Regulatory B and T Cell Responses in Patients With Autoimmune Thyroid Disease and Healthy Controls

Dan Med J. 2016 Feb;63(2):B5177.

Abstract

Autoimmune diseases occur due to faulty self-tolerance. Graves' disease (GD) and Hashimoto's thyroiditis (HT) are classic examples of organ-specific autoimmune diseases. GD is an auto-antibody-mediated disease where autoantibodies are produced against the thyroid stimulating hormone receptor (TSHR). HT is primarily a T-cell mediated disease, and whether B cells play a pathogenic role in the pathogenesis is still unclear. Both GD and HT are characterized by infiltration of the thyroid gland by self-reactive T cells and B cells. In the first paper of this thesis, the role of regulatory B cells (Bregs) and regulatory T cells (Tregs) were investigated in the context of GD and HT. First, we studied the role of the thyroid self-antigen, thyroglobulin (TG) in healthy donors. The self-antigen TG, but not the foreign recall antigen tetanus toxoid (TT), was able to induce interleukin 10 (IL-10) secretion by B cells and CD4+ T cells. These IL-10 producing B cells (B10 cells) from healthy donors were enriched with the CD5+ and CD24hi phenotype. In addition, TG was able to induce IL-6 production by B cells. In contrast, TT induced production of Th1-type pro-inflammatory cytokines including interferon-gamma (IFN-γ) and IL-2. In the second paper, the frequency and phenotype of B10 was investigated in healthy donors and patients with GD or HT. The frequencies of B10 cells were similar in the three groups, irrespective of whether IL-10 was induced by a combination of phorbol 12-myristate 13-acetate (PMA) and ionomycin, by CpG oligodeoxynucletodies (ODN) 2006, or by TG. Several phenotypes have been associated with B10 cells such as CD5+, CD25+, TIM-1+, CD24hiCD38hi and CD27+CD43+. We found that larger proportions of B10 cells in patients with GD or HT were CD25+ and TIM-1+ than B10 cells in healthy donors. In healthy donors, B10 cells were CD24hiCD38-, whereas for HT patients these cells were primarily CD24intCD38int. For GD patients, we found lower proportions of B10 cells within the CD27+CD43- and CD27-CD43- fractions than for healthy donors. Our data show that GD and HT are not associated with decreased frequencies of B10 cells. Accordingly, B10 cells may not be confined to one phenotype or subset of B cells. In the third paper, we studied the balance between IL-17-producing CD4+ T cells (Th17 cells) and IL-10-producing CD4+ T cells (Th10 cells) in healthy donors and patients with GD or HT. In HT patients, we found increased proportions of naïve Th17 cells after stimulation with the thyroid self-antigen thyroid peroxidase (TPO) and the Escherichia coli lipopolysaccharide (E. coli LPS). The proportions of Th10 cells were similar in healthy donors and in HT patients after antigen-specific stimulation. After TG stimulation, an increased Th17:Th10 ratio was found in HT patients within the naïve T cell compartment. Taken together, these data indicate that the thyroid self-antigens TG and TPO induced a skewed Th17:Th10 differentiation in HT patients. IL-6 and TGF-β have been reported to be important for human Th17 differentiation and, accordingly, HT patients showed higher baseline production of IL-6 and TGF-β1 than healthy donors. Moreover, the baseline expression of mRNA encoding the transcription factor Forkhead box protein 3 (FOXP3) was similar in HT patients and healthy donors, but HT patients displayed higher constitutive expression of the splice variant FOXP3Δ2, lacking exon 2, than healthy donors. Full-length FOXP3 has been shown to inhibit Th17 differentiation, while FOXP3Δ2 does not. Thus, increased IL-6 and TGF-β1 in the microenvironment and the increased expression of FOXP3Δ2 may contribute to the skewing of Th17 cells in HT patients. In conclusion, the human thyroid self-antigen TG is able to induce antigen-specific production of IL-10 in CD19+ B cells and CD4+ T cells among healthy donors and patients with GD or HT. Our data indicates that patients with GD or HT were not impaired in producing IL-10 and thus an immunoregulatory response. Additionally, TPO, a thyroid self-antigen, induced a higher frequency of Th17 cells in HT. This indicates that Th17 cells may play an important role in HT pathogenesis.

Publication types

  • Review

MeSH terms

  • Autoantibodies / blood
  • Autoantigens / immunology
  • B-Lymphocytes, Regulatory / immunology*
  • Case-Control Studies
  • Cell Differentiation
  • Graves Disease / immunology*
  • Hashimoto Disease / immunology*
  • Humans
  • Interleukin-10 / metabolism
  • Receptors, Thyrotropin / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology
  • Thyroglobulin / immunology

Substances

  • Autoantibodies
  • Autoantigens
  • Receptors, Thyrotropin
  • Interleukin-10
  • Thyroglobulin