary creatinine (Cr) were assessed. HT patients exhibited lower Se levels compared to controls ( < 0.001) with the rates of Se-deficient (<0.85 µmol/L) participants being 58.8% and 34%, respectively. Se-deficient patients exhibited higher thyroid stimulating hormone (TSH), Thyroid volume (TVol), thyroglobulin, antibody-titers, GPx3 activity and UIC/Cr compared to Se-sufficient patients (all < 0.001). In the Se-deficient patients, inverse correlations were seen between Se-levels with TSH, TVol, and Thyroid peroxidase antibody (TPO-Ab) (all < 0.001). This study is the first to uncover that coexisting Se-deficiency and elevated iodine in HT may enhance autoimmune reactions and accelerate the deterioration of thyroid function through oxidative stress. Our study also highlights the importance of optimal Se status in this disease, thus providing a rationale for the execution of intervention trials for the evaluation of the clinical benefits of antioxidant-status improvement in HT.
10.3390/antiox9111070
A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Hashimoto's Thyroiditis.
European thyroid journal
OBJECTIVE:To investigate clinical practice regarding the use of selenium supplementation in patients with Hashimoto's thyroiditis (HT) among members of the European Thyroid Association (ETA). METHODS:ETA members were invited to participate in an online survey investigating the use of selenium supplementation across the spectrum of benign thyroid diseases. Of 872 invited members, 242 (28%) completed the survey. After exclusion of basic scientists and non-European members, survey data from 212 respondents were eligible for further analyses. Responses from 65 (31%) individuals who did not at all recommend selenium, or only considered its use in the setting of a clinical trial, were not included in the final analysis of survey data from 147 respondents. RESULTS:While only a minority of respondents (29 of 147, 20%) stated that the available evidence warrants the use of Se in patients with HT, a statistically significant majority (95 of 147; 65%, < 0.001) used Se occasionally or routinely. Se was predominantly recommended for patients with HT not receiving LT4 (102 of 147; 69%) to reduce circulating thyroid autoantibody levels. Very few respondents routinely recommended Se to pregnant patients with HT. CONCLUSIONS:A minority of responding ETA members stated that the available evidence warrants the use of Se in HT, but a majority recommended it to some extent, especially to patients not yet receiving LT4. This is questionable, and selenium is not recommended to patients with HT according to current ETA guidelines. Ongoing and future trials may lead to the reversal of current medical practice.
10.1159/000504781
Positive effects of selenium supplementation in women with newly diagnosed Hashimoto's thyroiditis in an area with low selenium status.
Kryczyk-Kozioł Jadwiga,Zagrodzki Paweł,Prochownik Ewelina,Błażewska-Gruszczyk Anna,Słowiaczek Marian,Sun Qian,Schomburg Lutz,Ochab Ewa,Bartyzel Mirosław
International journal of clinical practice
OBJECTIVE:Autoimmune thyroid diseases, including Hashimoto's thyroiditis, are the most common ones among autoimmune diseases. The reported effects of selenium supplementation on the course of Hashimoto's thyroiditis are not consistent. It is therefore important to continue this line of research. DESIGN:The participants received selenium in the form of sodium selenite(IV) at a dose of 100 µg/day for 6 months. PATIENTS:Newly diagnosed and previously untreated Hashimoto's thyroiditis with euthyroidism or subclinical hypothyroidism. A total of 36 patients (aged 20 to 52 years) qualified for this study, of whom 29 women were successfully enrolled and completed the intervention. MEASUREMENTS:Both before and after supplementation the following parameters in serum were tested: anti-thyroid peroxidase antibodies, thyroid function indicators, selenium as well as antioxidant status parameters and other biochemical parameters (lipid profile, glucose). Iodine supply and subjective assessment of physical and psychological health were also monitored. RESULTS:Selenium supplementation decreased significantly level of anti-thyroid peroxidase antibodies what might have had a stabilizing effect on thyroid function, as values of thyroid parameters were within normal range before and at the end of the study. Mean level of selenium among patients was not different to healthy people in Poland. Median of ioduria was within normal range. CONCLUSIONS:The study shows a potential way of protective effect of selenium in limiting development of overt hypothyroidism. The increase in the concentrations of Se and SELENOP in the serum of patients verifies successful supplementation and good compliance, but did not affect the antioxidant status parameters measured.
10.1111/ijcp.14484
l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial.
