Figure 1

T1D onset and development. Genetic predisposition and environmental exposure interact with an impaired immune system to break tolerance towards pancreatic insulin-producing β-cells. Initial β-cell destruction leads to release of β-cell-specific auto-Ags, such as pro-insulin, GAD65, IA-2 and others. Upon auto-Ag-recognition, auto-reactive T cells expand, migrate to the pancreas (insulitis) and induce progressive β-cell destruction. In healthy individuals these auto-reactive T cells are controlled by regulatory T cells (Tregs). However, in T1D patients this regulatory counterpart is impaired causing a significant imbalance of this immune control mechanism. In addition, auto-Ag-activated B lymphocytes produce β-cell-specific auto-Abs. When patients present with clinical symptoms caused by insufficient β-cell-mass and subsequent aberrant glucose regulation, this auto-Ab profile allows for specific diagnosis of immune-mediated T1D. In general, T1D patients can only rely on exogenous insulin substitutions to stabilize their glucose metabolism. Possible therapeutic targets involved in the pathology of T1D are highlighted (gray boxes). Both systemic immunomodulation, amongst others monoclonal anti-CD3 antibodies and cyclosporine A, and Ag-based approaches have been explored to restore tolerance.