Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes

Abstract

There is a need for biomarkers to monitor the development and progression of type 1 DM. We analyzed mRNA expression levels for granzyme B, perforin, fas ligand, TNF-α, IFN-γ, Foxp3, IL-10, TGF-β, IL-4, IL-6, IL-17, Activation-induced cytidine deaminase (AID) and Immunoglobulin G gamma chain (IgG<gamma>) genes in peripheral blood of at-risk, new-onset and long-term type 1 DM, and healthy controls. The majority of the genes were suppressed in long-term type 1 DM compared to controls and new-onset patients. IFN-γ, IL-4 and IL-10 mRNA levels were significantly higher in new-onset compared to at-risk and long-term groups. There was decreased mRNA expression for AID and IgG<gamma> and up-regulation of IFN-γ with age in controls. Data suggest an overall depressed immunity in long-term type 1 DM. Increased gene expression levels for IFN-γ, IL-4 and IL-10 in new-onset patients from at-risk patients might be used as potential markers for progression of the disease.

Follicular helper T cell signature in type 1 diabetes

“…Although IFN-γ expression correlated with diabetes in NOD mice (2), other data suggested that diabetes in this model represented a Th2 rather than a Th1 phenomenon (3). Analysis of T cell differentiation in patients with T1D was similarly confusing: some work suggested increased IFNG mRNA (4) or stimulation-induced IFN-γ protein in individuals newly diagnosed with T1D (4,5); however, others found IFN-γ production to be significantly lower in patients with recent-onset T1D than in healthy control subjects (6,7). In one study, T cell reactivity to preproinsulin was shown to be Th2 dominant in autoantibody-positive subjects (8), again challenging the Th1 paradigm.…”

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

“…A general immune activation at the time of diagnosis of diabetes may also result from increased expression of IFNG, TNF, IL6, IL4, TGFB and IL10 mRNA compared with patients with type 1 diabetes of more than 5 years' duration [15].…”

CD4 T cell differentiation in type 1 diabetes

“…The characteristic transcription factors and a selection of surface markers associated with Th1 cells or Th2 cells is shown. [22]. This could potentially reflect a heightening of the Th1 response during conversion to overt disease.…”