Kyrgios Ioannis,Giza Styliani,Kotanidou Eleni P,Kleisarchaki Angeliki,Tsinopoulou Vasiliki Rengina,Papadopoulou Anastasia,Markantonatou Anthi-Marina,Kanellidou Eleni,Giannakou Anastasia,Galli-Tsinopoulou Assimina
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVE:Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 μg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS:Seventy-one (71) children and adolescents, with a mean age of 11.3 ± 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] ≥60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 μg l-selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION:At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Δ: -70.9 ± 22.1 vs -6.7 ± 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Δ: -116.2 ± 68.4 vs +262.8 ± 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION:In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT.
10.1111/jcpt.12765
Interaction of Genetic Variations in and Modulates the Risk of Hashimoto's Thyroiditis.
Santos Liliana R,Durães Cecília,Ziros Panos G,Pestana Ana,Esteves César,Neves Celestino,Carvalho Davide,Bongiovanni Massimo,Renaud Cédric O,Chartoumpekis Dionysios V,Habeos Ioannis G,Simões Manuel Sobrinho,Soares Paula,Sykiotis Gerasimos P
Thyroid : official journal of the American Thyroid Association
Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by , is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in on the risk of developing HT. In a case-control candidate gene association study, functional SNPs in the promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene , encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls. and SNPs were genotyped using TaqMan assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells. When all three SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR = 1.43, = 0.072). Among subjects harboring only major alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the minor allele. Conversely, in subjects heterozygous or homozygous for the risk allele, the presence of an minor allele significantly increased HT risk by 2.8-fold ( = 0.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling. The promoter genotype interacts with the promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.
10.1089/thy.2018.0480
Effects of Selenium Supplementation on Sperm Parameters and DNA-Fragmentation Rate in Patients with Chronic Autoimmune Thyroiditis.
Cannarella Rossella,Condorelli Rosita A,Calogero Aldo E,Bagnara Vincenzo,Aversa Antonio,Greco Emanuela A,Brunetti Antonio,La Vignera Sandro
Journal of clinical medicine
BACKGROUND:Selenium (Se) is an essential component of selenoenzymes, which have catalytic and antioxidant functions. A low Se status has been reported in patients with chronic autoimmune thyroiditis (AT) who benefit from Se supplementation. The role of Se in male reproduction is still a matter of debate. Although Se and selenoenzymes ensure sperm viability and protect against increased oxidative stress, only a few studies have assessed the effects of the administration of Se alone on sperm parameters, providing contrasting results. AIM:The aim of this study was to assess the effects of oral Se supplementation on conventional sperm parameters and DNA fragmentation (SDF) in patients with AT of reproductive age with normal thyroid function. PATIENTS AND METHODS:Only patients with AT and normal thyroid function were selected for this study. All included patients underwent oral Se supplementation at the dose of 83 µg once daily (Syrel, IBSA) for six months. Sperm conventional parameters, SDF, and thyroid function were assessed before and at the end of the treatment. RESULTS:Twenty AT patients with normal weight were enrolled. After Se supplementation, they showed a higher sperm concentration, a higher percentage of sperm with progressive motility, and a higher percentage with normal morphology. They also had lower semen leukocyte concentration, and a lower percentage of spermatozoa with DNA fragmentation compared with pre-treatment values. Free-thyroxine serum levels increased significantly, whereas free triiodothyronine showed an upward trend. The thyroid-stimulating hormone did not change significantly. CONCLUSION:Se supplementation may represent a possible non-hormonal therapeutic choice for the treatment of male infertility, although further studies are needed to confirm this evidence. The possible thyroid hormone dependency of these findings needs to be clarified.
10.3390/jcm10163755
Insufficient evidence to support the clinical efficacy of selenium supplementation for patients with chronic autoimmune thyroiditis.
Qiu Yuxuan,Xing Zhichao,Xiang Qiao,Yang Qianru,Zhu Jingqiang,Su Anping
Endocrine
BACKGROUND:This study critically reappraises the documentation on the clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis (AIT) with the goal of improving the normalization of the treatment of this disease. METHODS:A literature search was performed in the Medline, Embase, and Cochrane Library databases. Twenty-three trials conducted in adults with AIT comparing the efficacy of selenium with or without levothyroxine (LT4) versus placebo and/or LT4 were eligible. The assessed outcomes were primarily pooled using a random- or fixed effects model based on the results of the heterogeneity test. The quality of evidence was assessed per outcome. RESULTS:In LT4-treated populations, patients receiving selenium demonstrated lower thyroid peroxidase antibody (TPOAb) levels at 3 months (mean difference [MD], -236.88; 95% confidence interval [CI], -353.35 to -120.41; p < 0.0001), 6 months (MD, -407.17; 95% CI, -623.60 to -190.73; p = 0.0002), and 12 months (MD, -327.03; 95% CI, -613.78 to -40.28; p = 0.0254), while thyroglobulin antibody (TgAb) levels only decreased at 12 months. In non-LT4-treated population, the selenium group demonstrated significantly lower TPOAb levels after 3 months (MD, -203.07; 95% CI, -395.44 to -10.70; p = 0.0385) and 6 months (MD, -322.27; 95% CI, -597.50 to -47.04; p = 0.0217) but not after 12 months, while TgAb levels only decreased at 3 months. There was no significant change in thyroid stimulating hormone (TSH) levels. Lower thyroid echogenicity was observed in all patients receiving selenium at 3, 6, and 12 months. However, these participants had a significantly higher risk of reported adverse effects. CONCLUSIONS:Current evidence does not justify the emerging use of selenium supplementation in the treatment of AIT, despite it resulting in a decrease in autoantibody levels.
