NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 1 Clinical Department of Neurology (M. Reindl, F. Di Pauli, T. Berger), Department of Pediatrics I (K. Rostásy), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Correspondence to: M. Reindl markus.reindl@ i-med.ac.at The spectrum of MOG autoantibody- associated demyelinating diseases Markus Reindl, Franziska Di Pauli, Kevin Rostásy and Thomas Berger Myelin oligodendrocyte glycoprotein (MOG) has been identified as a target of demyelinating autoantibodies in animal models of inflammatory demyelinating diseases of the CNS, such as multiple sclerosis (MS). Numerous studies have aimed to establish a role for MOG antibodies in patients with MS, although the results have been controversial. Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of high-titre MOG antibodies in paediatric patients with acute disseminated encephalomyelitis, MS, aquaporin-4-seronegative neuromyelitis optica, or isolated optic neuritis or transverse myelitis, but only rarely in adults with these disorders. These studies indicate that MOG antibodies could be associated with a broad spectrum of acquired human CNS demyelinating diseases. This Review article discusses the current literature on MOG antibodies, their potential clinical relevance, and their role in the pathogenesis of MOG antibody-associated demyelinating disorders. Reindl, M. et al. Nat. Rev. Neurol. advance online publication 25 June 2013; doi:10.1038/nrneurol.2013.118 Introduction The spectrum of acquired CNS inflammatory demyelin- ating diseases comprises multiple sclerosis (MS) plus a range of less prevalent disorders, such as neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), Marburg disease, Balo concentric sclerosis, and Schilder disease (Figure 1). 1,2 These pathogenetically dis- tinct rare diseases typically show differences with regard to age of onset, clinical course, disease severity, radiologi- cal, pathological and cerebrospinal fluid (CSF) features, and treatment. However, overlapping clinical features, as well as similarities in MRI, serum and/or CSF findings, often make diagnosis of these diseases difficult, especially at onset (referred to as the first demyelinating event). In many autoimmune disorders, disease-associated autoantibodies have emerged as important diagnostic and prognostic biomarkers. 3 The role of antibodies in the diagnosis and differential diagnosis of inflammatory CNS demyelinating diseases is still unclear, however, with the notable exception of aquaporin-4 (AQP4) autoantibodies in NMO, a chronic demyelinating disease characterized by relapsing optic neuritis and longitudinally extending transverse myelitis (Box 1). Various myelin and nonmyelin antigens have been implicated as targets of humoral immune reactions in CNS demyelinating diseases. 4–7 Among these, reactiv- ity against myelin oligodendrocyte glycoprotein (MOG) has been the most extensively analysed, and the results indicate a possible role in the pathogenesis of MS. In this Review article, we discuss whether antibodies against MOG could be a useful biomarker for diagnosis and prog- nosis across the spectrum of acquired CNS demyelinating disease, and consider the extent to which MOG antibodies might participate in the pathogenesis of these conditions. MOG autoantibodies The target protein MOG is a member of the immunoglobulin superfamily, and is highly conserved between species. 8 The MOG gene maps to the region encoding the major histocompatibil- ity complex in humans and rodents. Full-length MOG consists of 218 amino acids (28 kDa) 9 and is exclusively expressed in the CNS on the outermost surface of the myelin sheath and the plasma membrane of oligodendro- cytes. 10 Although MOG is a minor component of myelin (0.05%), it is an important surface marker of oligodendro- cyte maturation because its temporal expression parallels that of myelination. 11 Evidence exists that MOG might act as a cell adhe- sion molecule, a regulator of microtubule stability, and a mediator of interactions between myelin and the immune system. 11 MOG was first identified as the primary anti- genic target of demyelinating antibodies in experimental autoimmune encephalomyelitis (EAE) induced by CNS tissue homogenates, 12 and studies have shown that anti- bodies against MOG can augment demyelination. 13,14 Several subsequent experimental studies have shown that the extracellular domain of MOG is highly encephalito- genic and induces both a cell-mediated and a humoral immune response. 7,15 Moreover, mice that are transgenic for MOG-specific T-cell and B-cell receptors develop spontaneous EAE. 16–19 Antibody detection The relevance of antibodies against MOG to the patho- genesis of MS in humans is still controversial. Most of Competing interests The authors declare no competing interests. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved