Development Of Autoimmune Thyroid Disease Research Articles

Study of Urinary Iodine Level Assessment and its Relation to Thyroid Function during Pregnancy

Abstract Background The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Aim of the study to evaluate the urinary iodine level as a marker of iodine status in pregnant women in 3rd trimester and assess its relation to thyroid functions. Patients and Methods This Cross Sectional Study was conducted on 100 subjects with their ages ranging from 18-35 years old, pregnant females, at the third trimester, selected from Obstetric Out- patient Clinic of Ain shams University Hospitals. Samples were collected from participants in cairo, during the Spring and Summer from March to August. Results in our study, there was a significant negative correlation between Urinary Iodine level and TSH as Iodine difficient group has the Highest TSH, and the Highest Thyroid Volume, as there was a significant negative correlation between Urinary Iodine level and Thyroid Volume. Conclusion TSH level and Thyroid Volume were global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to significantly higher in Iodine difficient group than Excess iodine group, And FT4 level was lower in Iodine difficient group than excess iodine group.

Effects of vitamin D in thyroid autoimmune pathologies: literature review and own data

Background. Vitamin D (VD) is a versatile steroid hormone that regulates the activity of several thousand genes. Over the past decades, numerous diseases associated with VD deficiency have been reported, including cancer and autoimmune thyroid disorders. Researches revealed that VD can influence the development and course of these diseases. The VD participation in modulation of the hypothalamus-pituitary-thyroid gland axis, both at the level of the pituitary gland and at that of the thyroid, has been shown. The effect of VD on autoimmune diseases, including thyroid autoimmune diseases, is widely studied. Most of the existing data support the relationship between VD deficiency and a greater tendency to develop and higher antibody titers associated with Hashimoto’s thyroiditis, Graves’ disease (GD) and postpartum thyroiditis. An important fact is that epidemiological studies have demonstrated a high prevalence of VD deficiency or insufficiency throughout the world. VD insufficiency is a potent dietary trigger that results in severe, chronic diseases. The question arises how reliable is the relationship between VD and autoimmune thyroid diseases (AITD). Although the results of the studies performed are somewhat contradictory, the vast majority of data indicates a link between VD deficiency and an increased risk of developing the disease, high antibody titers, and difficulties in treatment. Genetic polymorphisms associated with VD function and metabolism also have some influence on the risk of ATD. With regard to the precise nature of the relationship between VD and AITD, it is believed that VD plays a small but significant role in the AITD pathogenesis. After the AITD development, its consequence may be an increase in VD deficiency. It is the need to determine the effect of VD supplementation in the prevention and treatment of AITD and its optimal level directly for clinical practice. It is necessary for clinical practice to determine the effect of VD supplements in the prevention and treatment of AITD and its optimal level. A study, the purpose of which was to study the content of VD, namely 25(OH)D in 176 patients with GD complicated by autoimmune ophthalmopathy (AO) and to identify a correlation relationship with antithyroid antibodies (TPO, TSHR-Ab) was carried out at the State Institution “V.P. Komissarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine”. Materials and methods. The levels of 25(OH)D, TSH, TSHR-Ab, TPO were determined by enzyme immunoassay using standard kits from Siemens firm. During the study, 176 patients were divided into two groups, depending on the presence of AO: the first group consisted of patients with GD without AO (62 people), the second group included patients with GD and AO (114 people). Results. In GD, 91.78 % of patients (161 people) have an insufficient level of 25(OH)D content: a suboptimal level was recorded in 42 patients (23.86 %), and a deficit — in 119 patients (67.61 %). A significant negative correlation relationship was revealed between TSHR-Ab and 25(OH)D in the group of patients with GD and AO — with a lower level of 25(OH)D, the higher values of TSHR-Ab correlate. Compensation of the 25(OH)D deficiency leads to a significant (P< 0.05) decrease in the levels of TSHR-Ab and TPO in patients with GD. Besides, there is a large body of literature available lin-king vitamin D to thyroid autoimmunity as a result of cross-sectional studies and observations. Conclusions. Thus, there is still an urgent need for large multicenter studies to evaluate the effect of vitamin D supplementation on meaningful long-term clinical endpoints in AITD.