10.1007/s12020-021-02642-z
Increased Incidence of Hashimoto Thyroiditis in Selenium Deficiency: A Prospective 6-Year Cohort Study.
The Journal of clinical endocrinology and metabolism
CONTEXT:In 2015, we reported an increased prevalence of thyroid disease in a county of low habitual selenium (Se) intake in comparison to a neighboring county with higher intake in a cross-sectional survey in Shaanxi Province, China. OBJECTIVE:To explore longitudinal effects of low Se status, a prospective cohort study was conducted in the same area from 2013 to 2019, and thyroid peroxidase autoantibodies (TPO-Abs) and disease incidence were compared. METHODS:A total 1254 individuals from 1500 reinvited participants were successfully enrolled. Venous blood, fingernails, and urine samples were collected and analyzed to evaluate thyroid status, TPO-Abs, serum Se, and urinary iodine. Diagnosis of Hashimoto thyroiditis (HT) was based on elevated thyrotropin, presence of TPO-Abs, and ultrasound characteristics. Se deficiency was categorized using a serum concentration of 80 µg/L as a threshold, and tested by logistic regression for a relationship to TPO-Abs and HT. RESULTS:Se deficiency was observed in 46.2% of participants from the adequate-Se county (Ziyang) and in 89.7% from the low-Se county (Ningshan). Se concentrations in fingernails differed strongly by residency (Ziyang vs Ningshan; 678.7 vs 364.3 μg/kg; Z = -9.552; P < .001). Newly diagnosed HT in Ziyang was less frequent than in Ningshan (0.09% vs 0.31%; χ 2 = 4.350; P = .037). The conversion rate to seropositive TPO-Abs was 10.2% in Ningshan vs 5.6% in Ziyang. Excluding iodine as confounding factor, low-Se was confirmed as a risk factor for HT (relative risk [95% CI]; 3.65 [1.03-12.90]; P < .05). CONCLUSION:The data indicate an increased incidence of TPO-Ab seroconversion with low Se supply and support the hypothesis that Se deficiency contributes to HT as a modifiable risk factor.
10.1210/clinem/dgac410
Assessment of the Effect of Selenium Supplementation on Production of Selected Cytokines in Women with Hashimoto's Thyroiditis.
Nutrients
The impact of selenium on the course of Hashimoto's thyroiditis (HT) was mainly assessed by monitoring the titer of antithyroid autoantibodies in most of the studies conducted hitherto. On the other hand, the imbalance in activity of T cells such as Th1, Th2, Th17, and Treg may be relevant in the pathogenesis of this disease. Hence, the assessment of changes in the secretion of cytokines by these cells during selenium supplementation in patients with HT seems to be an important issue and was the main goal of this study. A further aim was to search for correlations among these cytokines, as well as markers of thyroid function, selenium/iodine status in the body, and other biochemical parameters. The group of 29 women with newly diagnosed Hashimoto's thyroiditis was supplemented with selenium in a dose of 100 µg/day for 6 months. Immunological parameters: interferon γ, tumor necrosis factor α, chemokine CXCL10, interleukin 4, interleukin 1β, interleukin 17, transforming growth factor β, and C-reactive protein, as well as selenium status parameters were determined in serum twice, i.e., before and after supplementation. Selenium supplementation was associated with a change in the production of two cytokines: interferon γ and interleukin 1β, for which a decrease and an increase in concentration were observed, respectively. The partial least squares (PLS) model revealed the presence of many relevant correlations among analyzed parameters. The stage of HT development, degree of thyroid dysfunction, and selenium supplementation of diet are interdependent factors which shape the profile of some cytokines secreted by cells participating in the autoimmunity process.
10.3390/nu14142869
Effects of Selenium Supplement on B Lymphocyte Activity in Experimental Autoimmune Thyroiditis Rats.
