Glycoproteins as targets of autoantibodies in CNS inflammation: MOG and more

Abstract

B cells and antibodies constitute an important element in different inflammatory diseases of the central nervous system (CNS). Autoantibodies can serve as a biomarker to identify disease subgroups and may in addition contribute to the pathogenic process. One candidate autoantigen for multiple sclerosis (MS) is myelin oligodendrocyte glycoprotein (MOG). MOG is localized at the outermost surface of myelin in the CNS and has been the focus of extensive research for more than 30 years. Its role as an important autoantigen for T cells and as a target of demyelinating autoantibodies has been established in several variants of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The literature regarding antibodies to MOG in MS patients is confusing and contradictory. Recent studies, however, have described high levels of antibodies to conformationally correct MOG in pediatric acquired demyelination, both acute disseminated encephalomyelitis (ADEM) and MS. In adult MS, such antibodies are rarely found and then only at low levels. In this review, we summarize key findings from animal models and patient studies, discuss challenges in detecting anti-MOG antibodies in patients and present recent approaches to identifying new autoantigens in MS.

Keywords: ADEM; Myelin oligodendrocyte glycoprotein; detection methods of autoantibodies; multiple sclerosis.

Figure 1.

Distribution of central nervous system (CNS) myelin proteins. A neuron with a myelinated axon is depicted. Myelin enwraps the axon at intervals called internodes omitting small openings termed nodes of Ranvier. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four zones have a characteristic protein composition, as depicted in the upper part of the picture. At th nodes of Ranvier, Neurofascin 186 (NF186) supports the clustering of Na+ channels. To allow saltatory conduction, the nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where the myelin protein Neurofascin 155 (NF155) binds tightly to the axonal complex of Contactin-1 and Contactin-associated protein (Caspr). Connexins form gap junctions between myelin layers at the paranode. 2’3’-cyclic-nucleotide 3’-phosphodiesterase (CNP) is an abundant cytoplasmic myelin protein, predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2 is found both at the innermost myelin-sheath and the axon, allowing it to bind to itself. Typical myelin proteins are found at the internode: Proteolipid protein (PLP) and Myelin basic protein (MBP) are the major myelin proteins, the quantitatively minor Myelin oligodendrocyte glycoprotein (MOG) is found at the outermost surface of the myelin sheath. Nectin-like (NECL) adhesion proteins and Myelin associated glycoprotein (MAG) are found at the periaxonal space. Nogo is also predominantly found at the adaxonal myelin membrane, its receptor Nogo-receptor 1 (NgR1) is found at the axonal membrane.