title: Defect of a subpopulation of natural killer immune cells in Graves' disease and Hashimoto's thyroiditis: normalizing effect of dehydroepiandrosterone sulfate.
abstract: BACKGROUND
  The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves' disease (GD) and Hashimoto's thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases.
  
  
  OBJECTIVE
  Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect.
  
  
  METHODS
  We studied 13 patients with recent onset Graves' disease, 11 patients with Hashimoto's thyroiditis at first diagnosis and 15 age-matched healthy subjects.
  
  
  METHODS
  NK cells were concentrated at a density of 7.75x10(6) cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16+/CD56+cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-beta (IFN-beta) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-alpha (TNF-alpha) from NK cells.
  
  
  RESULTS
  Lower spontaneous, IL-2- and IFN-beta-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P<0.001). A decrease in spontaneous and IL-2-modulated TNF-alpha release from NK cells was also found in both groups of patients (P<0.001). The co-incubation of NK cells with IL-2/IFN-beta+DHEAS at different molar concentrations (from 10(-8) to 10(-5) M/ml/NK cells) promptly normalized NKCC and TNF-alpha secretion in GD and HT patients.
  
  
  CONCLUSIONS
  A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.
authors.affiliation: Department of Internal Medicine, Geriatrics and Gerontologic Clinic and School of Endocrinology and Metabolism, University of Pavia, Via Emilio 12, 27100 Pavia, Italy. bruno.solerte@unipv.it
authors.forename: Sebastiano Bruno
authors.initials: SB
authors.lastname: Solerte
authors.forename: Sara
authors.initials: S
authors.lastname: Precerutti
authors.forename: Carmine
authors.initials: C
authors.lastname: Gazzaruso
authors.forename: Eleonora
authors.initials: E
authors.lastname: Locatelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Zamboni
authors.forename: Nicola
authors.initials: N
authors.lastname: Schifino
authors.forename: Roberto
authors.initials: R
authors.lastname: Bonacasa
authors.forename: Mariangela
authors.initials: M
authors.lastname: Rondanelli
authors.forename: Davide
authors.initials: D
authors.lastname: Taccani
authors.forename: Ettore
authors.initials: E
authors.lastname: Ferrari
authors.forename: Marisa
authors.initials: M
authors.lastname: Fioravanti
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D013967:Thyroiditis, Autoimmune / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D019314:Dehydroepiandrosterone Sulfate; D016899:Interferon-beta