“
“Interleukin (IL)-21 and protein tyrosine phosphatase non-receptor 22 (PTPN22) regulate lymphocyte

function and have been implicated in the pathogenesis of autoimmune diabetes. We sequenced the proximal promoter of the IL-21 gene for the first time and analysed the PTPN22 1858T polymorphism in type 1A diabetes (T1AD) Z-VAD-FMK patients and healthy controls (HC). We correlated the frequencies of islet and extra-pancreatic autoantibodies with genotypes from both loci. The case series comprised 612 T1AD patients and 792 HC. Genotyping of PTPN22 C1858T was performed on 434 T1AD patients and 689 HC. The −448 to +83 base pairs (bp) region of the IL-21 gene was sequenced in 309 Brazilian T1AD and 189 HC subjects. We also evaluated

human leucocyte antigen (HLA) DR3/DR4 alleles. The Ixazomib chemical structure frequencies of glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA)-2, anti-nuclear antibody (ANA), thyroid peroxidase (TPO), thyroglobulin (TG), thyrotrophin receptor autoantibody (TRAb), anti-smooth muscle (ASM) and 21-hydroxylase (21-OH) autoantibodies were higher in T1AD patients than in HC. The PTPN22 1858T allele was associated with an increased risk for developing T1AD [odds ratio (OR) = 1·94; P < 0·001], particularly in patients of European ancestry, 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 patient. In conclusion, only PTPN22 C1858T polymorphism and HLA-DR3 PLEK2 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 and anti-21-OH autoantibodies. The C1858T PTPN22 polymorphism was also associated with a higher frequency of GAD65 and TG autoantibodies. Type 1A diabetes (T1AD), characterized by T cell-mediated autoimmune destruction of pancreatic beta cells, is believed to result from a complex interplay between genetic predisposition, the immune system and environmental factors [1-3]. The major determinant of T1AD genetic susceptibility is conferred by the human leucocyte antigen (HLA)-DR and HLA-DQ alleles [4, 5]. Another important non-HLA gene, the protein tyrosine phosphatase non-receptor 22 (PTPN22), regulates T cell receptor signalling. The PTPN22 C1858T variant, which corresponds to the lymphoid protein tyrosine phosphatase-LYP-Arg620Trp variant associated with pathogenic T cell responses [6-9], 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].