**3.1 The role of Fas-mediated apoptosis in the pathogenesis of T1DM**

It is known that the Fas/FasL system plays a central role in maintaining peripheral autotolerance and tissue homeostasis of the organism [19, 20]. Fas-mediated apoptosis is induced by binding of the Fas(CD95/APO-1/TNFRSF6) receptor to the Fas(CD95L/CD178/TNFSF6) ligand on the corresponding cells [21]. Triggering the expression of cell surface Fas receptors (Fas) regulates the elimination of autoreactive T- and B-lymphocytes by apoptosis.

Fas-mediated apoptosis is the initiating phase of apoptotic signal transduction and refers to an extrinsic (receptor) pathway for triggering cell death.

Depending on the triggering mechanism of the apoptotic cascade, there are two main signaling pathways leading to the induction of apoptosis in mammalian cells: extrinsic (receptor) and intrinsic (mitochondrial or Bcl-2-regulated) [19, 22]. The extrinsic pathway is mediated by DR (Death Receptor) cell receptors, which include the Fas receptor (Fas). Fas contains the domain DD (Death Domain), the central physiological regulator of apoptosis, in its cytoplasmic part. Binding of Fas to the Fas ligand (FasL) activates the Fas-associated death domain adapter protein FADD (Fas-Associated Death Domain protein), which leads to the formation of the DISC effector complex (Death Initiating Signaling Complex) [23–25]. DISC activates procaspase-8, which undergoes autocatalytic cleavage and transforms into its active form, caspase-8, which initiates apoptosis of the target cell [26, 27].

The Fas (CD95/APO-1/TNFRSF6) receptor is a membrane protein that is a member of the tumor necrosis factor receptor superfamily (TNFRSF-Tumor Necrosis Factor Receptor Super Family) and belongs to the DR (Death Receptor) group of receptors [20]. The latest literature reports that Fas is normally ubiquitously expressed in human tissues at the basal level, and its activation threshold must be strictly regulated to avoid excessive cell death [18, 20]. There is a functionally active soluble form of Fas, which is the result of proteolytic cleavage of membrane-bound receptors or is formed during alternative splicing [28, 29].

Fas/APO-l-ligand (FasL/CD178/TNFSF6) is a membrane protein and is a member of the tumor necrosis factor (TNF) superfamily of ligands, which belong to cytokines [20, 28]. Like the TNF ligand, FasL can be released from the cell surface and be physiologically active in a soluble form [29–31].

Fas-mediated apoptosis ensures the elimination of cells of the immune system that are undesirable for the organism, and is also involved in the regulatory suppression of immune responses and cytotoxicity of T-lymphocytes [20].

According to literature, the role of death receptors in the destruction of b-cells in type 1 diabetes mellitus (T1DM) is widely discussed [1, 5, 20]. Studies using isolated human pancreatic islets have shown that exposure to stress factors (hyperglycemia, excess free radicals, reactive oxygen species, production of IL-1b by microenvironment cells) enhances Fas expression on b-cells, which leads to their death by mechanism of the Fas-mediated apoptosis [17]. Immunocompetent cells infiltrating pancreatic islet tissue produce pro-inflammatory cytokines: IL-1b, TNF-a, and IFN-g, which are known for their pro-apoptogenic properties [20, 32, 33]. IL-1b induces an increase in Fas expression on b-cells, which increases their readiness for Fas-mediated apoptosis, which is realized by autoreactive T cells expressing FasL. Activated cytotoxic T lymphocytes (CD8 + CTL), which are part of the inflammatory infiltrates of the pancreas (insulitis), can also destroy b-cells in a Fas-dependent receptor way [18, 30].

There are conflicting data in the literature on the surface expression of the Fas receptor on peripheral blood T lymphocytes in T1DM. 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].
