Signal transducer and activator of transcription (Stat)-6-dependent, but not Stat4-dependent, immunity is required for the development of autoimmunity in Graves' hyperthyroidism

Endocrinology. 2004 Aug;145(8):3724-30. doi: 10.1210/en.2004-0352. Epub 2004 Apr 29.


The role of T helper (Th) cells in experimental models of Graves' hyperthyroidism is still somewhat controversial. To further investigate the role of Th1- and Th2-dependent immunity during the development of Graves' hyperthyroidism, we tested mice with targeted deletion of signal transducer and activator of transcription-4 (Stat4) or Stat6 genes that, respectively, have impaired Th1 and Th2 immunity. We immunized wild-type BALB/c, Stat4(-/-), or Stat6(-/-) mice with human embryonic kidney cells (293 cells) expressing the extracellular domain of human TSH receptor (293-TBP cells). Fifty percent of wild-type BALB/c and Stat4(-/-) mice developed Graves' hyperthyroidism with elevated serum T(4) levels and thyroid stimulatory antibodies. In contrast, Stat6(-/-) mice resisted development of the disease. Stat4(-/-) mice exhibited a dominant Th2 immune response characterized by the production of IL-4 and IgG1 anti-TSH receptor antibodies. However, Stat6(-/-) mice displayed a strong Th1 immune response characterized by the production of interferon-gamma and IgG2a antibodies. Hyperthyroid mice showed enlargement of thyroid glands with hypertrophy and decreased amounts of colloid material, all characteristics of Graves' disease. These data demonstrate that in this model, Stat6-dependent Th2 immunity is critical for the development of Graves' hyperthyroidism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoimmunity*
  • DNA-Binding Proteins / physiology*
  • Female
  • Graves Disease / etiology
  • Graves Disease / immunology*
  • Immunoglobulin G / blood
  • Interferon-gamma / physiology
  • Interleukin-4 / biosynthesis
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Thyrotropin / immunology
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Thyroxine / blood
  • Trans-Activators / physiology*


  • DNA-Binding Proteins
  • Immunoglobulin G
  • Receptors, Thyrotropin
  • STAT4 Transcription Factor
  • STAT6 Transcription Factor
  • Stat4 protein, mouse
  • Stat6 protein, mouse
  • Trans-Activators
  • Interleukin-4
  • Interferon-gamma
  • Thyroxine