Autoimmune thyroid disease (AITD) results from loss of immunological tolerance and inappropriate immune reaction against the thyroid gland. Although the initial events leading to aberrant immune response are similar, the clinical expression of AITD may differ manifesting as either Hashimoto’s thyroiditis (HT) or Graves’ disease (GD). Recent evidence suggests that differential regulation of Fas and TRAIL system apoptotic molecules may be critical in the clinical expression of AITD. Fas receptor is expressed at the surface of various cell types, including the thyroid cell. FasL induces apoptosis on Fas expressing cells after interaction with the Fas receptor. Normally the expression of FasL is confined to immune effector cells as well as “immune-privileged” sites while it might also be expressed at varying levels by thyroid cells. Fas and FasL are also detected in soluble forms (sFas, sFasL). sFas is an alternatively spliced form of Fas that can inhibit Fas/FasL interaction by binding to FasL. sFasL is a proteolytic product of FasL, but its physiologic role in apoptosis is less clear. The TNF-related apoptosis inducing ligand (TRAIL) is a more recently characterized member of the TNF family of proteins that has the closest resemblance to FasL. TRAIL induces apoptosis by engaging its receptors, TRAIL-R1 and TRAIL-R2. TRAIL-R3, in contrast to TRAIL-R1 and R2, acts as a decoy receptor competing for TRAIL ligation and protecting cells from TRAIL-induced apoptosis. In HT, the prevailing view is that thyrocytes are induced to express Fas, TRAIL-R1 and TRAIL-R2 and that interaction with FasL/TRAIL expressing intrathyroidal lymphocytes leads to their apoptotic death. An alternative hypothesis suggests that simultaneous expression of both Fas and FasL by neighboring thyroid cells leads to their “fratricidal” apoptosis. In GD, thyrocytes may be capable of fighting off intrathyroidal T lymphocytes via induced expression of FasL/TRAIL. In addition increased sFas may inhibit Fas/FasL interaction and protect GD thyrocytes. Most of the studies on the expression of apoptotic molecules on thyroid cells and intrathyroidal lymphocytes were based on thyroid tissues obtained after surgery from patients with GD or HT under treatment. It is known however that treatment itself may alter the expression of apoptotic molecules and thus may obscure the real picture. Few studies have examined the expression of apoptotic molecules on peripheral T lymphocytes from patients with AITD and the information is therefore limited. Objective: The aim of the present study was to evaluate in a comprehensive manner the expression of Fas, FasL, TRAIL and TRAIL-R3 on peripheral blood cells together with sFas and sFasL in serum of patients with GD and HT in the untreated state and at different clinical stages in order to clarify whether these molecules are differentially expressed in the opposite clinical phenotypes of AITD. The chance of having any possible correlation between the expression of apoptotic molecules in peripheral blood cells and other clinical parameters, T regulatory cell expression or expression of molecules contributing to antigen presentation (CD28, CTLA-4) was also investigated.
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