Steinman, LarryBar-Or, AmitBehne, Jacinta M.Benitez-Ribas, DanielChin, Peter S.Clare-Salzler, MichaelHealey, DonaldKim, James I.Kranz, David M.Lutterotti, AndreasMartin, RolandSchippling, SvenVilloslada, PabloWei, Cheng-HongWeiner, HowardZamvil, Scott S.Yeaman, Michael R.Smith, Terry J.2016-11-182016Steinman, L., A. Bar-Or, J. M. Behne, D. Benitez-Ribas, P. S. Chin, M. Clare-Salzler, D. Healey, et al. 2016. “Restoring immune tolerance in neuromyelitis optica: Part I.” Neurology® Neuroimmunology & Neuroinflammation 3 (5): e276. doi:10.1212/NXI.0000000000000276. http://dx.doi.org/10.1212/NXI.0000000000000276.2332-7812http://nrs.harvard.edu/urn-3:HUL.InstRepos:29407772Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.en-USJournal Article2016-11-1810.1212/NXI.0000000000000276