Activity of the REL-B and p65 Subunits of NF-κB Demonstrates Innate Immune Activation in Children at Risk of Type 1 Diabetes

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NF-kB is a transcription factor family comprising five subunits involved in two pathways; classical pathway (including p65 transcriptional activity) plays an important role in innate immunity, and alternate (including RelB activity) in immune tolerance. In T1DM subjects, RelB and p65 activity is constitutively increased in peripheral blood. We investigated NF-kB in first-degree relatives (FDR) at risk of T1DM, to determine the timing of abnormal signalling relative to T1DM development, and its relationship to genetic predisposition to the disease. NF-kB nuclear binding activity was measured in 2 ml whole blood in children with T1DM, their parents, and islet antibody (AB) positive and negative FDR, and compared to healthy controls. Families including a proband with T1DM were HLA-typed and heritability of the phenotype was assessed. Mean RelB and p65 DNA binding activity was significantly elevated in individuals with T1DM, AB+ FDR and a small group of AB- FDR, as compared with healthy controls. In contrast, mean DNA binding activity of p50, p52 and c-Rel subunits of NF-kB did not differ between subjects. RelB DNA binding was positively associated with p65 binding. The DNA binding activity of RelB and p65 was independent of HLA genotype but heritable as a quantitative trait. RelB and p65 DNA binding activity identifies a risk phenotype, indicative of innate immune activation, in FDR of children with T1DM. Our data suggest this phenotype may be present early in the disease process in about 50% of at-risk families associated with shared genetic and/or environmental factors.