International journal of endocrinology
METHODS:45 healthy and adult female SD rats were randomly divided into three groups: normal control group, EAT model group, and selenium yeast supplement EAT group. The EAT model rats were induced by subcutaneous injection of porcine thyroglobulin and fed with high iodine water. The concentrations of serum thyroid-stimulating hormone (TSH), TGAb, TPOAb, and B cell activating factor (BAFF) were detected in each group by enzyme-linked immunosorbent assay (ELISA), and the expression of interleukin-10 (IL-10) in thyroid tissue was detected by immunohistochemistry. B cells and regulatory B cells (Bregs) ratios in the spleen of rats were analyzed by flow cytometry. RESULTS:In contrast with the EAT model group, the levels of serum TSH, TGAB, TPOAb, and BAFF were decreased, while IL-10 expression was increased in thyroid tissue, and Bregs ratio was upregulated in the spleen (all < 0.05) in the selenium yeast supplement EAT group. CONCLUSION:Selenium yeast supplement could partially attenuate immune imbalance in EAT rats, which may be related to the mechanism of modulating B lymphocyte activity.
10.1155/2021/9439344
The effects of selenium supplementation on antibody titres in patients with Hashimoto's thyroiditis.
Wang Lan-Feng,Sun Rong-Xin,Li Chen-Fei,Wang Xu-Hong
Endokrynologia Polska
INTRODUCTION:The objective of this study was to evaluate the effect of selenium supplementation on autoantibody titres, thyroid ultrasonography, and thyroid function in patients with Hashimoto's thyroiditis (autoimmune thyroiditis) and normal thyroid reference range. MATERIAL AND METHODS:A total of 100 patients were given 200 ug/d selenium yeast orally, their thyroid function, levels of serum selenium, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and urine iodine were measured, and thyroid ultrasonography was performed before administration and three and six months afterwards, and the data were statistically analysed. RESULTS:The subjects exhibited a selenium deficiency before the administration of selenium, and the serum levels increased to moderate levels three and six months after the selenium supplementation (p < 0.05). The titres of TGAb decreased significantly in patients after six months of selenium supplementation (p < 0.05). In the high antibody group, TgAb decreased after 6 months compared with baseline (p = p < 0.05), and TPOAb decreased after 3 and 6 months of selenium supplementation compared with baseline (p < 0.05). CONCLUSION:In patients with autoimmune thyroiditis and normal thyroid reference range, there was a general selenium deficiency, but after six months of treatment it was shown that selenium supplementation may be effective in reducing the titres of TGAb and TPOAb.
10.5603/EP.a2021.0074
Selenium and its relationship with selenoprotein P and glutathione peroxidase in children and adolescents with Hashimoto's thyroiditis and hypothyroidism.
Nourbakhsh Mitra,Ahmadpour Fatemeh,Chahardoli Behnam,Malekpour-Dehkordi Zahra,Nourbakhsh Mona,Hosseini-Fard Seyed Reza,Doustimotlagh Amirhossein,Golestani Abolfazl,Razzaghy-Azar Maryam
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
The essential trace element selenium (Se) is required for thyroid hormone synthesis and metabolism. Selenoproteins contain selenocysteine and are responsible for biological functions of selenium. Glutathione peroxidase (GPx) is one of the major selenoproteins which protects the thyroid cells from oxidative damage. Selenoprotein P (SePP) is considered as the plasma selenium transporter to tissues. The aim of this study was to evaluate serum Se and SePP levels, and GPx activity in erythrocytes of children and adolescents with treated Hashimoto's thyroiditis, hypothyroidism, and normal subjects. Blood samples were collected from 32 patients with Hashimoto's thyroiditis, 20 with hypothyroidism, and 25 matched normal subjects. All the patients were under treatment with levothyroxine and at the time of analysis all of the thyroid function tests were normal. GPx enzyme activity was measured by spectrophotometry at 340 nm. Serum selenium levels were measured by high-resolution continuum source graphite furnace atomic absorption. SePP, TPOAb (anti-thyroid peroxidase antibody), and TgAb (anti-thyroglobulin antibody) were determined by ELISA kits. T4, T3, T3 uptake and TSH were also measured. Neither GPx activity nor SePP levels were significantly different in patients with Hashimoto's thyroiditis or hypothyroidism compared to normal subjects. Although GPx and SePP were both lower in patients with hypothyroidism compared to those with Hashimoto's thyroiditis and normal subjects but the difference was not significant. Serum Se levels also did not differ significantly in patients and normal subjects. We did not find any correlation between GPx or SePP with TPOAb or TgAb but SePP was significantly correlated with Se. Results show that in patients with Hashimoto's thyroiditis or hypothyroidism who have been under treatment with levothyroxine and have normal thyroid function tests, the GPx, SePP and Se levels are not significantly different.
