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

model of spontaneous autoimmune diabetes similar to human T1DM, Th1-cells and cytotoxic T lymphocytes, even when the influence of IL-2, a factor that promotes the proliferation of T lymphocytes, is blocked on them exhibit increased resistance to apoptosis. At the same time, T-helpers are more resistant to apoptosis than cytotoxic T lymphocytes, which disrupts the normal balance of Th1-cells/cytotoxic T cells and contributes to the maintenance of autoimmune Th1-inflammation. Resistance of T lymphocytes of NOD mice to apoptosis is explained by increased expression of the apoptosis inhibitor Bcl-xL protein by T cells [9], as well as disturbances in the Fas/ FasL system, which provides the receptor-mediated pathway for apoptosis [10].

Autoreactive lymphocytes resistant to apoptosis migrate from the bloodstream to the target organ—the pancreas and form insulitis, consisting of T and B cells, as well as macrophages, dendritic cells (DC), natural killer cells (NK cells) and natural killer T cells (T-NK cells) [2]. Immunocompetent cells infiltrating the islet tissue produce pro-inflammatory cytokines TNF-α, IFN-g, and IL-1b, nitric oxide, cytotoxic enzymes (perforin and granzyme B), excess free radicals, and other compounds that cause b-cell death by apoptosis [4, 5]. IL-1b alone or in combination with TNF-α and IFN-g enhances Fas-receptor expression on b-cells, which leads to their apoptosis as a result of interaction with autoreactive lymphocytes expressing Fas-ligand [1]. Some authors consider Fas-mediated apoptosis as the leading mechanism of b-cell destruction [11, 12].

In the pathogenesis of T1DM, disturbances in Fas-mediated apoptosis of lymphocytes, which play a major role in maintaining peripheral autotolerance, are important. The Fas/FasL system is involved in the clonal deletion of autoreactive T cells in peripheral lymphatic organs, in the elimination of activated T cells, and thus is central to the regulation of the peripheral immune respons. In the immune system, Fas receptor (FasR) and Fas ligand (FasL) are involved in the regulation of immune responses and in T-lymphocyte-mediated cytotoxicity. FasL is mainly expressed by activated CD4+ and CD8+ T cells [13]. FasR is constitutively expressed by mature T lymphocytes, but its expression is increased after antigen activation, making T cells more susceptible to apoptosis. If there is a defect in the Fas/FasL system, activated lymphocytes can accumulate [14–16]. Thus, if these cells are not eliminated by Fas-mediated apoptosis, the probability of developing an autoimmune disease increases [17].

Thus, from the modern point of view, T1DM is considered as a polygenic, multifactorial disease, in which a genetic predisposition in combination with environmental triggers triggers the activation of specific autoimmune processes leading to the death of b-cells. The leading links in the pathogenesis of autoimmune damage to pancreatic b-cells are immune dysregulation and programmed cell death. Disturbances in the processes of initiation and implementation of apoptosis become fundamental in the development of the disease [18]. Meanwhile, pathogenetic factors and markers of programmed cell death in autoimmune lesions have not yet been sufficiently studied, which is of interest for further research.