The role of transforming growth factor beta in thyroid autoimmunity: current knowledge and future perspectives.

The complex mechanisms, which are related to the pathophysiology and the development of autoimmune thyroid diseases, involve transforming growth factor beta (TGF-β) and its interplay with the immune system. The aim of this review is to examine the role of TGF-β regarding thyroid autoimmunity and explore the potent role of this molecule either as a diagnostic or prognostic marker or a therapeutic target regarding autoimmune thyroid diseases. TGF-β is clearly a master regulator of the immune response, exerting either inhibitory or facilitatory effects on cells of the immune system. Thus, this molecule is involved in the pathogenesis and development of autoimmune thyroid diseases. Recent research has revealed the involvement of TGF-β in the pathophysiology of autoimmune thyroid diseases. The role of TGF-β in the development of autoimmune thyroid diseases varies, depending on its concentrations, the type of the activated TGF-β signalling pathway, the genetic predisposition of the patient and the pathophysiologic stage of the disease. TGF-β could emerge as a useful diagnostic or prognostic marker for the evolution of thyroid autoimmunity. Promising perspectives for the effective therapeutic use of TGF-β regarding thyroid autoimmunity exist. The main treatment approaches incorporate either enhancement of the immunosuppressive role of TGF-β or inhibition of its facilitatory role in the autoimmune thyroid diseases. Further research towards deeper understanding of TGF-β physiology and clinical application of its possible therapeutic role regarding thyroid autoimmunity is needed.

Inclusion of ALKBH5 as a candidate gene for the susceptibility of autoimmune thyroid disease

PurposeRNA demethylase AlkB homolog 5 (ALKBH5) gene is pivotal in N6-methyladenosine (m6A) modification. Therefore, this study aimed to explore the potential relationship between polymorphisms of ALKBH5 gene and the development of autoimmune thyroid disease (AITD). Material and methodsA case-control study of 979 AITD patients, including 620 Graves' disease (GD) and 359 Hashimoto's thyroiditis (HT), and 732 normal controls of the Chinese Han population was performed using high-throughput sequencing (HiSeq) genotyping method for detecting 5 variants in ALKBH5 gene (rs12936694, rs2124370, rs4925144, rs8068517, and rs9913266). In addition, the associations between ALKBH5 single nucleotide polymorphisms (SNPs) and clinical phenotypes of AITD were investigated. ResultsCompared to normal controls, rs9913266 displayed significant differences in allele and genotype distributions in AITD and GD. rs12936694 also showed significantly different frequencies of alleles in AITD and GD. The link of these 2 loci polymorprhisms to AITD and GD also existed after adjusting for age and gender. When stratified by sex, the minor allele of rs9913266 was associated with the risk of female AITD and HT development before and after adjusting for age and gender. There was a significant association between rs8068517 locus and GD in females after adjusting for the confounders. Finally, we observed significant correlations of haplotypes CGACA and CAGCG to the susceptibility of AITD and GD. ConclusionsOur results provided evidence of association of polymorphisms in ALKBH5 gene with AITD, GD, and HT patients, and hence ALKBH5 might be the candidate gene for susceptibility to AITD.

TGF-β Physiology as a Novel Therapeutic Target Regarding Autoimmune Thyroid Diseases: Where Do We Stand and What to Expect.

Transforming growth factor beta (TGF-β), as a master regulator of immune response, is deeply implicated in the complex pathophysiology and development of autoimmune thyroid diseases. Based on the close interplay between thyroid autoimmunity and TGF-β, scientific interest was shifted to the understanding of the possible role of this molecule regarding the diagnosis, prognosis, and therapy of these diseases. The main aim of this review is to present research data about possible treatment options based on the role of TGF-β in thyroid autoimmunity. Suggested TGF-β-mediated therapeutic strategies regarding autoimmune thyroid diseases include either the enhancement of its immunosuppressive role or inhibition of its facilitatory role in thyroid autoimmunity. For example, the application of hr-TGF-β can be used to bolster the inhibitory role of TGF-β regarding the development of thyroid diseases, whereas anti-TGF-β antibodies and similar molecules could impede its immune-promoting effects by blocking different levels of TGF-β biosynthesis and activation pathways. In conclusion, TGF-β could evolve to a promising, novel therapeutic tool for thyroid autoimmunity.