10.1016/j.jtemb.2015.10.003
Decreased Thyroid Peroxidase Antibody Titer in Response to Selenium Supplementation in Autoimmune Thyroiditis and the Influence of a Selenoprotein P Gene Polymorphism: A Prospective, Multicenter Study in China.
Wang Weiwei,Mao Jinyuan,Zhao Jiajun,Lu Juming,Yan Li,Du Jianling,Lu Zhaohui,Wang Hai,Xu Mingtong,Bai Xue,Zhu Lin,Fan Chenling,Wang Hong,Zhang Hongmei,Shan Zhongyan,Teng Weiping
Thyroid : official journal of the American Thyroid Association
Recent intervention studies have suggested that selenium (Se) is an effective treatment for autoimmune thyroiditis (AIT). However, the exact effect of Se on AIT is unclear as well as the mechanism of action. The aim of the present study was to explore the effect of Se on thyroid peroxidase antibody (TPOAb) titers in patients with AIT and to analyze the potential impact of the genetic background on the effect of Se supplementation. This was a randomized, placebo-controlled, double-blind trial. Three hundred and sixty-four patients with elevated TPOAb (>300 IU/mL) were recruited and randomized to receive Se yeast 200 μg/day supplementation or placebo. Urinary iodine concentration, serum thyrotropin, free thyroxine, TPOAb, Se, malondialdehyde, and serum glutathione peroxidase activity were measured at baseline and follow-up. Ninety-six patients were genotyped for single nucleotide polymorphism r25191G/A in the selenoprotein P ( gene. The median urinary iodine concentration was 182 μg/L. Serum Se increased significantly ( < 0.001) after Se treatment. TPOAb titer decreased by 10.0% at 3 months and by 10.7% at 6 months after Se supplementation, while there was a moderate increase in TPOAb titers over the follow-up period in patients receiving placebo. Glutathione peroxidase activity significantly increased ( < 0.001), and malondialdehyde significantly decreased ( < 0.001) after 6 months of Se supplementation. TPOAb titers decreased to variable extents in patients with different genotypes of single nucleotide polymorphism r25191G/A after Se supplementation. Serum TPOAb titers in patients with the AA genotype showed a more significant decrease (by 46.2%) than those with the GA and GG genotypes (by 14.5 and 9.8% respectively) at 3 months of Se supplementation ( = 0.070). Se supplementation significantly reduced TPOAb titers in patients with AIT, and there may be an important genetic component influencing interindividual differences in the decrease in TPOAb titers.
10.1089/thy.2017.0230
Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto's Thyroiditis.
Sun Qian,Mehl Sebastian,Renko Kostja,Seemann Petra,Görlich Christian L,Hackler Julian,Minich Waldemar B,Kahaly George J,Schomburg Lutz
International journal of molecular sciences
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, = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, = 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.
10.3390/ijms222313088
Selenium regulates T cell differentiation in experimental autoimmune thyroiditis in mice.
International immunopharmacology
Selenium (Se) is an essential trace element that plays an important role in thyroid physiology. Se supplementation can reduce levels of autoimmune thyroid antibodies, which may be beneficial in Hashimoto's thyroiditis (HT). However, the long-term benefits of Se supplementation for HT patients are controversial and there is no clear clinical evidence to support it, so further basic and clinical research is needed. The effect of Se on immune cells, especially T cells, in autoimmune thyroiditis (AIT) has not been elucidated. Here, we replicated a mouse model of experimental autoimmune thyroiditis (EAT) on a high-iodine diet and treated it with Se supplementation. At week 8 of the experiment, Se supplementation reduced the destruction of thyroid follicles and the infiltration rate of lymphocytes in EAT mice, and reversed the disturbance of peripheral blood thyroxine and thyroid autoantibody levels. Further examination revealed that Se had broad effects on T-cell subsets. Its effects include reducing the production of pro-inflammatory cytokines by Th1 cells, inhibiting the differentiation and production of cytokines by Th2 and Th17 cells, and upregulating the differentiation and production of cytokines by Treg cells. These changes help alleviate thyroid follicle damage during EAT. In conclusion, selenium supplementation has the potential to improve the prognosis of AIT by altering the subset differentiation and/or function of CD4+ T cells.
10.1016/j.intimp.2023.110993
Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto's thyroiditis: A prospective randomized-controlled trial.
