Innate Immune Activity Is Detected Prior to Seroconversion in Children With HLA-Conferred Type 1 Diabetes Susceptibility

Abstract

The insult leading to autoantibody development in children who will progress to develop type 1 diabetes (T1D) has remained elusive. To investigate the genes and molecular pathways in the pathogenesis of this disease, we performed genome-wide transcriptomics analysis on a unique series of prospective whole-blood RNA samples from at-risk children collected in the Finnish Type 1 Diabetes Prediction and Prevention study. We studied 28 autoantibody-positive children, out of which 22 progressed to clinical disease. Collectively, the samples covered the time span from before the development of autoantibodies (seroconversion) through the diagnosis of diabetes. Healthy control subjects matched for date and place of birth, sex, and HLA-DQB1 susceptibility were selected for each case. Additionally, we genotyped the study subjects with Immunochip to identify potential genetic variants associated with the observed transcriptional signatures. Genes and pathways related to innate immunity functions, such as the type 1 interferon (IFN) response, were active, and IFN response factors were identified as central mediators of the IFN-related transcriptional changes. Importantly, this signature was detected already before the T1D-associated autoantibodies were detected. Together, these data provide a unique resource for new hypotheses explaining T1D biology.

A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes

“…Twenty-eight subjects who seroconverted (22 progressed to T1D) were matched (date and place of birth, sex, HLA-DQ genotype) with 30 ABN subjects. Further experimental details including whole blood preparation and microarray hybridization are available as published (13). We performed computational deconvolution using CIBERSORT (https://cibersort.stanford.edu/) to access the impact of changing cell frequencies in whole blood from the DIPP cohort.…”

“…Previously, when longitudinal microarray data from BABYDIET were interrogated for differential expression of predefined IFN genes, expression of type 1 IFN genes was transiently increased before seroconversion (12). In the DIPP study, the longitudinal data were aligned relative to seroconversion and then divided into groups for pseudotemporal differential gene expression analyses in progressors to T1D, averaging all data in each group, and thus disregarding most of the time points (13). Nonetheless, in DIPP, differentially expressed (DE) genes associated with type I IFN were again identified in seropositive children progressing to T1D.…”

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

“…Children genetically at risk for type 1 diabetes present a type I IFNinducible transcriptional signature that precedes the development of autoantibodies [14,15], and IFNα plays a major role as mediator of HLA class overexpression in human islet cells, a key event in early type 1 diabetes [16,17]. Laser-captured islets obtained from living donors with recent onset type 1 diabetes showed a significant increase in nearly 50% of the IFN-stimulated genes (ISGs) evaluated [18].…”

Is Type 1 Diabetes “Going Viral”?

“…As the virus is eliminated, less virus is sensed, and the balance of effector and regulatory cells swings back to minimize any overreaction. However, individuals with susceptibility to T1D have genetic variants that include key signaling (4), which will present b-cell and viral antigens to the infiltrating immune cells (5). Following the recognition of their respective antigens, activation of immune cells in an environment lacking in normal regulatory control (6) will lead to both the expansion of effector cells (7) and maturation of B cells that can produce b-cell-specific antibodies and viral-specific antibodies (8).…”