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Impaired Caspase-3 Expression by Peripheral T Cells in Chronic Autoimmune Thyroiditis and in Autoimmune Polyendocrine Syndrome-2

Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry (F.V., V.Te., F.D.), University of Siena, 53100 Siena, Italy; Departments of Pediatrics (M.S.) and Clinical Sciences-Endocrinology (D.G., V.Tr.), University La Sapienza, 00161 Rome, Italy; and Unit of Endocrinology (G.A., V.Tr., M.T.), Scientific Institute Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy

Address all correspondence and requests for reprints to: Francesco Dotta, M.D., Unità Operativa di Diabetologia, 3 Lotto 5S, Policlinico Le Scotte, Viale Bracci 18, 53100 Siena, Italy. E-mail: fradotta{at}tin.it.

Context: Activation-induced cell death (AICD) is a major mechanism in the regulation of peripheral tolerance, and caspase-3 represents its major executioner. AICD impairment contributes to the persistence of autoreactive T cells, and defective AICD has been reported in autoimmune thyroiditis as well as in type 1 diabetes mellitus.

Objective: The objective of this study was to evaluate the involvement of caspase-3 in the regulation of AICD resistance in thyroid and polyendocrine autoimmunity.

Design/Settings/Patients/Intervention: Caspase-3 expression was analyzed in peripheral blood lymphocytes from 26 adults (A-AT) and 25 children (Y-AT) affected by autoimmune thyroiditis and 13 individuals affected by chronic autoimmune thyroiditis plus Addison’s disease [autoimmune polyendocrine syndrome-2 (APS-2)] in comparison with 32 age-matched normal control subjects (NC).

Outcome Measures: Caspase-3 mRNA expression in peripheral T cells was evaluated by quantitative real-time PCR; protein expression of both procaspase-3 and activated caspase-3 by Western blot analysis was followed by scanning densitometry.

Results: Caspase-3 mRNA expression was significantly reduced in resting lymphocytes from both A-AT (P = 0.001) and Y-AT (P = 0.016) compared with NC. After lymphocyte activation, protein levels of caspase-3 active form were significantly reduced in A-AT (P = 0.023) and Y-AT (P = 0.001) compared with NC. The APS-2 group displayed characteristics similar to the A-AT group because both caspase-3 mRNA and protein active form levels were significantly reduced compared with NC (P = 0.004 and 0.002, respectively).

Conclusion: Our data show that peripheral lymphocytes of subjects affected by thyroid autoimmunity or APS-2 show defective expression of the major executioner of AICD, thus potentially contributing to AICD resistance and to the development of autoimmunity.