Death of the autoimmune thyrocyte: Is it pushed or does it jump?

Programmed cell death or apoptosis is central both in physiology during dev elopment and in disease. The mechanism of apoptosis is under the control of antiapoptotic survival genes of the Bcl-2 family and proapoptotic death re ceptors of the TNF superfamily (Fas, TNFR, TRAILR). Following death signal, the death receptor binds to its own receptor and initiates, through bindin g of adaptors, a cascade of events mediated by the autoproteolytic activati on of specific enzymes called caspases. This enzyme activation is ultimatel y responsible for the dissembly of basic nuclear and cytoplasmic cell struc tures leading to cell death. In certain cell systems, antiapoptotic genes o f the Bcl-2 family prevent the proapoptotic pathway. One of their roles is to maintain mitochondrial function integrity. In autoimmune destructive thy roiditis high levels of apoptosis have been demonstrated particularly withi n the destructed follicles near the infiltrated areas in comparison to Grav es' disease and non autoimmune glands. In Hashimoto's thyroiditis Pas expre ssion has been found increased on thyrocytes and in vitro can be modulated by proinflammatory cytokines. Fast expression on thyrocytes remains controv ersial. Thyroid cells from Graves' disease and multinodular glands are know n to kill Pas expressing target cells although Hashimoto's thyrocytes are n ot efficient effector cells. Intrathyroidal lymphocytes from Hashimoto's th yroids maintain functional killer activity. These findings would suggest th at intrathyroidal lymphocytes could be responsible for thyrocyte death in v ivo. Whether this mechanism is Fas/FasL, TRAIL/TRAILR dependent can not be confirmed as specific blocking reagents were not able to inhibit cell induc ed death. In Hashimoto's thyroiditis an impairment of Bcl-2 and Bcl-X antia poptotic genes on thyrocytes has also been detected. Bcl-X expression can b e down-regulated in vitro by incubation with cytokines. These findings sugg est that thyrocyte death may not exclusively be the result of specific inte ractions between death receptor and their ligands but it may involve simult aneous impairment of protective genes of the Bcl-2 family. Whether the impa irment of the Bcl-2 family is a direct consequence of environmental stimuli or is the result of an intrinsic thyrocyte (mitochondrial?) alteration is as yet not known.