Thyroid Disorders in Pediatric Patients with Turner Syndrome; A 16 Years' Experience

Background Turner syndrome patients are more likely to develop autoimmune diseases in contrast to the general population. Many research have had controversial results suggest a possible relation between the cytogenetic findings and development of autoimmune thyroid disease in Turner syndrome. Therefore, we aimed to evaluate the prevalence of thyroid disorders and the possible relationship between thyroid disorders with the cytogenetic findings in these patients. Materials and Methods: The present retrospective study took place in pediatric endocrinology clinic of Imam Reza Hospital (Mashhad, Iran), and every pediatric patient who were younger than 18 years old with the clinical phenotype of Turner syndrome and had complete thyroid function tests enrolled. The medical records of these patients were evaluated and patients were recalled if any further information was needed. The study data including thyroid function tests as well as patients' age, height, weight, and karyotype findings were entered in a check list and the relationship between thyroid functions tests and karyotype findings were evaluated. Results: Among the 79 patients enrolled in the present study, the mean ± standard deviation of age was 10.82 ± 2.6 years. The most of the study population had negative anti-TPO results (62 patients, 78%). Among all patients, eight patients (10.1%) had autoimmune hypothyroidism There was not any significant relationship between thyroid function tests with different cytogenetic findings (P>0.05). Conclusion Hypothyroidism (26.6%) was the most common thyroid disorder among Turner syndrome patients. Although there was not any significant relationship between thyroid function tets, Z-scores for hight and weight with cytogenetic findings; however, our findings highlights the need for more specific screening programs for evaluating the thyroid functions in turner patient.

Cushing's Syndrome Effects on the Thyroid.

The most known effects of endogenous Cushing’s syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus–pituitary–thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the “central hypothyroidism”. These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus–pituitary–thyroid axis activity. During active Cushing’s syndrome, the “immunological tolerance” guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing’s syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing’s syndrome patients, both during the active disease and after its remission.

Immunomodulatory Function of Vitamin D and Its Role in Autoimmune Thyroid Disease.

Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.

METTL3 gene polymorphisms contribute to susceptibility to autoimmune thyroid disease.

Autoimmune thyroid disease (AITD) is a classic autoimmune disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). In this study, we explored the potential relationship between single-nucleotide polymorphisms (SNPs) of methyltransferase like 3 (METTL3) gene and the development of AITD. The distribution of METTL3 genotypes at seven loci (rs1139130, rs1263790, rs1263791, rs17197156, rs2242526, rs3752411, and rs4417466) in 960 AITD (599 GD and 361 HT) patients and 732 unrelated healthy volunteers was examined using high-throughput sequencing technology in a case-controlled manner and their correlations with AITD development were statistically analyzed. METTL3 genotypes at these seven SNPs were not correlated with both GD and HT except a borderline association between rs3752411and GD after adjusted for age, sex, and thyroid function under the recessive model. Subgroup analysis demonstrated that the minor allele frequencies of rs2242526 and rs4417466 were higher in male AITD patients than in healthy volunteers before adjusted for confounding factors and the genotype distribution of rs4417466 was significantly different between the two groups. Additionally, the genotype frequencies of rs1139130, rs1263791, rs2242526, and rs4417466 were positively related with GD in male patients. Likewise, the allele distribution of rs1263791, rs2242526, and rs4417466 in male GD patients differed significantly from that in male controls. Multivariate logistic regression analyses revealed a significant association between allele frequencies of these three loci and GD in male patients after adjusted for the confounding factors. Moreover, the genotype of rs3752411 was strongly associated with GD in females as well. Furthermore, distribution of rs3752411 genotype was significantly associated with hypothyroidism in HT patients. Our study for the first time revealed a strong correlation between METTL3 mutations and AITD predisposition, implying that METTL3 may be a new candidate gene for AITD treatment.

