Commentary: Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)‐specific autoantibody repertoire

Abstract

Myelin oligodendrocyte glycoprotein (MOG) is the only myelin protein known to initiate a demyelinating autoantibody response in EAE, an animal model for multiple sclerosis (MS). The pathophysiological significance of MOG-specific autoantibodies in MS is, however, controversial, as high titer antibody responses to MOG are also found in many patients with nondemyelinating neurological diseases. In this issue of the European Journal of Immunology, von Büdingen et al. demonstrate that demyelination in a primate model of MOG-induced EAE is mediated by MOG-specific antibodies directed against discontinuous, rather than linear, MOG epitopes. This functional segregation of pathogenic vs. non-pathogenic autoantibodies in terms of epitope specificity may be crucial to understand the relevance of MOGspecific responses in human disease. This commentary discusses these findings in the context of the structure and immunobiology of MOG, and their implications with respect to antibody-mediated demyelination in MS. Humoral responses in the pathogenesis of multiple sclerosisLoss of immunological self-tolerance to myelin antigens in genetically susceptible individuals plays a major role in the pathogenesis of multiple sclerosis (MS), a complex inflammatory demyelinating disease of the central nervous system (CNS) [1]. MS is often discussed as a purely T cell mediated disease, but there is increasing indirect evidence that antibody-dependent mechanisms are also involved in disease pathogenesis. Immunopathological studies identified immunoglobulins and complementactivation products deposited on the surface of intact myelin sheaths at the active edge of demyelinating lesions, as well as the presence of opsonized myelin debris that is cleared from the lesions by activated macrophages [2][3][4][5][6][7]. Plasma exchange can also dramatically reduce clinical disease activity in a subset of MS patients [8,9]. This provides further circumstantial evidence that humoral factors can be involved in disease pathogenesis, but their mode of action remains obscure.The tacit assumption made on the basis of immunopathological findings is that this mode of action involves autoantibodies recognizing determinants exposed on the surface of the myelin sheath. Immunopathological studies indicate that the clinical significance of antibodymediated demyelination in this response varies between patients. There is no evidence at all that antibody is involved in lesion formation in 20-40% of patients [5,6], whilst in some subtypes of MS such as Devic's disease (neuromyelitis optica) antibody-mediated effects may play a dominant role in disease pathogenesis [7]. There is also a wide variation in the clinical response of MS Eur. J. Immunol. 2004. 34: 2065-2071 patients to plasma exchange [8,9]. This supports the concept that the effector mechanisms involved in disease pathogenesis can vary significantly between patients, but its relationship to antibody-mediated demyelination remains unproven.It is obvious that if we were able to identify those patients in who...

Chapter 4 B Cells and Autoantibodies in the Pathogenesis of Multiple Sclerosis and Related Inflammatory Demyelinating Diseases

“…Antibodies that bind to native MOG are most relevant to the disease, but are not detectable with all assays. Many of these studies used Western blots, which only detect antibodies to denatured antigen, or ELISAs, which cannot distinguish between responses to folded and unfolded proteins (Mathey et al, 2004). Furthermore, the results obtained with Western blots and ELISAs do not necessarily correlate, even with the same sera .…”

Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology

“…B cell responses in MS pathogenesis are implicated by the presence of Ig deposits and myelin debris in demyelinating lesions (3)(4)(5)(6)(7)(8), and the observation that plasma exchange dramatically reduces clinical disease in a subset of patients (9). Of particular interest to the present study, antibodies to myelin oligodendrocyte glycoprotein (MOG) are detected in the sera and plaques of MS patients (10), and thus are possible predictors of disease progression (11).…”

“…Attempts have been made to distinguish between pathogenic and nonpathogenic antibodies against MOG antigens in MS and EAE (6). ELISA assays of the antibodies generated by immunization with human or rat MOG do not readily distinguish among different determinants (25).…”

Significance of autoantibodies

“…This is illustrated, for example, by the finding that the recognition of a specific epitope within the MOG protein distinguishes the multiple sclerosis-specific autoantibody response to MOG from that in nondemyelinating disease. 18 The study of autoantibodies has thus far usually been based on a rather simple one-to-one paradigm of a direct antigen-autoantibody interaction as the key pathogenetic process. However, the immune system, like the neural system is based on a complex multitude of molecular interactions, and pathogenetic processes are influenced by a multitude of factors.…”