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The role of granzyme A in initiation of type 1 diabetes

The role of granzyme A in initiation of type 1 diabetes

PhD/Honours project

Sensing of nucleic acids by innate immune pathways is essential for normal immunity against viruses, and defects in this process lead to autoimmune diseases such as type 1 diabetes. Cleavage of intracellular DNA is mediated by molecules of the SET complex, and this complex can be activated by the serine protease granzyme A. Mutations in molecules in the SET complex, such as the 3’ endonuclease Trex1, result in autoimmunity in mice and man that is driven by excessive production of type 1 IFN. Type I interferons (IFN) have been implicated in initiation of islet autoimmunity and development of type 1 diabetes. While studying cytotoxic T cell-mediated b cell death in type 1 diabetes, we discovered that non-obese diabetic (NOD) mice lacking granzyme A have accelerated diabetes, and a 6-fold increase in islet expression of genes regulated by type I IFN. Our data indicate a crucial role for granzyme A in controlling activation of innate immunity. While type 1 IFN in NOD mice is not required for diabetes development, excessive activation in a genetic background that is prone to autoimmunity, results in accelerated disease. We plan to identify the mechanism by which granzyme A contributes to accelerated diabetes development.

Supervised by:

  • A/Prof Helen Thomas
  • Disease Focus:

  • Type 1 diabetes
  • Research Unit:

  • Islet biology