IL-21 has been implicated in the pathogenesis of type 1 diabetes on the basis of the knowledge of the immune pathophysiology of a non-obese diabetic (NOD) mouse

strain [13, 14]. IL-21 stimulates the proliferation of both T and B cells and terminal differentiation of natural killer (NK) cells, enhances the cytotoxic activity of CD8+ T cells [15-17], counteracts the suppressive effects of regulatory T cells [18] and stimulates non-immune cells to generate inflammatory mediators [19]. Recently, the importance of IL-21 [20] and its related T helper type 17 (Th17) cells [21, 22] has emerged in the pathogenesis of type 1 diabetes as well in other autoimmune diseases [23, 24] in humans. The Th-cell-subset-specific GDC-0199 ic50 expression of the IL-21 proximal promoter is controlled via the action of several transcription factors, including

nuclear factor-activated T cells, cytoplasmic 2 (NFATc2), T-bet and leucine-zipper transcription factor Maf (c-MAF) [25, 26]. Due to the pleiotropic effects of IL-21 on immune regulation, it is important to elucidate the genetically driven changes in its function and regulation that Ganetespib might affect the autoimmune process and cause beta cell destruction. The presence of autoantibodies against islet-cell antigens is the first indication of diabetes development and is a well-established fact. Currently, four autoantibodies are used to predict the development of T1AD: antibodies against glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (ICA512, also termed IA-2), insulin and the recently discovered zinc T8 transporter (ZnT8) [1, 2, 27]. T1AD is also associated frequently with other immune-mediated disorders [27, 28] such as autoimmune thyroiditis [29, 30], Addison’s disease [31], pernicious anaemia [32, 33] and coeliac disease [30, 34]. During the past few years, extensive research has been conducted to predict the occurrences of autoimmune diseases through the detection of organ-specific antibodies in T1D patients [27, 35]. Early detection of antibodies and latent organ-specific

dysfunction is important to alert physicians to take appropriate Niclosamide measures to prevent the progression to full-blown disease. Several autoimmune diseases are related to T1AD and elevated IL-21 expression in both human and animal models, as well as to a high frequency of the PTPN22 C1858T polymorphism. The Brazilian population is one of the most heterogeneous in the world, composed mainly of European (Caucasian descent, 0·771), African (0·143) and Amerindian (Native South American, 0·085) ancestry [36]. We hypothesized that the variants of these genes that regulate immune function would influence not only diabetes risk, but also the expression of other tissue-specific autoantibodies among patients with T1D in a Brazilian population.