Leiden University Scholarly Publications

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Kracht, M.J.L. (2019)

Unravelling beta cell destruction in type 1 diabetes

Doctoral Thesis
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 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...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
Type 1 diabetes
Neoepitopes
Beta-cell
Autoimmunity
Endoplasmic reticulum stress
Insulin
All authors
Kracht, M.J.L.
Supervisor
Hoeben, R.C.; Roep, B.O.
Co-supervisor
Zaldumbide, A.
Committee
Kooten, C. van; Zwaginga, J.J.; Nikolic, T.; Wiertz, E.J.H.J.; Eizirik, D.L.
Qualification
Doctor (dr.)
Awarding Institution
Medicine / Leiden University Medical Center (LUMC), Leiden
Date
2019-06-25