Dendritic cells (DCs) play a crucial role in establishing and maintaining the balance between immunity to pathogens and tolerance to self. Whether DCs evoke T cell activation or tolerance in response to antigen presentation is determined by the physiological context in which they differentiate and mature. DC differentiation and inflammatory signalling is abnormal in type 1 diabetes (T1D), but the relationship between this abnormality and disease pathogenesis requires clarification. We have shown constitutive activation and defective inflammatory responses in critical sub-units of the NF-kappaB transcription factor family, known as RelB and p65, which are required for myeloid DC differentiation, in T1D monocytes and DCs. Abnormal RelB activation may constitute a novel T1D risk phenotype. Our data indicate that peripheral blood cell RelB activation and associated inflammatory gene expression is increased in autoantibody-negative first-degree relatives of T1D patients. In autoantibody-positive and autoantibody-negative subjects, serum inflammatory cytokine expression is heterogeneous. We hypothesize that premature RelB activation and pro-inflammatory cytokine production during DC differentiation compromises the development of immunological tolerance and contributes to T1D pathogenesis. In this project we wish to investigate whether RelB activation and inflammatory cytokine expression in peripheral blood is associated with distinct pancreatic pathology in T1D and at-risk subjects. This information could enable us to stratify pancreatic pathology in living T1D patients and at-risk subjects, based on their peripheral blood RelB and inflammatory biomarker status. Moreover strategies for early therapeutic intervention to prevent or treat T1D may differ depending on pancreatic pathology.