**Table 1.**

 *The relative and absolute amount of CD95+-cells and T-lymphocytes expressing the Fas receptor in the peripheral blood of patients with T1DM and persons with a high risk of developing T1DM.* 

 **Figure 1.**

 *The histogram shows the number of CD3+CD95+-, CD4+CD95+- and CD8+CD95+ -lymphocytes in the control group (A–C) and in the group of T1DM patients in the state of carbohydrate metabolism decompensation (D–F).* 

 Among the subpopulations of T-lymphocytes, a significant increase in the percentage of CD8+CD95+-cells from the total amount of cytotoxic T-lymphocytes (CD8+CTLs) in all groups of examined patients should be noted compared to the control group ( **Figure 2** ). The increase in the relative amount of Fas-expressing CD8+CTLs is most pronounced with disease decompensation (groups IIa and IIb). An increase in the number of cells with the CD8+CD95+ phenotype in T1DM is probably

*The Role of Apoptosis in Autoimmune Destruction of Pancreatic b-Cells DOI: http://dx.doi.org/10.5772/intechopen.108290*

### **Figure 2.**

*Percentage of CD8+CD95+ cells from the total number of cytotoxic T-lymphocytes. Notes: (1) \*Differences in the studied indicator with the control group (I) are statistically significant (p < 0.05); (2) \*\*differences in the studied indicator with the control group (I) are statistically significant (p < 0.01); (3) \*\*\* differences in the studied indicator with the control group (I) are statistically significant (p < 0.001).*

a compensatory mechanism aimed at the elimination of autoreactive cytotoxic T-lymphocytes by apoptosis. According to the literature, it is the effector CD8+CTLs that play the dominant role in the destruction of pancreatic β-cells [2, 20].

At the same time, a significant increase in the number of cells with the CD8+CD95+ phenotype in the blood of individuals with a high risk of developing T1DM (group IV) compared with the control group (group I) is an unfavorable prognostic factor. These data indicate that already in the latent stage of T1DM there is an expansion of autoreactive clones of cytotoxic T-lymphocytes in peripheral blood, followed by their migration to the target organ (pancreas), which leads to the progression of the autoimmune process.

In addition to assessing the surface expression of the Fas receptor and Fas ligand, it is necessary to consider the pathogenetic significance of soluble forms of Fas and FasL in the development of autoimmunity in T1DM, since the diagnostic and prognostic significance of these indicators of Fas-mediated apoptosis is actively studied in systemic and organ-specific autoimmune diseases, in sepsis, acute renal failure, oncological diseases [29, 32, 37]. A comprehensive assessment of the effectiveness of Fas-mediated apoptosis with the determination of all biomarkers (surface and soluble) involved in this variant of the receptor pathway for triggering the apoptotic program can provide a more accurate understanding of the mechanisms and significance of Fas/FasL system dysregulation in the pathogenesis of T1DM.

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. It

has been reported that a high level of serum sFas correlates with the severity of the septic process [28]. It has been shown that the content of sFas in the blood increased with increasing renal dysfunction in patients with acute kidney injury [29, 31].

According to the literature data, the soluble form of Fas competes with the membrane Fas receptor for the binding of the Fas ligand, which prevents the "physiological" apoptosis of the cells to be eliminated. With an increase in the sFas content in the circulation, not all "defective" cells can implement their apoptotic program. As a result, they accumulate in the peripheral blood, which leads to an aggravation of the pathological process.

We also studied the content of the soluble form of Fas-ligand in the serum of T1DM patients and those at risk for developing T1DM.

The content of sFasL with compensation for T1DM was significantly higher than in the decompensation group and significantly lower than in the risk group (**Table 2**). It should be noted a significant increase in the content of sFasL in the risk group, which is consistent with the literature data. According to the authors, an increase in sFasL in the latent stage of T1DM has a protective value and is aimed at eliminating autoaggressive lymphocyte clones by Fas-mediated apoptosis [8].

Thus, our results indicate a pronounced dysregulation in the Fas/FasL system, which is observed at all stages of the development of T1DM.

Disturbances in the functioning of the Fas receptor (Fas) and Fas ligand (FasL), as key inducers of receptor-dependent apoptosis, are actively studied in the pathogenesis of diseases associated with both inhibition and enhancement of apoptosis in cells of shock organs [30]. It has recently been found that Fas-mediated caspase-8 activation plays an important role in the regulation of pathogenic mechanisms in bacterial infections [26]. It has been shown that an increase in the soluble form of FasL in the blood is one of the early markers of heart failure progression [29].

In the pathogenesis of T1DM, disturbances in Fas-mediated apoptosis are of a bivalent nature. So, if in relation to b-cells the development of apoptosis is associated with the progression of the disease, then from the point of view of the elimination of activated autoreactive lymphocytes, apoptosis is desirable and can slow down the destruction of pancreatic b-cells. The dual role of the receptor (external) pathway for triggering apoptosis in the pathogenesis of T1DM is due to the expression of its mediating molecules (Fas and FasL) by both effector cells (autoreactive T cells) and target cells (pancreatic b-cells) [20].


*Notes: (1) n—the number of examined persons; (2) \*differences in the studied indicator with the control group (I) are statistically significant (p < 0.05); (2) \*\*differences in the studied indicator with the control group (I) are statistically significant (p < 0.01).*
