Transcriptional changes underlying progression from islet autoantibody positivity to type 1 diabetes

Type 1 diabetes (T1D) usually has a preclinical phase identified by the presence of circulating autoantibodies to pancreatic islet antigens, and most young children who have multiple autoantibodies progress to diabetes within 10 years. While autoantibodies denote underlying islet autoimmunity, how this process is initiated and then progresses to clinical diabetes on a background of genetic susceptibility is not clearly understood. We analysed gene expression by RNA-seq in four types of immune cells from five genetically at-risk children with islet autoantibodies who progressed to diabetes in ≤ 3 years (‘progressors’) and in five at-risk children matched for sex, age and HLA who had not progressed to diabetes (‘non-progressors’). RNA-seq analysis was performed for CD4+ T cells, CD8+ T cells, NK cells and B cells in a screening cohort of 10 genetically at-risk children. All children had autoantibodies to two or more islet antigens, five of whom progressed to clinical T1D within 36 months. Sampling was performed 36 months before and at diabetes onset in the progressors. Progressors and non-progressors were matched for age, sex and HLA genotype. The data for the CD4+ Tcells was generated separately to all other cell types, and that there are multiple sequencing runs within each data set. Autoantibodies measured were as follows: insulin autoantibodies (IAA), glutamic acid decarboxylase 65 autoantibodies (GADA), tyrosine phosphatase-like insulinoma antigen autoantibodies (IA2A) and transporter 8 (COOH R/W dimer) (ZnT8A) autoantibodies. Positive cut-offs for these antibodies were defined as IAA ≥ 0.7 mU/L, GADA > 5.0 U/mL, IA2A > 3.0 U/mL and ZnT8A ≥ 3.1U/mL, respectively. Note: This deposition provides genewise read counts, from which our analyses can be reproduced, but the raw sequence data files cannot be made publicly available because of privacy issues with human samples. The raw sequence data will be made available for appropriate research projects upon application to the WEHI Data Access Committee ([e-mail]).