The CT/TT genotype frequency was 187% in the T1AD patients and 106% in the healthy controls [odds ratio (OR) = 194; self-confidence interval (CI): 137C273; 0001; Table 1]. and with a higher frequency of GAD65 and TG autoantibodies. HLA-DR3/DR4 alleles predominated in T1AD patients. A heterozygous allelic IL-21 gene variant (g.-241 T A) was found in only one individual. In conclusion, only PTPN22 C1858T polymorphism Cediranib (AZD2171) and HLA-DR3 and/or DR4 alleles, but not allelic variants in the 5-proximal region of the IL-21 gene were associated with T1AD risk. Patients with T1AD had increased frequencies of anti-islet-cell, anti-thyroid, anti-nuclear, anti-smooth muscle mass and anti-21-OH autoantibodies. The C1858T PTPN22 polymorphism was also associated with a higher frequency of GAD65 and TG autoantibodies. C1858T variant, which corresponds to the lymphoid protein tyrosine phosphatase-LYP-Arg620Trp variant associated with pathogenic T cell responses [6C9], has emerged recently as an important risk factor for type 1 diabetes and other autoimmune diseases [10,11]. Cytokines also play an important role in T1AD pathogenesis. They are the central mediators of inflammation and control innate and adaptive immune responses as well as tissue damage, defence, repair and remodelling [12]. Interleukin (IL)-21, a new member of the type 1 cytokine superfamily and a critical regulator of T and B cell function, is usually produced by numerous subsets of CD4+ T cells. IL-21 has been implicated in the pathogenesis of type 1 Cediranib (AZD2171) 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 [15C17], 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 expression of the IL-21 proximal Cediranib (AZD2171) promoter is usually 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 might impact 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 PROM1 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, considerable 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 usually important to alert physicians to take appropriate 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 C1858T polymorphism. The Brazilian populace is one of the most heterogeneous in the world, composed mainly of European (Caucasian descent, 0771), African (0143) and Amerindian (Native South American, 0085) ancestry [36]. We Cediranib (AZD2171) hypothesized that this 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 populace. Therefore, we analyzed a variant of the gene with a well-documented influence on T cell receptor signalling and diabetes risk, and searched for variants in the proximal promoter region of the gene related to autoimmune risk in T1AD patients and healthy controls in S?o Paulo, Brazil, which has a populace with high genetic diversity. alleles were also Cediranib (AZD2171) analysed. Materials and methods Samples All T1AD patients satisfied the American Diabetes Association.