Autoantibodies to neurofascin-186 and gliomedin in multifocal motor neuropathy Francesca Notturno a, ⁎, Tiziana Di Febo b , Nobuhiro Yuki c,h , Blanca M. Fernandez Rodriguez d , Davide Corti d , Eduardo Nobile-Orazio e , Marinella Carpo f , Angelo De Lauretis g , Antonino Uncini a a Department of Neuroscience and Imaging, University “G. d'Annunzio”, Chieti–Pescara, Italy b Experimental Zooprophylactic Institute of Abruzzo and Molise “G. Caporale”, Teramo, Italy c Department of Medicine, National University of Singapore, Singapore d Institute for Research in Biomedicine, Bellinzona, Switzerland e 2nd Neurology, Department of Medical Biotechnology and Translational Medicine, IRCCS Humanitas Clinical Institute, Milan University, Rozzano, Milan, Italy f Neurology Unit, Ospedale Treviglio, Bergamo, Italy g Department of Respiratory Medicine, Catholic University, Rome, Italy h Department of Physiology, National University of Singapore, Singapore abstract article info Article history: Received 15 February 2014 Received in revised form 2 September 2014 Accepted 4 September 2014 Keywords: Chronic inflammatory demyelinating neuropathy Gliomedin Neurofascin Multifocal motor neuropathy We tested autoantibodies to neurofascin-186 (NF186) and gliomedin in sera from patients with multifocal motor neuropathy (MMN, n = 53) and chronic inflammatory demyelinating polyneuropathy (CIDP, n = 95) by ELISA. IgG antibodies to NF186 or gliomedin were found in 62% of MMN and 1% of CIDP sera, and IgM antibodies to the same antigens in 12% of MMN and 1% of CIDP sera. These autoantibodies activated complement. Ten percent of the MMN sera without IgM anti-GM1 reactivity had anti-NF186 antibodies. Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Multifocal motor neuropathy (MMN) with conduction block is a slowly progressive neuropathy, presenting with asymmetrical, predom- inantly distal limb weakness without sensory loss (Vlam et al., 2011). IgM anti-GM1 antibodies are detected in half of the patients with MMN, and most patients with MMN respond to intravenous immuno- globulin, supporting the autoimmune etiology. In vivo and in vitro stud- ies on the pathogenic properties of IgM anti-GM1 antibodies yielded conflicting results (Uncini et al., 1993, Takigawa et al., 1995; Hirota et al., 1997), but higher titers correlated with more severe weakness. The anti-GM1 antibodies bind to the nodes of Ranvier, activate comple- ment and, disrupt voltage-gated sodium (Nav) channel clusters and axo-glial junctions, resulting in motor nerve conduction failure and muscle weakness (Susuki et al., 2007). However, half of the patients do not harbor IgM anti-GM1 antibodies (Vlam et al., 2011), suggesting that other autoantibodies are implicated in the pathogenesis of MMN. Neurofascin, a member of the L1 family of cell adhesion molecules, exists in 2 isoforms; neurofascin-186 (NF186) which is a neuronal pro- tein exposed on the axon surface at the nodes of Ranvier and associated with the β1 and β3 chains of the Nav channel, and neurofascin-155 (NF155) which is a myelin protein localized at the paranodal junction (Ratcliffe et al., 2001; Sherman et al., 2005). Gliomedin is localized at the Schwann cell microvilli that contact the node of Ranvier and is a ligand for NF186 (Eshed et al., 2005). Gliomedin belongs to the group of type II transmembrane collagens and contains two collagenous domains and an olfactomedin-like domain. Saltatory nerve conduction requires high-density accumulation of Nav channels at the nodes of Ranvier and the NF186–gliomedin complex plays a crucial role in anchoring Nav channels to the nodes of Ranvier by binding with Journal of Neuroimmunology 276 (2014) 207–212 ⁎ Corresponding author at: Department of Neuroscience and Imaging, University “G. d'Annunzio”, via dei Vestini, 66100 Chieti, Italy. Tel.: +39 3483221913. E-mail address: francnotturno@yahoo.it (F. Notturno). http://dx.doi.org/10.1016/j.jneuroim.2014.09.001 0165-5728/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim