Evaluation of efficiency of Fas-mediated apotosis of peripheral blood lymphocytes in patients with type 1 diabetes mellitus

Abstract

The Fas/FasL system is known to play a central role in maintaining peripheral self-tolerance and tissue homeostasis of the organism [12, 18]. Fas-mediated apoptosis is induced by binding of the Fas(CD 95/APO-l/TNFRSF6)-receptor to the Fas(CD 95L/CD 178/TNFSF6)-ligand on the respective cells [24]. Triggering of the expression of cell surface Fas receptors (Fas) regulates the elimination of autoreactive T- and B-lymphocytes by apoptosis. It is known that impaired activation of Fas-mediated apoptosis in individual subpopulations of T-cells plays an important role in the pathogenesis of type 1 diabetes mellitus (T1DM). The main key point in the development of T1DM is resistance to apoptosis of activated autoreactive T-lymphocytes, which migrate from the bloodstream to the pancreas and take an active part in β-cells destruction. Аt the present time, most of the results on the study of Fas-mediated apoptosis in T1DM were obtained in experiments in vitro [11, 18, 31]. There is no doubt that in vivo autoimmune pathological changes are more profound, and extrapolation of the results obtained in the experiment to the organism is not always valid. Тhereby, it seems relevant to evaluate the efficiency of Fas-mediated apoptosis of T-lymphocytes in the blood of patients with T1DM, depending on the compensation phase and the duration of the disease. In the article, the markers of Fas-mediated apoptosis of peripheral blood lymphocytes in patients with type 1 diabetes mellitus and individuals with high risk of T1DM development have been studied. The surface expression of Fas in individual subpopulations of T-lymphocytes was еvaluated. The inhibition of Fas-mediated apoptosis of autoreactive CD 95+-cells by soluble Fas-receptor was detected in patients with decompensation of T1DM. In compensation phase of T1DM Fas-mediated apoptosis of lymphocyte was successfully realized via the soluble Fas ligand (sFasL). The increased level of soluble FasL was revealed in compensation phase of T1DM and in individuals with high risk of T1DM development. This probably has a protective value, since the soluble FasL is involved in the removal of the peripheral blood autoreactive CD 95+-cells.

The Role of Apoptosis in Autoimmune Destruction of Pancreatic b-Cells

“…We found that the content of soluble forms of Fas (sFas ̶ soluble Fas) and FasL (sFasL ̶ soluble FasL) in the blood serum of T1DM patients did not depend on the duration of the disease, but changed depending on the state of carbohydrate metabolism compensation. In patients with T1DM in the phase of decompensation of the disease, a significant increase in the content of sFas was observed compared with the control group and other examined groups of patients (patients in the phase of T1DM compensation, persons with a high risk of developing T1DM) [34]. Our results are consistent with literature data on the relationship between an increase in the concentration of sFas in the serum of patients and worsening of the course of the disease.…”

“…In experimental studies in NOD mice, a decrease in the expression of the proapoptotic Fas antigen on the surface of T lymphocytes was revealed [8,9]. The results of our own studies revealed a statistically significant increase in Fas receptor expression in certain subpopulations of peripheral blood T lymphocytes in T1DM patients, regardless of the duration and state of disease compensation, compared with the control group [34]. We examined 63 patients with a reliably established diagnosis of T1DM and 15 individuals with a high risk of developing T1DM.…”

“…These proteins are regulators of the mitochondrial apoptosis triggering pathway [51], which plays an important role in b-cell death in T1DM [5,52]. The Bax/Bcl-2 ratio regulates the balance between the processes of induction and inhibition of apoptosis [34,53]. It has been established that overexpression of antiapoptotic proteins of the Bcl-2 family protects b-cells from apoptosis in T1DM [53][54][55].…”