oa Children With Type 1 Diabetes, Role Of Pro-inflammatory Cytokines As Disease Biomarkers

Background: Cytokines are important mediators of the inflammatory response in type 1 diabetes (T1D). We have previously observed pro-inflammatory cytokine profiles in children with islet autoimmunity. In the present study we examined the role of cytokine profiles as immunological biomarkers of T1D in a case-control study of 162 children at T1D onset and 164 community controls matched for age, sex and time. The diagnosis of T1D was based on presence of islet autoantibodies and clinical criteria. Methods: We measured 50 cytokines, chemokines and growth factors using the Millipore Cytokine Magnetic Bead Multiplex Assay. Heat maps and multivariate analyses were used assess how cytokine expression profiles may identify cases of T1D. Results: The levels of 30 cytokines, chemokines and growth factors were significantly different (p<0.01) in T1D cases vs controls; of these 11 were > 2-fold higher in T1D cases: Interleukin (IL)1β, IL6, IL10, IL13, IL15, IL23; Soluble CD40 ligand (sCD40L), tumor necrosis factor (TNF)β, epidermal growth factor (EGF), transforming growth factor (TGF)α and thrombopoietin (TPO). Using principal component analyses, case and control samples separated into two distinct clusters with little overlap, suggesting that cytokine profiles can accurately classify cases and controls. This was supported by partial least squares analysis, which estimates classification accuracy to be above 95% with leave-one-out cross-validation. Partial least squares analysis also ranked the contribution of each cytokine to accurate classification, in which the top 10 cytokines/chemokines were chemokine C-C motif ligand (CCL)8, sCD40L, TNFβ, chemokine C-X-C motif (CXCL)1, CXCL10, IL1β, IL10, IL13, TNF-related apoptosis-inducing ligand (TRAIL) and EGF. Conclusions: Our findings demonstrate that cytokine expression profiles may be useful biomarkers for classifying patients with T1D and indicate involvement of multiple immunological pathways in progression to T1D. Validation of these results in other T1D populations is needed.