Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon-Dependent Pathway

Diabetes. 2017 Dec;66(12):3041-3050. doi: 10.2337/db17-0517. Epub 2017 Jul 21.


Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Single-Stranded / metabolism
  • Diabetes Mellitus, Type 1 / etiology*
  • Female
  • Granzymes / deficiency
  • Granzymes / physiology*
  • Immune Tolerance*
  • Interferon Type I / physiology*
  • Islets of Langerhans / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction


  • DNA, Single-Stranded
  • Interferon Type I
  • Granzymes