Regulation of apoptosis in endocrine autoimmunity: insights from Hashimoto's thyroiditis and Graves' disease.
Dysregulation of apoptosis is associated with the pathogenesis of organ-specific autoimmune diseases, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors such as Fas. A comparative analysis of the expression of Fas and FasL, the antiapoptotic molecule Bcl-2, and apoptosis in both thyrocytes and thyroid-infiltrating lymphocytes (TILs) from patients with either Graves' disease (GD) or Hashimoto's thyroiditis (HT) was performed. GD thyrocytes expressed less Fas than HT thyrocytes, whereas GD TILs had higher levels of Fas and FasL than HT TILs. GD thyrocytes expressed higher levels of Bcl-2 compared with HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. Consistently, thyrocyte apoptosis was marked in HT and poor in GD thyroids, and TIL apoptosis was marked in GD and poor in HT. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl-2 favors apoptosis of infiltrating lymphocytes. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and hypertrophy associated with stimulatory thyroid-stimulating hormone receptor antibodies. In contrast, the regulation of Fas/FasL/Bcl-2 expression in HT can promote thyrocyte apoptosis via homophylic Fas-FasL interactions, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. Fas-mediated apoptosis may be a general mechanism of cell damage in destructive organ-specific autoimmunity.
Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
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C
Salmaso
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Bagnasco
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Pesce
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P
Montagna
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Brizzolara
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Altrinetti
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Richiusa
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A
Galluzzo
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Giordano
D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015551:Autoimmunity / Q000502:physiology*; D053222:Fas Ligand Protein; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013961:Thyroid Gland / Q000737:chemistry; D013967:Thyroiditis, Autoimmune / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D019014:fas Receptor / Q000032:analysis
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor