Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease.
Several mechanisms are probably involved in determining the evolution of autoimmune thyroid disease (AITD) towards either hypothyroidism and the clinical syndrome known as Hashimoto's thyroiditis (HT) or toward hyperthyroidism and the symptoms of Graves' disease (GD). To gain further insight into such mechanisms we performed an exhaustive comparative analysis of the expression of key molecules regulating cell death (Fas, Fas ligand [FasL], Bcl-2) and apoptosis in both thyrocytes and thyroid infiltrating lymphocytes (TILs) from patients with either GD or HT. GD thyrocytes expressed less Fas/FasL than HT thyrocytes, whereas GD TILs had higher levels of Fas/FasL than HT TILs. GD thyrocytes expressed increased levels of the antiapoptotic molecule Bcl-2 compared to the low levels detected in HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. The patterns of apoptosis observed were consistent with the regulation of Fas, FasL, and Bcl-2 described above. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl2 favors apoptosis of infiltrating lymphocytes, possibly limiting their autoreactive potential and impairing their ability to mediate tissue damage. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and favor the thyrocyte hypertrophy associated with immunoglobulins stimulating the thyrotropin (TSH) receptor. In contrast, the regulation of Fas/FasL/Bcl2 expression in HT promotes thyrocyte apoptosis, tissue damage, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. These findings help define key molecular mechanisms contributing to the clinical outcome of thyroid autoimmunity.
Giordano
C
C
Laboratory of Immunology, Endocrinology, Institute of Clinica Medica, University of Palermo, Italy. cgiordan@unipa.it
Richiusa
P
P
Bagnasco
M
M
Pizzolanti
G
G
Di Blasi
F
F
Sbriglia
M S
MS
Mattina
A
A
Pesce
G
G
Montagna
P
P
Capone
F
F
Misiano
G
G
Scorsone
A
A
Pugliese
A
A
Galluzzo
A
A
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation; D006111:Graves Disease / Q000473:pathology; D006801:Humans; D008214:Lymphocytes / Q000737:chemistry / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013959:Thyroid Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013961:Thyroid Gland / Q000737:chemistry / Q000473:pathology*; D013967:Thyroiditis, Autoimmune / Q000473:pathology; D019014:fas Receptor / Q000032:analysis / Q000235:genetics* / Q000502:physiology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019014:fas Receptor