Development of Autoimmune Thyroid Disease in Multiple Sclerosis Patients Post-Alemtuzumab Improves Treatment Response.

Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20% and 40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect. The objective of this work is to determine whether MS disease progression following alemtuzumab treatment differs in patients who develop AITD compared to those who do not. A retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 was conducted at a tertiary referral center. Thyroid status, new relapses, Expanded Disability Status Scale (EDSS) score change, and disability progression following alemtuzumab were evaluated. Twenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [interquartile range]; AITD: -0.25 [-1 to 0.5] vs non-AITD: 0 [1-0]. P = .007]. Multivariable regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (P = .011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (P = .023). There was no difference in the number of new focal T2 lesions and contrast-enhancing magnetic resonance imaging lesions developed following alemtuzumab between the 2 groups. Graves disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate.

Associations of Yersinia Enterocolitica Infection with Autoimmune Thyroid Diseases: A Systematic Review and Meta-Analysis.

Yersinia enterocolitica infection is reportedly associated with the development of autoimmune thyroid diseases (AITD). However, evidence that such infection can lead to AITD is controversial. Thus, this study was aimed to investigate the associations of Y. enterocolitica infection with AITD. A meta-analysis was performed using PubMed, Web of Science, Embase and Cochrane library to identify relevant studies. The odds ratios (OR) and associated 95% confidence intervals [CI] were obtained. Data were analyzed by STATA 13.0 (Stata Corporation, College Station, TX, USA). Of 215 articles identified, 8 studies with a total of 1490 participants met the criteria and were included in the meta-analysis. There was a significant association between Y. enterocolitica positivity and AITD (OR: 4.31 [CI 95%: 1.81-10.07], P-value: 0.00). According to the subgroup analysis, Y. enterocolitica infection statistically increased the risk of Graves' disease (GD) (OR: 6.12, [CI 95%: 3.71-10.10], P-value: 0.00). Likewise, the pooled OR of association between Y. enterocolitica positivity and hashimoto's thyroiditis (HT) was 2.84 (CI 95%: 0.71-11.25, P-value: 0.1). The current studies suggest that Y. enterocolitica may be associated with the development of AITD. Further study is needed to explore the underlying mechanisms.

The value of central regulators of the immune response in the development of autoimmune thyroid diseases

The specific relationship between the endocrine and immune systems is represented by a numerous number of factors and mechanisms that form the structure and ensure the function of each of the two systems. For example, immunocompetent cells can produce immunologically active substances, as well as some hormones. On the other hand, immune cells are available to the effects of endogenous hormones. Currently, the so-called cross-regulation of endocrine and immune mechanisms in an equilibrium of pro-and anti-inflammatory responses has not been sufficiently studied. Among other autoimmune lesions, autoimmune thyreopathy occupies a significant place. The development of an autoimmune lesion of the thyroid gland is a complex process, which is the result of the interaction of infiltrating lymphocyte and thyrocyte tissue that can express a wide range of molecules involved in the immune response. Immunological and immunogenetic factors play a major role in the pathogenesis of autoimmune thyroid diseases, such as autoimmune thyroiditis and Graves disease. Despite the fact that more than 100 years have passed since the first description of autoimmune thyroiditis and Graves disease has been known for many centuries, the mechanisms of these pathologies are still not fully understood.

