title: Relative levels of the inflammatory cytokine TNFα and the soluble CD40 ligand profile in serum correlate with the thyrotoxic activity of Graves' disease.
abstract: BACKGROUND
  Interactions between CD40 and its ligand (CD40L) have important roles in T-cell-dependent activation of B cells, which may be related to the thyrotoxic activity of Graves' disease (GD). Soluble forms of CD40 ligand (sCD40L) are released from activated T cells and platelets, and several types of inflammatory cytokines are increased in patients with hyperthyroid GD. The aim of this study was to assess sCD40L and other cytokines as clinical indicators of disease activity or as possible markers of remission in GD.
  
  
  METHODS
  Serum levels of sCD40L, interleukin 18 (IL-18), tumor necrosis factor-alpha (TNFα), and TNFα receptors 1 and 2 (TNFR1 and TNFR2) were investigated in patients with active GD (GD-A), intractable GD (GD-IT), inactive GD (GD-IA), GD in remission (GD-R), and Hashimoto's thyroiditis (HT), and in control subjects (CON).
  
  
  RESULTS
  Serum concentrations of sCD40L were higher in the GD-A and GD-IT groups than in the HT and CON groups. Similarly, serum concentrations of IL-18, which induces Th1 cytokines, such as interferon-γ, were higher in the GD-A and GD-IT groups than in all other groups. Serum levels of TNFR1 and TNFR2 were also significantly higher in the GD-A than in all other groups. The mean serum concentration of TNFα was higher in the GD-R compared with the GD-A and GD-IT groups, although the difference was not significant. Serum sCD40L concentrations in the GD-R group were lower than in the GD-A and GD-IT groups. Finally, the ratio of serum TNFα to sCD40L was higher in the GD-R group than in the GD-A and GD-IT groups. This is the first report that serum sCD40L is increased in active GD, and that the serum TNFα:sCD40L ratio is a marker for remission in GD.
  
  
  CONCLUSIONS
  Our results suggest that not only thyrotoxicosis, but also the activity of the immunoreaction presenting as anti-thyrotropin receptor antibodies (TRAb) titer in GD, affects inflammatory cytokine serum profiles. Serum profiles of cytokines vary in patients with GD depending on disease activity. An elevated serum TNFα:sCD40L ratio indicates declining disease activity and reflects a shift from Th2 to Th1 dominance, suggesting that suppression of sCD40L or increased production of TNFα is required to initiate or maintain remission of GD.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Itoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okamura
authors.forename: Maiko
authors.initials: M
authors.lastname: Kimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshino
authors.forename: Masaki
authors.initials: M
authors.lastname: Makino
authors.forename: Nobuki
authors.initials: N
authors.lastname: Hayakawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000166:cytology; D023201:CD40 Ligand / Q000097:blood* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006111:Graves Disease / Q000097:blood* / Q000276:immunology; D006801:Humans; D007249:Inflammation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013601:T-Lymphocytes / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand