A Type I Interferon Transcriptional Signature Precedes Autoimmunity in Children Genetically at Risk for Type 1 Diabetes

TLDR

Diagnosis of type 1 diabetes is preceded by circulating pancreatic autoantibodies, yet the events leading to islet autoimmunity are poorly understood, though viral infections and type I interferon–responsive genes have been linked to the disease. The study aimed to identify IFN‑β–inducible genes and use them to define a type I interferon transcriptional signature in peripheral blood mononuclear cells. Using the 225‑gene signature, the authors measured its expression in healthy controls, patients with established T1D, and a longitudinal birth cohort of children genetically predisposed to T1D. The IFN signature was elevated in genetically predisposed children before autoantibody appearance, was transient and linked to recent upper respiratory infections, and genetic variation in IFN‑responsive genes modified T1D risk, indicating that transient type I interferon upregulation is a preclinical risk factor for autoimmunity.

Abstract

Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and antiviral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β-inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (n = 25). Using this predefined set of 225 IFN signature genes, we investigated the expression of the signature in cohorts of healthy controls (n = 87), patients with T1D (n = 64), and a large longitudinal birth cohort of children genetically predisposed to T1D (n = 109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically predisposed children before the development of autoantibodies (P = 0.0012) but not in patients with established T1D. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P = 0.0064), and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14(+) monocytes. DNA variation in IFN-inducible genes altered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which increased expression is a known risk factor for disease. These findings identify transient increased expression of type I IFN genes in preclinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D.