Hu Yifang,Feng Wenwen,Chen Huanhuan,Shi He,Jiang Lin,Zheng Xuqin,Liu Xiaoyun,Zhang Wensong,Ge Yaoqi,Liu Yun,Cui Dai
Clinical and translational science
Selenium (Se) is an essential trace element in human. Recent studies of Se supplementation on the effect of Hashimoto's thyroiditis (HT) have been reported, but the exact benefit is unclear as well as the underlying immunologic mechanism. We aimed to evaluate the clinical effect of Se supplement in patients with HT, and explore the potential mechanism against thyroid autoimmunity. A prospective, randomized-controlled study was performed in patients with HT assigned to two groups. Se-treated group (n = 43) received selenious yeast tablet (SYT) for 6 months, whereas no treatment in control group (n = 47). The primary outcome is the change of thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TGAb). Second, thyroid function, urinary iodine, Se, Glutathione peroxidase3 (GPx3), and Selenoprotein P1 (SePP1) levels were measured during the SYT treatment. Meanwhile, regulatory T cells (Tregs) and their subsets activated Tregs (aTregs), resting Tregs, and secreting Tregs, as well as Helios and PD-1 expression on these cells were also detected. The results showed that SYT treatment significantly decreased TPOAb, TGAb, and thyroid stimulating hormone (TSH) levels, accompanied with the increased Se, GPx3, and SePP1, compared with the control group. Subgroup analysis revealed that subclinical HT may benefit more from this treatment in the decrease of TSH levels by interaction test. Moreover, the percentage of aTregs, Helios/Tregs, and Helios/aTregs were significantly higher in the Se-treated group than control. In conclusion, Se supplementation may have a beneficial effect on thyroid autoantibodies and thyroid function by increasing the antioxidant activity and upregulating the activated Treg cells.
10.1111/cts.12993
Metabolic Characteristics of Hashimoto's Thyroiditis Patients and the Role of Microelements and Diet in the Disease Management-An Overview.
International journal of molecular sciences
Hashimoto's thyroiditis (HT) is the most common autoimmune disease and the leading cause of hypothyroidism, in which damage to the thyroid gland occurs due to the infiltration of lymphocytes. It is characterized by increased levels of antibodies against thyroid peroxidase and thyroglobulin. In this review, we present the metabolic profile, the effectiveness of micronutrient supplementation and the impact of dietary management in patients with HT. For this current literature review, the databases PubMed, Cochrane, Medline and Embase were reviewed from the last ten years until March 2022. This article provides a comprehensive overview of recent randomized controlled trials, meta-analyses, and clinical trials. Many patients with HT, even in the euthyroid state, have excess body weight, metabolic disorders, and reduced quality of life. Due to frequent concomitant nutritional deficiencies, the role of vitamin D, iodine, selenium, magnesium, iron and vitamin B12 is currently debated. Several studies have underlined the benefits of vitamin D and selenium supplementation. There is still no specific diet recommended for patients with HT, but a protective effect of an anti-inflammatory diet rich in vitamins and minerals and low in animal foods has been suggested. There is insufficient evidence to support a gluten-free diet for all HT patients. Pharmacotherapy, along with appropriate nutrition and supplementation, are important elements of medical care for patients with HT. The abovementioned factors may decrease autoantibody levels, improve thyroid function, slow down the inflammatory process, maintain proper body weight, relieve symptoms, and prevent nutritional deficiencies and the development of metabolic disorders in patients with HT.
10.3390/ijms23126580
Histological Alterations in Hashimoto's Disease: A Case-Series Ultrastructural Study.
Medicines (Basel, Switzerland)
BACKGROUND:Hashimoto's thyroiditis (HT) is an autoimmune disease exhibiting stromal fibrosis and follicular cell destruction due to lymphoplasmacytic infiltration. Besides deprecated analyses, histopathological approaches have not employed the use of electron microscopy adequately toward delineating subcellular-level interactions. METHODS:Biopsies for ultrastructural investigations were obtained from the thyroids of five patients with HT after a thyroidectomy. Transmission electron microscopy (TEM) was utilized to study representative tissue specimens. RESULTS:Examination indicated interstitial extravasated blood cells and a plethora of plasma cells, based on their subcellular identity landmarks. These antibody-secreting cells were profoundly spotted near follicular cells, fibroblasts, and cell debris entrenched in collagenous areas. Pathological changes persistently affected subcellular components of the thyrocytes, including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and other intracellular vesicles. Interestingly, significant endothelial destruction was observed, specifically in the larger blood vessels, while the smaller vessels appeared comparatively unaffected. CONCLUSIONS:Our TEM findings highlight the immune-related alterations occurring within the thyroid stroma. The impaired vasculature component and remodeling have not been described ultrastructurally before; thus, further exploration is needed with regards to angiogenesis in HT in order to achieve successful prognostic, diagnostic, and treatment-monitoring strategies.
10.3390/medicines10090051
A Global Regulatory Network for Dysregulated Gene Expression and Abnormal Metabolic Signaling in Immune Cells in the Microenvironment of Graves' Disease and Hashimoto's Thyroiditis.
