Early suppression of immune response pathways characterizes children with prediabetes in genome-wide gene expression profiling

• Published in: Journal of autoimmunity 2010-08, Vol.35 (1), p.70-76
• Main Authors: Elo, Laura L, Mykkänen, Juha, Nikula, Tuomas, Järvenpää, Henna, Simell, Satu, Aittokallio, Tero, Hyöty, Heikki, Ilonen, Jorma, Veijola, Riitta, Simell, Tuula, Knip, Mikael, Simell, Olli, Lahesmaa, Riitta
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Antigen presentation; Antigen Presentation - genetics; Autoantibodies; Biological and medical sciences; Child; Child, Preschool; Computational Biology; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Differential gene expression; Early Diagnosis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Profiling; Genes, T-Cell Receptor - genetics; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Immune Tolerance; Insulin - metabolism; Longitudinal data; Male; Medical sciences; Molecular networks; Pathway analysis; Prediabetes; Prognosis; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Type 1 diabetes
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2010.03.001

Abstract Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic β cells in the islets of Langerhans. Although defects in various T cell subsets have been linked to the disease pathogenesis, mechanisms initiating or enhancing the autoimmunity in prediabetes remain poorly understood. To unravel genes and molecular pathways affected by the diabetes-associated autoimmunity, we investigated transcriptomic profiles of prospective whole-blood samples from children who have developed T1D-associated autoantibodies and eventually clinical T1D. Gene-level investigation of the data showed systematic differential expression of 520 probesets. A network-based analysis revealed then a highly significant down-regulated network of genes involved in antigen presentation as well as T-cell receptor and insulin signaling. Finally, detection of dynamic changes in the affected pathways at the early or late phases of autoimmunity showed down-regulation of several novel T1D-associated pathways as well as known key components of immune response. The longitudinal genome-wide data generated in the present study allows the detection of dynamic changes relevant to the disease that may be completely missed in conventional cross-sectional studies or in genome-wide association studies. Taken together, our analysis showed systemic high-level repression of immune response pathways associated with T1D autoimmunity.