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Defect of a subpopulation of natural killer immune cells in Graves’ disease and Hashimoto’s thyroiditis: normalizing effect of dehydroepiandrosterone sulfate

¹ Department of Internal Medicine, Geriatrics and Gerontologic Clinic and School of Endocrinology and Metabolism, University of Pavia, Via Emilio 12, 27100 Pavia, Italy, ² IRCCS Salvatore Maugeri Foundation, Internal Medicine Unit and ³ Division of Geriatrics, University of Verona, Verona, Italy and ⁴ ASPS Margherita Geriatric Department, Pavia, Italy

(Correspondence should be addressed to B Solerte; Email: bruno.solerte{at}unipv.it)

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.

Design: 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 7.75 x 10⁶ 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-ß (IFN-ß) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor- (TNF-) from NK cells.

Results: Lower spontaneous, IL-2- and IFN-ß-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- 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-ß + DHEAS at different molar concentrations (from 10^–8 to 10^–5 M/ml/NK cells) promptly normalized NKCC and TNF- 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.