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Stimulation of autophagy by autoantibody-mediated activation of death receptor cascades

Roberto Towns1, Massimo Pietropaolo, John W Wiley

  • 1Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109-2200, USA. rtowns@med.umich.edu

Autophagy
|June 19, 2008
PubMed

Insights

Autoantibodies against Fas (CD95) stimulate autophagy, a cellular protective response, in neuroblastoma cells. This finding offers new insights into diabetic neuropathy and chronic intestinal pseudo-obstruction (CIP) pathophysiology.

Area of Science:

  • Immunology
  • Cell Biology
  • Neuroscience

Background:

  • Membrane death receptor activation is linked to apoptosis and non-apoptotic cellular events.
  • Previous research indicated sera from specific patient groups stimulate autophagy in neuroblastoma cells via autoantibody-mediated Fas activation.
  • Fas pathway activation typically results in minimal apoptosis in neuroblastoma cells due to low procaspase-8 expression.

Purpose of the Study:

  • To investigate the novel finding that anti-Fas autoantibodies induce autophagy.
  • To explore the implications of this phenomenon in the pathophysiology of diabetic neuropathy and neurogenic chronic intestinal pseudo-obstruction (CIP).
  • To understand the role of autophagy as a potential early cellular protective response.

Main Methods:

  • Utilized SH-SY5Y human neuroblastoma cells.
  • Investigated sera from patients with type 2 diabetes with neuropathy and neurogenic chronic intestinal pseudo-obstruction (CIP).
  • Examined autoantibody-mediated activation of Fas (CD95) in a complement-independent manner.

Main Results:

  • Sera from a subset of patients with type 2 diabetes with neuropathy or CIP stimulated autophagy in neuroblastoma cells.
  • This stimulation was mediated by autoantibody activation of Fas (CD95).
  • Fas activation led to minimal apoptosis due to low procaspase-8 levels.

Conclusions:

  • Autoantibody-mediated activation of Fas (CD95) can induce autophagy, a potentially cytoprotective pathway.
  • This mechanism provides novel insights into the pathophysiology of diabetic neuropathy and CIP.
  • Autophagy activation by autoantibodies may represent an early cellular response, with the balance potentially shifting towards programmed cell death under certain conditions (e.g., increased cytokines or altered autoantibody ratios).

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