Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis

Abstract

Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demyelination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these auto Abs. Compared with healthy controls, native MOGspecific IgGs were most frequently found in serum of clinically isolated syndromes (P < 0.001) and relapsing-remitting MS (P < 0.01), only marginally in secondary progressive MS (P < 0.05), and not at all in primary progressive MS. We demonstrate that epitopes exposed in this cell-based assay are different from those exposed on the refolded, extracellular domain of human recombinant MOG tested by solid-phase ELISA. In marmoset monkeys induced to develop MS-like CNS inflammatory demyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other myelin constituents. We conclude that (i) epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs; (ii) these Abs, which are not detected in solidphase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and (iii) the cell-based assay provides a practical serologic marker for early detection of CNS autoimmune demyelination including its preclinical stage at least in the primate MS model. allergic encephalomyelitis ͉ autoimmunity ͉ clinically isolated syndrome ͉ demyelination

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

“…In the CSF, antigen microarrays in MS have detected antibodies to lipid (6) and ␣B-crystallin (23) and of note, the ␣B-crystallin reactive antibodies were of low affinity, detectable at 1:20 dilution (23). High-affinity autoreactive antibodies in the serum have not been consistently found in MS (24)(25)(26)(27)(28). We found that unique autoantibody signatures characterize RRMS, SPMS and PPMS based on reactivity to CNS antigens and HSP.…”

Antibody response in MOG35–55 induced EAE

“…In addition, myelinspecific antibodies have been identified in areas of vesicular demyelination (Genain et al, 1999), suggesting that they directly promote CNS damage, at least in a subset of MS patients . Among these antibody responses, those directed against conformational epitopes of myelin-oligodendrocyte glycoprotein (MOG) are considered to be potentially pathogenic in MS (Lalive et al, 2006;Menge et al, 2007;Lalive, 2008;Lalive et al, 2011;Weber et al, 2011).…”

MOG79–90 Peptide in Complex with Recombinant MHC Class II Molecules Ameliorates Experimental Autoimmune Encephalomyelitis

“…The extracellular part of this protein could be a potential target for pathogenic antibodies and immune cells. Indeed, MOGspecific autoantibodies have been detected in actively demyelinating lesions and cerebrospinal fluid (CSF) of MS patients (9,14,20). In addition, high frequencies of MOGreactive T cells in blood and CSF have also been reported in MS (6,10,13).…”