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Article Addendum

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

Roberto Towns, Massimo Pietropaolo and John W. Wiley

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Activation of membrane death receptors has been connected to apoptosis and, recently, other non-apoptotic events. For example, we reported recently that sera from either a subset of patients with type 2 diabetes with neuropathy or a subpopulation of patients with neurogenic chronic intestinal pseudo-obstruction (CIP) stimulate autophagy in SH-SY5Y human neuroblastoma cells via complement-independent, autoantibody-mediated activation of Fas (CD95). Activation of the Fas pathway causes minimal activation of apoptosis in these cells since procaspase-8 shows low constitutive levels of expression in neuroblastoma cells. The observation that anti-Fas autoantibodies induce autophagy is novel and provocative. This finding has implications regarding the pathophysiology of diabetic neuropathy, CIP and, perhaps, other autoimmune disorders. For example, recent reports suggest that expression or activity of proapoptotic caspases can be enhanced by activation of more than one membrane death receptor, as could happen by combinations of cytokines and autoantibodies. The observation that autophagy, a putative cytoprotective pathway that has also been implicated in non-apoptotic cell death, is activated by autoantibodies against Fas, may represent an early cellular protective response. An increase in cytotoxic cytokine levels or the ratio of agonist:antagonist autoantibodies may “tip” the balance of the cellular response to activation of programmed cell death pathways.

Addendum to: Towns R, Guo C, Shangguan Y, Hong S, Wiley JW. Type 2 diabetes with neuropathy: autoantibody stimulation of autophagy via Fas. Neuroreport 2008; 19:265-9.
and
De Giorgio R, Volta U, Stanghellini V, Cogliandro RF, Barbara G, Corinaldesi R, Towns R, Guo C, Hong S, Wiley JW. Neurogenic chronic intestinal pseudo-obstruction: Anti-neuronal antibody-mediated activation of autophagy via Fas. Gastroenterology 2008; in press.

Authors

Roberto Towns

University of Michigan

Massimo Pietropaolo

University of Michigan

John W. Wiley

University of Michigan

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