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Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis.

ABSTRACT: A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10+ B-cell differentiation in GD. A similar tendency was observed in healthy donors, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4+ T cells. To assess the maximal frequency of inducible IL-10+ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10+ B-cell frequency was similar in the three groups and correlated with free T3 levels in GD patients. IL-10+ B cells from both patient groups displayed CD25 or TIM-1 more frequently than did those from healthy donors. B-cell expression of two surface marker combinations previously associated with regulatory B-cell functions, CD24hiCD38hi and CD27+CD43+, did not differ between patients and healthy donors. In conclusion, our findings indicate that autoimmune thyroiditis is not associated with reduced frequency of IL-10+ B cells. These results do not rule out regulatory B-cell dysfunction, however. The observed phenotypic differences between IL-10+ B cells from patients and healthy donors are discussed.

SUBMITTER: Kristensen B

PROVIDER: S-EPMC4446335 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis.

Kristensen Birte B Hegedüs Laszlo L Lundy Steven K SK Brimnes Marie K MK Smith Terry J TJ Nielsen Claus H CH

PloS one 20150527 5

A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10+ B cells. Little is known about the ability of self-antigens to induce IL-10+ B cells in Graves' disease (GD), Hashimoto's thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure ...[more]

PMID: 26016954

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Project description:ObjectiveAutoimmune thyroid diseases (AITD), mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common organ-specific autoimmune diseases characterized by circulating antibodies and lymphocyte infiltration. Follicular helper T (Tfh) cell dysregulation is involved in the development of autoimmune pathologies. We aimed to explore the role of intrathyroidal and circulating Tfh cells in patients with GD and HT.MethodsUltrasound-guided thyroid fine-needle aspiration (FNA) was conducted in 35 patients with GD, 40 patients with HT, and 22 patients with nonautoimmune thyroid disease (nAITD). Peripheral blood samples were also obtained from 40 patients with GD, 40 patients with HT, and 40 healthy controls. The frequencies of intrathyroidal and circulating Tfh cells from FNA and peripheral blood samples were assessed by flow cytometry. Additionally, the correlations between the frequencies of the Tfh cells and the levels of autoantibodies and hormones or disease duration were analyzed.ResultsThe frequency of intrathyroidal CD4+CXCR5+ICOShigh Tfh cells was higher in HT patients than in GD patients. Significant correlations were identified between the percentages of circulating and intrathyroidal Tfh cells and the serum concentrations of thyroid autoantibodies, especially thyroglobulin antibodies (TgAb), in AITD. Intrathyroidal CD4+CXCR5+ICOShigh Tfh cells were positively correlated with free triiodothyronine (FT3) in HT patients but negatively correlated with FT3 in GD patients. In addition, HT patients with a longer disease duration had an increased frequency of intrathyroidal CD4+CXCR5+ICOShigh and CD4+CXCR5+PD-1+ Tfh cells. In contrast, in the GD patients, a longer disease duration did not affect the frequency of intrathyroidal CD4+CXCR5+ICOShigh but was associated with a lower frequency of CD4+CXCR5+PD-1+ Tfh cells.ConclusionsOur data suggest that intrathyroidal Tfh cells might play a role in the pathogenesis of AITD and they are potential immunobiomarkers for AITD.

Project description:BackgroundThree genes have been confirmed as major joint susceptibility genes for endocrine autoimmune disease:human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 and protein tyrosine phosphatase non-receptor type 22. Recent studies showed that a genetic variation within the interferon induced helicase domain 1 (IFIH1) locus (rs1990760 polymorphism) is an additional risk factor in type 1 diabetes and Graves' disease (GD).MethodsThe aim of the present study was to investigate the role of the rs1990760 polymorphism within the IFIH1 gene in German patients with GD (n = 258), Hashimoto's thyroiditis (HT, n = 106), Addison's disease (AD, n = 195) and healthy controls (HC, n = 227) as well as in 55 GD families (165 individuals, German) and 100 HT families (300 individuals, Italian). Furthermore, the interaction between rs1990760 polymorphism with human leukocyte antigen (HLA) risk haplotype DQ2(DQA*0501-DQB*0201), the risk haplotypes DQ2/DQ8 (DQA*0301-DQB*0302) and the status of thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb) and TSH receptor antibody (TRAb) in patients and families were analysed.ResultsNo significant differences were found between the allele and genotype frequencies for rs1990760 IFIH1 polymorphism in patients with GD, HT, AD and HC. Also no differences were observed when stratifying the IFIH1 rs1990760 polymorphism for gender, presence or absence of thyroid antibodies (GD:TRAb and HT:TPOAb/TgAb) and HLA risk haplotypes (DQ2:for GD and HT, DQ2/DQ8:for AD). Furthermore the transmission analysis in GD and HT families revealed no differences in alleles transmission for rs1990760 IFIH1 from parents with or without HLA risk haplotype DQ2 to the affected offspring. In contrast, by dividing the HT parents according to the presence or absence of thyroid Ab titers, mothers and fathers both positive for TPOAb/TgAb overtransmitted the allele A of IFIH1 rs1990760 to their HT affected offspring (61.8% vs 38.2%;p = 0.05;corrected p [pc] = 0.1). However, these associations did not remain statistically significant after correction of the p-values.ConclusionIn conclusion, our data suggest, no contribution from IFIH1 rs1990760 polymorphism to the pathogenesis of either Graves' disease, Hashimoto's thyroiditis or Addison's disease in our study populations. However, in order to exclude a possible influence of the studied polymorphism in specified subgroups within patients with autoimmune thyroid disease, further investigations in larger populations are needed.

