The Role of Fas in Autoimmune Diabetes

We found that the ability to upregulate Fas is acquired by β cells during the natural course of diabetes in nonobese diabetic mice mice, indicating that Fas-mediated apoptosis of β cells may be the major mechanism for decrease in insulin production and establishment of diabetes

Alexander V Chervonsky

2004

Scholarcy highlights

  • Adaptive immunity provides protection from the multitude of exogenous infectious agents, which are recognized by clonal receptors expressed by T and B lymphocytes
  • We found that the ability to upregulate Fas is acquired by β cells during the natural course of diabetes in nonobese diabetic mice mice, indicating that Fas-mediated apoptosis of β cells may be the major mechanism for decrease in insulin production and establishment of diabetes
  • Expression of functional Fas ligand protein could be demonstrated in a thymocyte killing assay, in which overnight coincubation of B6 thymocytes with β cells isolated from transgenic animals but not from nontransgenic littermates led to apoptosis of thymocytes
  • The diabetes-inducing potential of the CD8+ T cells was overwhelming, so that even otherwise protected NOD-RIP-FasL-31 mice showed accelerated diabetes. These results suggested that the underlying mechanism for diabetes induction must be uniform for all RIP-FasL transgenic strains
  • That young RIP-FasL transgenic NOD mice showed accelerated diabetes following CD8+ T cell transfer, suggesting that young NOD mice can be induced to express Fas on their β cells to levels that make them sensitive to FasL expressed by β cells, but which are too low to be detected by immunohistochemical staining
  • None of the NODlpr/lpr mice had elevated glucose levels at the end of a 25-week observation period, while Fas-sufficient littermates showed over 75% incidence of diabetes
  • Based on the data of T cell transfer experiments, one would anticipate that Fas-negative NODlpr/lpr mice would be resistant to spontaneous diabetes, given that Fas-mediated apoptosis is a major mechanism of β cell destruction
  • Expression of Fas by pancreatic β cells has been shown to have a major influence on the susceptibility of nonobese diabetic mice mice to diabetes and to be associated with a critical transformation in the course of diabetes from benign infiltration to detrimental destruction of the islets

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