Multiple sclerosis is a chronic inflammatory disease of the CNS char- acterized by sharply demarcated areas of demyelination and axonal loss or damage, resulting in a multiplicity of neurological deficits 1 . The etiology of MS remains uncertain, but the disease is generally thought to result from an autoimmune response against myelin pro- teins in genetically susceptible individuals 2 . Immunological, immunohistochemical and molecular analyses of MS tissue suggests that the development of this disease is driven by a T helper cell type 1 (T H 1) inflammatory response, in concert with an autoantibody response directed against defined components of CNS myelin 3–5 . So far, MS has been regarded as a primary demyelinating disor- der, and much effort has been devoted to investigating the relation- ship between the evolution of lesions and clinical progression in terms of myelin destruction and repair. Current data relating to the role of axonal damage in the pathogenesis of MS show that there is a strong correlation among the extent of axon damage in the spinal cord, paralysis and loss of ambulation 6 . In our EAE model of MS, we previously found that axonal damage is evident from the earliest stage of disease and increases in severity with disease progression 7 . These observations suggest that axonal injury is an important pathological determinant of permanent disability in MS 6 . Unlike the PNS, regenerative nerve fiber growth and structural plasticity are limited in the adult CNS after insult 8 . In many cases, it has been shown that rather than the absence of growth-promoting mole- cules in the CNS, it is the presence of axon outgrowth inhibitors, including components of both CNS myelin and astroglial scars, that limits regeneration 8 . Since its identification as a principal inhibitor of neurite out- growth, Nogo A has received much attention 9 . The nogo gene is differ- entially spliced to generate three isoforms: A, B and C. Nogo A is the longest variant, is CNS-specific and contains a unique amino-termi- nal sequence (amino-Nogo). The carboxy-terminal portion of the Nogo A protein is common to all isoforms and contains two putative transmembrane domains that are separated by a short extramembra- nous region (Nogo-66). Both amino-Nogo and Nogo-66 have been reported to be inhibitory in vitro: amino-Nogo has a stronger neurite outgrowth inhibitory activity, whereas Nogo-66 is more potent in inducing growth cone collapse 10 . The mode of action of the Nogo-66 domain occurs via the Nogo- 66 receptor, NgR 10,11 . Notably, other inhibitory myelin proteins, namely myelin-associated glycoprotein (MAG) and oligodendro- cyte myelin glycoprotein (OMgp), exert their effects by interacting with the NgR system 12,13 . The emergence of Nogo A as a major inhibitor of neurite outgrowth and the identification of Nogo-66- mediated inhibition through the NgR has led to the development of strategies aimed at overcoming Nogo-mediated inhibition by tar- geting either NgR or Nogo A, thereby providing some prospect for spinal cord regeneration and repair 14,15 . Whereas most of the work on the effects of Nogo has been conducted in models of spinal cord injury, the role of Nogo in neurodegenerative diseases such as MS has not been assessed. Consequently, we have investigated the role of Nogo in the develop- ment of a chronic form of EAE provoked by the myelin oligodendro- cyte glycoprotein (MOG) 16 . We postulated that eliciting an immune 1 Neuroimmunology Laboratory, Department of Biochemistry, School of Molecular Sciences, La Trobe University, Bundoora, Victoria 3086, Australia. 2 Department of Neurology and Neurological Sciences, School of Medicine, 3 Department of Neurobiology, Developmental Biology, School of Medicine, and 4 Department of Biological Sciences, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. Correspondence should be addressed to C.C.A.B. (c.bernard@latrobe.edu.au). Published online 6 June 2004; doi:10.1038/nn1261 The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination Tara Karnezis 1,2 , Wim Mandemakers 3 , Jonathan L McQualter 1 , Binhai Zheng 4 , Peggy P Ho 2 , Kelly A Jordan 1 , Belinda M Murray 1 , Ben Barres 3 , Marc Tessier-Lavigne 2 & Claude C A Bernard 1 Inhibitors associated with CNS myelin are thought to be important in the failure of axons to regenerate after spinal cord injury and in other neurodegenerative disorders. Here we show that targeting the CNS-specific inhibitor of neurite outgrowth Nogo A by active immunization blunts clinical signs, demyelination and axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Mice vaccinated against Nogo A produce Nogo-specific antibodies that block the neurite outgrowth inhibitory activity associated with CNS myelin in vitro. Passive immunization with anti-Nogo IgGs also suppresses EAE. Our results identify Nogo A as an important determinant of the development of EAE and suggest that its blockade may help to maintain and/or to restore the neuronal integrity of the CNS after autoimmune insult in diseases such as MS. Our finding that Nogo A is involved in CNS autoimmune demyelination indicates that this molecule may have a far more complex role than has been previously anticipated. ARTICLES 736 VOLUME 7 | NUMBER 7 | JULY 2004 NATURE NEUROSCIENCE © 2004 Nature Publishing Group http://www.nature.com/natureneuroscience