Frontiers in immunology
Background:Although the pathogenetic mechanisms of Hashimoto's thyroiditis (HT) and Graves' disease (GD) have been elucidated, the molecular mechanisms by which the abnormal immune function of cellular subpopulations trigger an autoimmune attack on thyroid tissue largely remains unexplained. Methods:The study included 2 HT patients, 2 GD patients, and 1 control donor. The thyroid samples were extracted for single-cell RNA sequencing, whole transcriptome, full-length transcriptome (Oxford Nanopore Technologies), and metabolome sequencing. Identification of immune cells with dysregulated gene expression and abnormal metabolic signaling was performed in the microenvironment, both at the bulk and single-cell levels. Based on functional enrichment analysis, the biological processes and pathways involved in abnormal immune cells were further explored. Finally, according to cell communication analysis, the global regulatory network of immune cells was constructed. Results:CD4 T cells, CD8 T cells, and macrophages were abnormally increased in patients with HT and GD. The differentially expressed genes of these cells were significantly involved in signaling pathways, including Th1 and Th2 cell differentiation, Th17 cell differentiation, cytokine-cytokine receptor interaction, and NF-kappa B signaling pathway. Moreover, in HT, CD4 T cells interact with macrophages the IL16-CCR5/FGF10-FGFR1/CXCL13-CXCR3 axis, and macrophages interact with CD8 T cells the CD70-CD27 axis, thereby activating the T-cell receptor signaling pathway and NF-kappa B signaling pathway. In GD, CD4 T cells interact with macrophages the CXCR3-CXCL10/PKM-CD44/MHCII-NFKBIE axis, and macrophages interact with CD8 T cells the IFNG-IFNGR1/CCR7-CCL21 axis, thereby activating T-cell receptor signaling pathway, Th1 and Th2 cell differentiation, and chemokine signaling pathway. Conclusion:In HT and GD, immune dysregulated cells interact and activate relevant immune pathways and further aggravate the immune response. This may trigger the immune cells to target the thyroid tissue and influence the development of the disease.
10.3389/fimmu.2022.879824
Microcystin-LR induced transgenerational effects of thyroid disruption in zebrafish offspring by endoplasmic reticulum stress-mediated thyroglobulin accumulation and apoptosis.
Environmental pollution (Barking, Essex : 1987)
MC-LR can interfere with thyroid function in fish, but the underlying mechanism is still unclear. Current study focuses to study the intergenerational inheritance of MC-LR-induced thyroid toxicity in zebrafish and in rat thyroid cells. In vivo experiments, adult female zebrafish (F0) were exposed to MC-LR (0, 5, and 25 μg/L) for 90 days and mated with male zebrafish without MC-LR exposure to generate F1 generation. F1 embryos were allowed to develop normally to 7 days post-fertilization (dpf) in clear water. In the F0 generation, MC-LR induced disturbance of the hypothalamic-pituitary-thyroid (HPT) axis, leading to a decrease in the production of thyroid hormones. Maternal MC-LR exposure also induced growth inhibition by altering thyroid hormones (THs) homeostasis and interfering with thyroid metabolism and development in F1 offspring. Mechanistically, MC-LR caused excessive accumulation of ROS and induced ER stress that further lead to activation of UPR in the F0 and F1 offspring of zebrafish. Interestingly, our findings suggested that MC-LR exposure hampered thyroglobulin turnover by triggering IRE1 and PERK pathway in zebrafish and FRTL-5 thyroid cells, thus disturbing the thyroid endocrine system and contributing to the thyroid toxicity from maternal to its F1 offspring of zebrafish. Particularly, inhibition of the IRE1 pathway by siRNA could alleviate thyroid development injury induced by MC-LR in FRTL-5 cells. In addition, MC-LR induced thyroid cell apoptosis by triggering ER stress. Taken together, our results demonstrated that maternal MC-LR exposure causes thyroid endocrine disruption by ER stress contributing to transgenerational effects in zebrafish offspring.
10.1016/j.envpol.2023.121117
Endoplasmic reticulum stress in autoimmune diseases: Can altered protein quality control and/or unfolded protein response contribute to autoimmunity? A critical review on Sjögren's syndrome.
