HLA-DR3-DQ2<sup>+</sup>huCD4<sup>+</sup>IA/IE<sup>-/-</sup>RIP.B7.1<sup>+</sup> mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4<sup>+</sup>, CD8<sup>+</sup> B220<sup>+</sup>, CD11b<sup>+</sup> and CD11c<sup>+</sup> immune cells).
Strikingly, adoptive transfer of miR-183 and miR-96 overexpressing antigen-specific T cells into INS-HA/Rag2KO mice accelerated the development of autoimmune diabetes, whereas transfer of antagomiR-treated cells delayed the disease onset.
Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes.
PTPN22 (1p13.2), STAT4 (2q32.2), CTLA4 (2q33.2), HLA (6p21), IL2RA (10p15.1), INS (11p15.5), ERBB3 (12q13.2), SH2B3 (12q24.12), and CLEC16A (16p13.13) were convincingly associated with autoimmune diabetes in adults (P ≤ 0.002), with consistent directions of effect as reported for pediatric type 1 diabetes.
Our results of INS VNTR polymorphism in patients with the onset of diabetes after 35 years of age confirm the association of Class I INS VNTR with autoimmune diabetes and the protective effect of Class III INS VNTR on the insulin secretion in GADA-positive subjects.
Here, we demonstrate that syngeneic transplantation of hematopoietic stem cells encoding proinsulin transgenically targeted to APCs totally prevents the development of spontaneous autoimmune diabetes in NOD mice.
A peptide that spans the junction of the insulin B chain and the connecting (C) peptide in proinsulin has been reported to stimulate T cells from humans at risk for type 1 diabetes and autoimmune diabetes-prone NOD mice.
Carriers of pathogenic variants had HLA-DRB1 risk alleles for autoimmune diabetes and clinical characteristics compatible with type 1 diabetes except for the absence of autoimmunity.
The distribution of DRB1-DQB1 haplotypes and their association with onset-related characteristics of autoimmune diabetes varies across major racial/ethnic groups in the USA.
Compared with those with low GADA titers, patients with high GADA titers had more prominent traits of insulin deficiency and a profile of more severe autoimmunity resulting in higher A1C, lower BMI, a lower prevalence of metabolic syndrome and its components (P < 0.02 for all), a higher prevalence of IA-2As, TPO antibodies (P < 0.003 for both), and DRB1*03-DQB1*0201 (50 vs. 26.8%, P = 0.001), and a decreasing frequency of DQB1*0602 and DRB1*0403 (from type 2 to low and to high GADA titer autoimmune diabetes; P < 0.001 for trend for both comparisons).
Only the combination of major histocompatibility complex class I chain-related A gene 5.1 and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult.
Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes Study (UKPDS) Group.
Vaccination with a co-expression DNA plasmid containing GAD65 fragment gene and IL-10 gene induces regulatory CD4(+) T cells that prevent experimental autoimmune diabetes.
Interleukin (IL)-21 and protein tyrosine phosphatase non-receptor 22 (PTPN22) regulate lymphocyte function and have been implicated in the pathogenesis of autoimmune diabetes.
Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes.