title: Altered balance between self-reactive T helper (Th)17 cells and Th10 cells and between full-length forkhead box protein 3 (FoxP3) and FoxP3 splice variants in Hashimoto's thyroiditis.
abstract: T helper type 17 (Th17) cells play a pathogenic role in autoimmune disease, while interleukin (IL)-10-producing Th10 cells serve a protective role. The balance between the two subsets is regulated by the local cytokine milieu and by the relative expression of intact forkhead box protein 3 (FoxP3) compared to FoxP3Δ2, missing exon 2. Th17 and Th10 cell differentiation has usually been studied using polyclonal stimuli, and little is known about the ability of physiologically relevant self-antigens to induce Th17 or Th10 cell differentiation in autoimmune thyroid disease. We subjected mononuclear cells from healthy donors and patients with Hashimoto's thyroiditis (HT) or Graves' disease (GD) to polyclonal stimulation, or stimulation with human thyroglobulin (TG), human thyroid peroxidase (TPO), or Esherichia coli lipopolysaccharide (LPS). TPO and LPS induced increased differentiation of naive CD4(+) CD45RA(+) CD45R0(-) T cells from HT patients into Th17 cells. Th10 cell proportions were decreased in HT after polyclonal stimulation, but were comparable to those of healthy donors after antigen-specific stimulation. Taken together, our data show that an increased Th17 : Th10 ratio was found in HT patients after stimulation with thyroid-specific self-antigens. We also observed an elevated baseline production of IL-6 and transforming growth factor (TGF)-β1 and of mRNA encoding FoxP3Δ2 rather than intact FoxP3. This may contribute to the skewing towards Th17 cell responses in HT.
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Kristensen
authors.forename: L
authors.initials: L
authors.lastname: Hegedüs
authors.forename: H O
authors.initials: HO
authors.lastname: Madsen
authors.forename: T J
authors.initials: TJ
authors.lastname: Smith
authors.forename: C H
authors.initials: CH
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000187:drug effects / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D004926:Escherichia coli / Q000737:chemistry; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006111:Graves Disease / Q000276:immunology* / Q000473:pathology; D050031:Hashimoto Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007453:Iodide Peroxidase / Q000276:immunology / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D013954:Thyroglobulin / Q000276:immunology / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: D015703:Antigens, CD; D001324:Autoantigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D033862:Iron-Binding Proteins; D008070:Lipopolysaccharides; D020033:Protein Isoforms; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D013954:Thyroglobulin; C056658:TPO protein, human; D007453:Iodide Peroxidase
keywords: Graves' disease; Hashimoto's thyroiditis; Th17 cells; interleukins; regulatory T cells