Association of serum IL-21 and vitamin D concentrations in Chinese children with autoimmune thyroid disease

BackgroundThe etiology of Autoimmune thyroid disease (AITD) in pediatric age is multifactorial and mainly implicated with immune disorder. Previous studies have reported that interleukin-21 (IL-21) and vitamin D play crucial roles in autoimmune diseases. We investigated the correlation between IL and 21 and 25(OH)D and their potential role in the pathogenesis of AITD. MethodsTotal of 54 primary Graves disease (GD) patients, 36 Hashimato's thyroditis (HT) cases and 30 healthy subjects from The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University from September through November 2017 to 2019. The serum concentrations of IL-21, 25(OH)D, thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), antibodies against receptor for TSH (TRAb) and thyroglobulin antibody (TGAb) were determined. ResultsThe serum concentration of 25(OH)D was lower while IL-21 was higher in the GD patients and HT patients than in the control patients. Serum 25(OH)D concentration was negatively correlated with TPOAb and TGAb while serum IL-21 concentration was positively correlated with TPOAb, TGAb and TRAb in the HT group. Moreover, the serum concentration of 25(OH)D had a significant negative correlation with serum IL-21 concentration in the HT and GD children before or after treatment. Therefore, we studied the correlation between IL and 21 and 25(OH)D, and infer that they play a role in AITD. Moreover, adding Vitamin D could inhibit the expression concentrations of TPOAb, TGAb and IL-21. ConclusionIL-21 and Vitamin D may be involved in the occurrence and development of AITD. Targeting IL-21 and Vitamin D may be a promising therapeutic approach for AITD in the future.

Oxidative stress and its role in the development of autoimmune thyroid diseases

A large number of socially significant diseases is accompanied with oxidative stress and carry with tissue damage. Free radicals play a crucial role in the development of these diseases. Similar processes occur under the influence of ionizing radiation and bacterial infections. Recently, was indicated the significant role of oxidative stress in the development of autoimmune thyroiditis. It is assumed that the synthesis of thyroid hormones depends on the concentration of H2O2, which, due to its high toxicity, must be in strict accordance with the activity of antioxidant systems. Many biochemically negative processes occur on the apical membrane of the thyrocyte, which allows limiting the effect of free radicals and avoid cell destruction. However, in pathological conditions, enzymatic systems are disturbed and their components become abnormally activated in the cytoplasm, and it is leads to functional and morphological disorders. A deeper understanding of oxidative stress and its role in the development of autoimmune thyroiditis can contribute to the identification of new methods for its assessment, the expansion of therapeutic ranges for this disease. This review discusses oxidative stress, which is the accumulation of active damaging agents (free radicals, prooxidants, reactive oxygen species) that initiate cell damage and lead to the development of various pathological conditions.

Association of cytokine Th2 gene polymorphisms with autoimmune thyroid diseases in Tunisian population.

Autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases. Th2 cytokines act on the development of AITD. This study was conducted on Tunisian patients with AITD to investigate the association of Th2 cytokine gene polymorphisms and haplotype combination with GD or HT risk. A total of 156 controls, 160 patients with HT and 88 patients with GD were genotyped for IL-4 rs2243250, IL-5 rs2069812, IL-6 rs1800796 and IL-13 rs1800925 polymorphisms by PCR-RFLP. The AITD risk was assessed by a logistic regression analysis using the SNP stats statistical program. False-positive report probability (FPRP) was estimated to evaluate significant findings. IL-13 rs1800925 was associated with GD, after adjustment for age and gender, in codominant, dominant and allele genetic models (p=.0072; p=.0018; p=.012, respectively). Significant association of the IL-6 rs1800796C/G genotype with GD was also detected (p=.025). Furthermore, increased risk of HT was still found for IL-13 rs1800925T allele (p=.039, OR=1.39) and for IL-4 rs2243250T/T genotype both in codominant (p=.033, OR=2.59) and recessive (p=.011, OR=2.73) models after adjustment for age and gender. Interestingly, haplotype analysis performed on the IL-4, IL-5 and IL-13 genes revealed a high risk of HT with CTT haplotype (p=.008, OR=2.12). However, the CCT haplotype is a protective factor (OR=0.36). Patients carrying the CT haplotype with only one minor allele had a moderate risk of HT (OR=1.56). The FPRP analysis showed that the association of IL-13 rs1800925 polymorphism with GD and HT and the association of CTT haplotype with HT were noteworthy. In conclusion, the IL-4, IL-5, IL-6 and IL-13 polymorphism may play a role in susceptibility to GD and HT in the Tunisian population. Furthermore, gene-gene interaction between the IL-4, IL-5 and IL-13 significantly increases the risk of AITD. Further studies with larger numbers of individuals are needed to confirm the results.

