Early suppression of immune response pathways characterizes children with prediabetes in genome-wide gene expression profiling.
Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic beta 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.
Elo
Laura L
LL
Turku Centre for Biotechnology, University of Turku and Abo Akademi University, FI-20521 Turku, Finland. laura.elo@utu.fi <laura.elo@utu.fi>
Mykkänen
Juha
J
Nikula
Tuomas
T
Järvenpää
Henna
H
Simell
Satu
S
Aittokallio
Tero
T
Hyöty
Heikki
H
Ilonen
Jorma
J
Veijola
Riitta
R
Simell
Tuula
T
Knip
Mikael
M
Simell
Olli
O
Lahesmaa
Riitta
R
D017951:Antigen Presentation / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D042241:Early Diagnosis; D005260:Female; D020869:Gene Expression Profiling; D019672:Genes, T-Cell Receptor / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007108:Immune Tolerance; D007328:Insulin / Q000378:metabolism; D008297:Male; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D007328:Insulin