Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases
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.
Section snippets
Patients
Seventy-eight pediatric and 188 adult patients and controls were recruited in Austria. This study was approved by the ethical committee of Innsbruck Medical University (study no. UN3041 257/4.8) and informed consent was obtained from all patients or parents/legal guardians.
All serum and CSF samples were collected between 2000 and 2010. We included 78 pediatric cases with ADEM (n = 27), CIS (n = 18), RRMS (n = 18) or other neurological diseases (OND, n = 15) as well as 188 adult patients with ADEM (n =
Results
High-titer serum anti-MOG IgG antibodies are predominantly present in pediatric ADEM patients.
The presence of serum antibodies to MOG was evaluated with a live cell staining IF assay in the above described cohort. As depicted in Fig. 1, antibody positive samples showed co-localization of IgG Abs (red) with the membrane protein MOG (green), whereas the CD2 transfected control cells showed no co-staining.
A significantly higher proportion of MOG IgG seropositivity was detected in ADEM patients as
Discussion
This study shows the specific presence of high-titer IgG antibodies to native MOG in a subgroup of ADEM patients with predominance in pediatric cases. In contrast, an ELISA using recombinant human MOG was not able to detect these ADEM specific antibodies, possibly due to missing glycosylation and lack of correct antigen structure.
Former studies using cell-based assays reported a higher proportion of MOG IgG seropositivity in patients with MS compared to controls [13], [15]. These findings are
Acknowledgments
This study was supported by a research grant (no. 2007104) of the Interdisciplinary Center for Research and Treatment (IFTZ) of Innsbruck Medical University.
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These authors contributed equally to the manuscript.