Anti-tumour necrosis factor α therapy - Does it increase the risk of thyroid disease or protect against its development?

Tumour necrosis factor α (TNF-α) is a cytokine involved in the pathogenesis of many diseases, primarily those associated with auto-immunisation. Anti-TNF-α drugs are used in the therapy of many of them, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis, or inflammatory bowel disease. TNF-α is also a key factor in the pathogenesis of autoimmune thyroid disease (AITD). The incidence of AITD in people with other autoimmune diseases is increased compared to the general population. Therefore, it would be interesting to find out if anti-TNF-α therapy of other autoimmune diseases could influence the possible development or re-gression of thyroid gland dysfunction, especially AITD. The main aim of the study is to assess the effect of anti-TNF-α therapy used in inflammatory and immunological diseases on thyroid function and the development of AITD. The real impact of anti-TNF-α therapy on the development of AITD remains an open question. The available studies concern the adult population; there are no data regarding this problem in children. Due to the increasing use of anti-TNF-α therapy also in the paediatric population, it seems reasonable to evaluate this subject in this group of patients.

Lower proportion of CD19+IL-10+ and CD19+CD24+CD27+ but not CD1d+CD5+CD19+CD24+CD27+ IL-10+ B cells in children with autoimmune thyroid diseases

Introduction: As it is generally known, regulatory B cells (Bregs) control inflammation and autoimmunity. The significance of Bregs in the population of children with autoimmune thyroid diseases (AITD) still offers plenty of potential to explore. The aim of this study was to estimate the expression of Bregs (phenotype CD19+CD24+CD27+IL-10+, CD19+IL-10+, CD1d+CD5+CD19+IL-10+ and CD1d+CD5+CD19+CD24+CD27+) in a paediatric cohort with AITD and in health controls.Materials and methods: A total of 100 blood samples were obtained from 53 paediatric patients with Graves’ disease (GD) (N = 12 newly diagnosed, mean age 12.5 ± 3.5 and N = 17 during methimazole therapy, mean age 12.7 ± 4.4), Hashimoto’s thyroiditis (HT) (N = 10 newly diagnosed, mean age 13.3 ± 2.9 and N = 10 during L-thyroxine therapy, mean age 13.7 ± 3.4) and compared with healthy controls (C) (N = 15, mean age 13.1 ± 3.1). The expressions of the immune cell populations were analysed by four-color flow cytometry using a FASC Canto II cytometer (BD Biosciences).Results: There was a decreasing tendency in the number of lymphocytes B producing IL-10 (B10) cells among all B lymphocytes and more widely, also among all lymphocytes, in each study group, as compared to C. We reported a reduction in IL-10 production in Bregs with the expression of CD19+CD24+CD27+IL-10 and CD1d+CD5+CD19+IL-10+ in both untreated and treated AITD.Conclusions: Our data demonstrate that the reduction in the number of Bregs with CD19+CD24+CD27+IL-10+ and CD19+IL-10+ expression could be responsible for breaking immune tolerance and for AITD development in children.

Uterus globulin associated protein 1 (UGRP1) is a potential marker of progression of Graves' disease into hypothyroidism

Approximately 20% of Graves' disease (GD) patients may result eventually in hypothyroidism in their natural course. Uterus globulin-associated protein 1 (UGRP1) was associated with GD in our previous study. Here we investigated the role of UGRP1 in the development of autoimmune thyroid disease (AITD). The results showed that UGRP1 was expressed in the thyrocytes of most Hashimoto's thyroiditis (HT) patients and a proportion of GD patients (293 HT and 198 GD). The pathologic features of UGRP1-positive thyrocytes resembled “Hürthle cells”, and were surrounded by infiltrated leukocytes. The positivity rate of TPOAb in UGRP1-positive GD patients was much higher than that in -negative GD patients. Moreover, UGRP1 was co-expressed with Fas and HLA-DR in the thyrocytes of AITD patients. We also found IL-1β but not Th1 or Th2 cytokines was able to upregulate the expression of UGRP1. Our findings indicated that UGRP1 may be a novel marker in thyrocytes to predict GD patients who develop hypothyroidism.