Barrera María-José,Aguilera Sergio,Castro Isabel,González Sergio,Carvajal Patricia,Molina Claudio,Hermoso Marcela A,González María-Julieta
Autoimmunity reviews
For many years, researchers in the field of autoimmunity have focused on the role of the immune components in the etiopathogenesis of autoimmune diseases. However, some studies have demonstrated the importance of target tissues in their pathogenesis and the breach of immune tolerance. The immune system as well as target tissue cells (plasmatic, β-pancreatic, fibroblast-like synoviocytes, thyroid follicular and epithelial cells of the lachrymal glands, salivary glands, intestine, bronchioles and renal tubules) share the characteristic of secretory cells with an extended endoplasmic reticulum (ER). The function of these cells depends considerably on a normal ER function and calcium homeostasis, so they can produce and secrete their main components, which include glycoproteins involved in antigenic presentation such as major histocompatibility complex (MHC) class I and II. All these proteins are synthesized and modified in the ER, and for this reason disturbances in the normal functions of this organelle such as protein folding, protein quality control, calcium homeostasis and redox balance, promote accumulation of unfolded or misfolded proteins, a condition known as ER stress. Autoimmune diseases are characterized by inflammation, which has been associated with an ER stress condition. Interestingly, patients with these diseases contain circulating auto-antibodies against chaperone proteins (such as Calnexin and GRP94), thus affecting the folding and assembly of MHC class I and II glycoproteins and their loading with peptide. The main purpose of this article is to review the involvement of the protein quality control and unfolded protein response (UPR) in the ER protein homeostasis (proteostasis) and their alterations in autoimmune diseases. In addition, we describe the interaction between ER stress and inflammation and evidences are shown of how autoimmune diseases are associated with an ER stress condition, with a special emphasis on the second most prevalent autoimmune rheumatic disease, Sjögren's syndrome.
10.1016/j.autrev.2018.02.009
Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.
JAMA
Importance:Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective:To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection:Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis:The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures:The primary outcome was preterm birth (<37 weeks' gestational age). Results:From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance:Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.
10.1001/jama.2019.10931
Regulatory factor X1 induces macrophage M1 polarization by promoting DNA demethylation in autoimmune inflammation.
JCI insight
Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of Regulatory factor X1 (RFX1) in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Furthermore, we found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. We identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.
10.1172/jci.insight.165546
Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis.
Hua Xiumeng,Hu Gang,Hu Qingtao,Chang Yuan,Hu Yiqing,Gao Linlin,Chen Xiao,Yang Ping-Chang,Zhang Yu,Li Mingyao,Song Jiangping
Circulation
BACKGROUND:Myocarditis can develop into dilated cardiomyopathy, which may require heart transplantation. The immunological network of myocarditis phases remains unknown. This study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis. METHODS:Mice were treated with myosin heavy chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing analysis of cells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory, and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone heart transplantation. RESULTS:We identified 26 cell subtypes among 34 665 cells. Macrophages constituted the main immune cell population at all disease phases (>60%), and an inflammation-associated macrophage cluster was identified in which the expression of -regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then released to participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. T-helper 17 cells, in which the expression of -regulated genes was upregulated, constituted the main T-cell population detected at the acute inflammatory phase, whereas regulatory T cells were the main T-cell population detected at the subacute inflammatory phase, and γδ T cells releasing were the main T-cell population observed at the myopathy phase. Moreover, the expression level correlated with the extent of inflammation. In addition, PX-478 could alleviate the inflammatory responses of the different EAM phases. Last, was expressed at higher levels in patients with acute autoimmune myocarditis than in patients with dilated cardiomyopathy and healthy control subjects. CONCLUSIONS:We present here a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidate the contribution of to the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and T-helper 17 cells. Moreover, an inhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.
10.1161/CIRCULATIONAHA.119.043545
IRGM1 links mitochondrial quality control to autoimmunity.
Nature immunology
Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA-dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1 tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.
10.1038/s41590-020-00859-0
Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto's thyroiditis.
Nature communications
Hashimoto's thyroiditis (HT) is the most common autoimmune disease characterized by lymphocytic infiltration and thyrocyte destruction. Dissection of the interaction between the thyroidal stromal microenvironment and the infiltrating immune cells might lead to a better understanding of HT pathogenesis. Here we show, using single-cell RNA-sequencing, that three thyroidal stromal cell subsets, ACKR1 endothelial cells and CCL21 myofibroblasts and CCL21 fibroblasts, contribute to the thyroidal tissue microenvironment in HT. These cell types occupy distinct histological locations within the thyroid gland. Our experiments suggest that they might facilitate lymphocyte trafficking from the blood to thyroid tissues, and T cell zone CCL21 fibroblasts may also promote the formation of tertiary lymphoid organs characteristic to HT. Our study also demonstrates the presence of inflammatory macrophages and dendritic cells expressing high levels of IL-1β in the thyroid, which may contribute to thyrocyte destruction in HT patients. Our findings thus provide a deeper insight into the cellular interactions that might prompt the pathogenesis of HT.
10.1038/s41467-022-28120-2