Journal of the Peripheral Nervous System 16(Supplement):45–47 (2011) Fas-mediated T-cell apoptosis in chronic inflammatory demyelinating polyneuropathy Cristoforo Comi 1,2 1 Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD) and Department of Neurology, ‘‘A. Avogadro’’ University of Eastern Piedmont, Maggiore Hospital, Novara; 2 Neurorehabilitation Institute ‘‘M.L. Novarese’’, Moncrivello (VC), Italy Abstract The Fas receptor is expressed by activated lymphocytes and is involved in switching off the immune response. Defective Fas function causes the autoimmune lymphoproliferative syndrome, but is also involved in common autoimmune disorders. Fas- mediated T-cell apoptosis is impaired in chronic inflammatory demyelinating polyneuropathy (CIDP), but not in Guillain-Barr ´ e syndrome (GBS). The defect seems to have a genetic component and involve the extrinsic apoptotic pathway mediated by caspase-8. The analysis of clinical features shows that Fas function is lower in CIDP patients with a progressive course and axonal damage, suggesting that defective Fas function favors not only CIDP development but also its aggressive evolution. Moreover, testing T-cell Fas function in patients with acute-onset demyelinating polyneuropathy can help in early discrimination between GBS and acute-onset CIDP. Key words: apoptosis, CIDP, Fas, marker, T cell Introduction: The Role of Fas–FasL System in Autoimmunity Fas is a transmembrane receptor, exerting a dual role in the immune response. On one hand, Fas is expressed by activated lymphocytes, and its triggering by Fas ligand (FasL) expressed by several cell lines induces apoptosis of the Fas+-activated lymphocytes, which is a mechanism to switch off the immune response (Strasser et al., 2009). On the other hand, cytotoxic lymphocytes express FasL and kill target cells expressing Fas, which is a mechanism to clear viral infections (Rieux-Laucat et al., 2003). Fas induces cell apoptosis by triggering a cas- cade of caspases through two partly intercon- nected pathways; the extrinsic pathway involves caspase-8-mediated direct activation of the cascade, Address correspondence to: Dr. Cristoforo Comi, Interdisciplinary Research Centre of Autoimmune Diseases (IRCAD) and Depart- ment of Neurology, A. Avogadro University of Eastern Pied- mont, Maggiore Hospital, Novara, Italy. Tel: +3903213733965; Fax: +3903213733298; E-mail: cristoforo.comi@med.unipmn.it whereas the intrinsic pathway proceeds through mitochondrial release of cytochrome c and activation of caspase-9. Both pathways converge in the acti- vation of effector caspases, such as caspase-3, -6, and -7. The system is under the control of several inhibitors belonging to the family of FLICE-inhibitory protein (FLIP), bcl-2, and inhibitor of apoptosis protein (IAP) (Dianzani et al., 2003). Inherited defects of Fas function cause auto- immune lymphoproliferative syndrome (ALPS), a condition that is characterized by hematological auto- immunities and non-neoplastic accumulation of lym- phocytes in the spleen and lymph nodes. Patients with ALPS usually display expansion of atypical T cells expressing the T-cell receptor (TCR)α/β , but lacking CD4 and CD8, and markers of helper and cytotoxic lymphocytes, respectively, and therefore named double-negative T cells (DNT) (Straus et al., 1999; Dianzani et al., 2003). Most frequently, mutations affect the Fas gene (ALPS-Ia), but mutations of the FasL (ALPS-Ib) or caspase-10 genes (ALPS-II) have been reported as well; in other patients (ALPS-III), the mutated gene is not known.  2011 Peripheral Nerve Society 45