Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

IL-10 receptor and endoplasmic reticulum stress impairs STAT3 activation in type 1 diabetes patients and their healthy first degree relatives (#117)

Mamdouh Sedhom 1 , Andrew Cotterill 2 , Katharine Irvine 3 , Ray Steptoe 1 , Ranjeny Thomas 1
  1. The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD, Australia
  2. Mater Children’s Hospital, Brisbane, QLD, Australia
  3. Centre for Liver Disease Research, The University of Queensland School of Medicine, Wooloongabba, QLD, Australia

Autoimmune diseases including type 1 diabetes (T1D) result from disordered immune tolerance. We showed that an endoplasmic reticulum (ER) stress signature predicted poor outcome in recent-onset T1D patients, and is observed in a proportion of at-risk first degree relatives (FDR). To determine the relationship of ER stress to immune cell signalling, we compared monocyte and T cell STAT3 phosphorylation in response to IL-6 and IL-10 in 30 T1D, 35 FDR, 11 healthy controls, and 22 rheumatoid arthritis (RA) disease controls. Cytokine-stimulated signalling was detected in peripheral blood monocytes and T cells by flow cytometry. Expression of ER stress genes GRP78 and DDIT3 was quantified from PBMCs by RT-PCR. Induction of phospho (P)-STAT3 by IL-10 but not IL-6 was significantly reduced in T1D and FDR monocytes and T cells relative to healthy or RA controls. Basal levels of total STAT3 were comparable in all groups. This reduction in P-STAT3 response in T1D patients and FDR was associated with reduced IL-10-, but not IL-6-receptor expression by monocytes and T cells. IL-10 receptor expression and P-STAT3 induction in response to IL-6 and IL-10 were negatively associated with GRP78 and DDIT3 ER stress gene expression. IL-10 was shown to block ER stress in gut epithelium. Thus, our data implicate a disease-specific IL-10 receptor defect and its consequences on excess ER stress and disordered peripheral tolerance in T1D pathogenesis.