Project description:BackgroundProgrammed cell death-ligand 1 (PD-L1) has an important role in regulating immune reactions by binding to programmed death 1 (PD-1) on immune cells, which could prevent the exacerbation of autoimmune thyroid disease (AITD). The aim of this study was to evaluate the association of PD-L1 polymorphism with AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT).MethodsA total of 189 GD patients, 234 HT patients, and 846 healthy age- and sex-matched controls were enrolled in this study. We analyzed PD-L1 single nucleotide polymorphism (SNP) (rs822339) and investigated the associations with clinical disease course and outcome.ResultsGenotype frequency at the PD-L1 marker RS822339 in GD (P=0.219) and HT (P=0.764) patients did not differ from that among healthy controls. In patients with GD, the A/G or G/G genotype group demonstrated higher TBII titer (20.6±20.5 vs. 28.0± 25.8, P=0.044) and longer treatment duration (39.0±40.4 months vs. 62.4±65.0 months, P=0.003) compared to the A/A genotype group. Among patients in whom anti-thyroid peroxidase (TPO) antibody was measured after treatment of GD, post-treatment antiTPO positivity was higher in the A/G or G/G genotype group compared to the A/A genotype group (48.1% vs. 69.9%, P=0.045). Among patients with HT, there was no significant difference of anti-TPO antibody positivity (79.4% vs. 68.6%, P=0.121), anti-thyroglobulin antibody positivity (80.9% vs. 84.7%, P=0.661), or development to overt hypothyroidism (68.0% vs. 71.1%, P=0.632) between the A/A genotype group and the A/G or G/G genotype group.ConclusionThe genotype frequency of PD-L1 (rs822339) is not different in patients with AITD compared with healthy controls. The intact PD-1/PD-L1 pathway in GD and HT might be important to maintain chronicity of AITD by protecting immune tolerance. However, the PD-L1 SNP could be associated with difficulty in achieving remission in patients with GD, which may be helpful to predict the possibility of longer treatment. Further studies are required to investigate the complex immune tolerance system in patients with AITD.

Project description:BACKGROUND:The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703. METHODS:High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM. RESULTS:DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008. CONCLUSION:Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

Project description:Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disorder that frequently evolves from asymptomatic, T-cell mediated chronic inflammation toward overt hypothyroidism. Previously, we have demonstrated a role for T-bet, a T helper 1/CD8+ T cell transcription factor (TF), and FoxP3, a regulatory T cell TF, in disease progression and severity, but the basis behind their altered mRNA expression remains unknown. In this study, we aimed to leverage the role for microRNAs, representing negative transcriptional regulators, across the spectrum of HT clinical presentations using the same, well-characterized RNA sample cohort.Ten hypothyroid, untreated patients (hypoHT), 10 hypothyroid cases rendered euthyroid by l-thyroxine therapy (substHT), 11 spontaneously euthyroid HT subjects (euHT), and 10 healthy controls (ctrl) were probed for three candidate immunoregulatory miRNA (miR-9-5p, miR-29a-3p, and miR-210-3p) using quantitative real-time PCR measurements. Data were normalized to U6snRNA and fold difference in expression calculated by the efficiency corrected 2-??Ct model.Compared to healthy controls, peripheral blood (PB) T cells of HT patients exhibited significantly diminished miR-29a-3p expression levels [median expression levels (IQR), HT vs CTRL, 0.62 (0.44-1.01) vs 1.373 (0.63-2.7), P?=?0.046], and a similar, but not significant decline in miR-210-3p abundance [HT vs CTRL, 0.64 (0.39-1.31) vs 1.2 (0.5-2.56), P?=?0.24, Wilcoxon test]. A significant inverse correlation was observed between the two differentially expressed transcripts, T-bet mRNA and miR-29a-3p. Moreover, altered miR-29a-3p/T-bet expression in T cells of untreated HT patients was related to low serum FT4, high serum thyrotropin, and decreased thyroid volumes. Of note, miR-210-3p expression was positively correlated to HIF1?, and inversely to FoxP3 mRNA levels, but no evidence of differential expression for any of these miRNA-mRNA pairs was observed. Finally, miR-9-5p expression levels were no different in HT vs control comparisons, or related to clinicopathological features.T cell miR-29a-3p is downregulated in HT patients and associated with clinical and biochemical parameters of progressive thyroid injury, plausibly subsequent to altered control of T-bet expression in PB T cells. As such miR-29a-3p/T-bet axis should be further explored as a biomarker or as a plausible target for therapeutic interventions in HT.

Dataset Information

Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis.

Publications

Characterization of Regulatory B Cells in Graves' Disease and Hashimoto's Thyroiditis.

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