Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases

Abstract

Recent studies demonstrated the presence of autoantibodies to native myelin oligodendrocyte glycoprotein (MOG) in juvenile patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). However, so far no longitudinal studies on anti-MOG antibodies have been performed. Therefore, we determined serum and CSF antibodies against native human MOG in 266 pediatric and adult subjects with ADEM, clinically isolated syndrome (CIS), MS, other neurological diseases (OND) and healthy controls (HC) and longitudinal samples of 25 patients with ADEM, CIS, MS and OND using an immunofluorescence assay. We detected serum high-titer MOG IgG in 15/34 (44%) patients with ADEM, but only rarely in CIS (3/38, 8%), MS (2/89, 2%), OND (1/58, 2%) and HC (0/47). Longitudinal analysis of serum anti-MOG IgG showed different temporal dynamics of serum antibody responses in ADEM, CIS and MS and indicated an association of a favorable clinical outcome in ADEM with a decrease in antibody titers over time.

Introduction

Multiple sclerosis (MS), the most frequent demyelinating disease of the central nervous system (CNS), is considered to be caused by an autoimmune attack to myelin sheaths involving cellular and humoral components of the immune system. The resulting inflammatory reaction subsequently leads to demyelination and axonal loss [1], [2]. Whereas MS was long assumed to be a CD4 T cell mediated autoimmune disease, there is rising evidence of an important contribution of humoral immune responses to the pathogenesis in at least a subgroup of patients [3], [4], [5]. Detection of oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) and an elevated intrathecal IgG synthesis in more than 90% of MS patients are well established [6], [7]. Although numerous studies addressed this question, the role of these antibodies in the disease process is still unknown [8]. One extensively studied potential target structure for autoantibodies is the myelin oligodendrocyte glycoprotein (MOG), which is localized on the outer surface of myelin sheaths and oligodendrocytes [9]. It has been shown that antibodies against MOG can induce and enhance demyelination in vitro [10] and in experimental autoimmune encephalomyelitis (EAE) [11]. Although these results indicate a pathogenic potential of anti-MOG antibodies, there is an ongoing controversy about the presence of anti-MOG antibodies in CSF and serum of MS patients and their contribution to the disease process. Recent data indicate that pathogenic antibodies recognize the correct membrane topology and glycosylation pattern of MOG [12]. Therefore, detection of antibodies to conformational epitopes on surface exposed and glycosylated MOG would add more reliably to their pathogenic role. Hallmark studies detected increased serum levels of these antibodies in MS patients using cells expressing native human MOG on their surface [13], [14], [15]. Additionally, MOG-specific autoantibodies were recently shown to be more present in children with acute disseminated encephalomyelitis (ADEM) and MS, but only rarely in adult-onset MS [16], [17], [18]. In contrast to MS, ADEM is considered a typically monophasic inflammatory demyelinating disease [19], more prevalent in childhood [20]. At onset, ADEM may be difficult to be distinguished from a clinically isolated syndrome (CIS), the most common first manifestation of MS, and vice versa. Thus, early diagnostic differentiation by a reliable biomarker would be of great value for the management of patients and appropriate treatment decisions [19]. Therefore, we investigated serum and CSF antibody levels against recombinant native MOG and recombinant refolded MOG in adult and pediatric patients with different CNS demyelinating diseases and controls. Furthermore, we analyzed longitudinal patterns of anti-MOG antibody responses in CNS demyelinating diseases in a subset of patients with ADEM, CIS and MS.