Type 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing beta cells. Genetic predisposition, impaired immune regulation, and beta cell (dys)function all... Show moreType 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing beta cells. Genetic predisposition, impaired immune regulation, and beta cell (dys)function all contribute to disease initiation and progression. A critical gap in our knowledge is what causes the break in peripheral tolerance that eventually leads to beta cell destruction. We propose that neoepitopes generated by dysfunctional beta cells activate immune surveillance, causing beta cell autoimmunity. ER stress imposed both by intrinsic beta cell physiology and by external secondary triggers seems to be a crucial component in this process. Understanding the molecular mechanisms underlying beta cell dysfunction and neoantigen generation is critical to identify clinically relevant neoepitopes. This subsequently provides more insight in the disease dynamics as well as contribute to translational research in the development of biomarker assays and development of therapeutic strategies targeting autoreactive T-cells and beta cell function. Our task will be to restore the balance between immune reactivity and beta cell function, in order to prevent, treat, or cure type 1 diabetes. Show less
Alpha1-antitrypsin is an important neutrophil elastase inhibitor that protects lung tissue from the destructive effects of neutrophil elastase released by degranulating neutrophils. In addition to... Show moreAlpha1-antitrypsin is an important neutrophil elastase inhibitor that protects lung tissue from the destructive effects of neutrophil elastase released by degranulating neutrophils. In addition to the liver, local production by macrophages and airway and alveolar epithelial cells may contribute to the formation of an anti-elastase screen in the lung. The Z mutation (E342K) of _1-antitrypsin, compromising over 95% of the _1-antitrypsin deficiency patients, causes subtle misfolding of the protein that permits polymer formation and accumulation within the endoplasmic reticulum (ER) of hepatocytes leading to plasma deficiency. This causes hepatic cirrhosis and early-onset lung emphysema. The discovery of ZZ polymers in broncho-alveolar lavage fluid and pulmonary tissue and their identification many years after liver transplantation led to the proposal that pulmonary pathology could be induced by polymers. Overexpression of Z _1-antitrypsin is known to induce polymer formation, prime cells for an exaggerated ER stress response upon a second hit and initiate NF-_B signalling. However, whether endogenous expression in primary bronchial epithelial cells and monocyte-derived macrophages has similar consequences remained unclear. This thesis concentrate on these specific questions. In addition, we focused on the ER stress response induced by P.aeruginosa as a possible second hit in _1-antitrypsin deficiency Show less