HLA alleles, especially amino-acid signatures of HLA-DPB1, might contribute to the molecular pathogenesis of early-onset autoimmune thyroid disease.

The major histocompatibility complex region has been suggested to play an important role in the development of autoimmune thyroid disease (AITD). In this study, we investigated the associations of human leukocyte antigen (HLA) alleles and amino acid variants of HLA with early-onset AITD. HLA class I and class II genes were analyzed in 116 Korean children with AITDs (Graves’ disease [GD]: 71, Hashimoto’s disease [HD]: 45) and 142 healthy controls. HLA-B*46:01 (OR = 3.96, Pc = 0.008), -C*01:02 (OR = 2.51 Pc = 0.04), -DPB1*02:02 (OR = 3.99, Pc = 0.04), and -DPB1*05:01 (OR = 4.6, Pc = 0.003) were significantly associated with GD, and HLA-A*02:07 (OR = 4.68, Pc = 0.045) and -DPB1*02:02 (OR = 6.57, Pc = 0.0001) with HD. The frequency of HLA-DPB1*05:01 was significantly higher in GD patients than in HD patients (Pc = 0.0005). Furthermore, differences were found between patients with Thyroid associated ophthalmopathy (TAO) and those without TAO in the distribution of HLA-B*54:01 (8.6% vs. 30.6%, P = 0.04) and -C*03:03 (37.1% vs. 11.1%, P = 0.02). In the analysis of amino acid variants of HLA molecules, both Leu35 (OR = 23.38, P = 0.0002) and Glu55 (OR = 23.38, P = 0.0002) of HLA-DPB1 were strongly associated with GD and showed different distributions between GD and HD (P = 0.001). Our results suggest that HLA alleles, especially amino-acid signatures of the HLA-DP β chain, might contribute to the molecular pathogenesis of early-onset AITD.

Elevated thyroglobulin level is associated with dysfunction of regulatory T cells in patients with thyroid nodules.

ObjectiveThyroid nodules are usually accompanied by elevated thyroglobulin (Tg) level and autoimmune thyroid diseases (AITDs). However, the relationship between Tg and AITDs is not fully understood. Dysfunction of regulatory T cells (Tregs) plays an important role in the development of AITDs. We aimed to evaluate the effects of Tg on the function of Tregs in patients with thyroid nodules.MethodsTg levels and the functions of Tregs in peripheral blood and thyroid tissues of patients with thyroid nodules from Nanjing First Hospital were evaluated. The effects of Tg on the function of Tregs from healthy donors were also assessed in vitro. The function of Tregs was defined as an inhibitory effect of Tregs on the effector T cell (CD4+ CD25− T cell) proliferation rate.ResultsThe level of Tg in peripheral blood correlated negatively with the inhibitory function of Tregs (R = 0.398, P = 0.03), and Tregs function declined significantly in the high Tg group (Tg >77 μg/L) compared with the normal Tg group (11.4 ± 3.9% vs 27.5 ± 3.5%, P < 0.05). Compared with peripheral blood, the function of Tregs in thyroid declined significantly (P < 0.01), but the proportion of FOXP3+ Tregs in thyroid increased (P < 0.01). High concentration of Tg (100 μg/mL) inhibited the function of Tregs and downregulated FOXP3, TGF-β and IL-10 mRNA expression in Tregs in vitro.ConclusionsElevated Tg level could impair the function of Tregs, which might increase the risk of AITDs in patient with thyroid nodules.