Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with a complex pathogenesis [
1]. MS pathology has been characterized by chronic inflammation, which leads to focal plaques of demyelination in the white matter [
2]. More than 50% of MS lesions show complement (C) and immunoglobulin G (IgG) deposition on demyelinating axons, classified as type II pathology [
3,
4], but there is no consensus as to either the specificity or pathologic role of IgG antibodies in blood or cerebrospinal fluid (CSF) of MS patients [
1]. Plasma exchange, which removes IgGs, as well as immune complexes and cytokines, was effective for a group of patients confirmed to have had type II MS pathology [
5]. This suggests that antibody and C are effectors of pathology in MS. Localization of C deposition has been shown in areas of active demyelination in patients with IgG myelin oligodendrocyte glycoprotein (MOG)-antibody-associated encephalomyelitis and pattern II MS [
6‐
8]. One candidate autoantigen in MS is MOG, which is expressed by oligodendrocytes and on the outermost surface of the myelin sheath [
9,
10]. Autoantibodies against MOG are implicated in pediatric MS [
11] and acute disseminated encephalomyelitis (ADEM) [
12] as well as in a subset of water channel aquaporin-4 (AQP4)-IgG seronegative neuromyelitis optica spectrum disorder (NMOSD) [
13‐
15].
The most extensively used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is an adjuvant-driven experimental autoimmune disease, which in most formulations is dependent on CD4+ T cells. In a commonly used EAE variant, immunization of C57BL/6 mice with an encephalitogenic peptide (MOG p35–55) induces a chronic inflammatory demyelinating disease that has been shown to be independent of IgG or B cells [
16], whereas immunization with recombinant human MOG or a fusion protein of myelin basic protein and proteolipid protein induces EAE that is dependent on B cells and antibody [
17‐
20]. It has previously been shown that injection of monoclonal antibody against MOG into Lewis rats with EAE induced demyelination [
21,
22]. Serum from guinea pigs with chronic-relapsing EAE could also induce demyelination, when transferred into subarachnoid space of normal rats and the degree of demyelination correlated with high titers of anti-MOG antibody in serum [
22]. However, direct demonstration of demyelination induced by MOG-specific antibody has not been reported. We have previously demonstrated complement-dependent astrocytopathology and demyelination in mice that received neuromyelitis optica (NMO) patient-derived IgG [
23]. We also showed a requirement for type I IFN signaling for NMO-like pathology, showing that it was reduced in mice lacking the receptor for type I IFN [
24]. This observation aligned with clinical findings that recombinant IFN-β is not an effective therapy for NMO whereas it shows effect for MS [
25‐
27]. Interestingly, MOG-IgG-positive patients also showed increased disease activity under treatment with IFN-β [
14,
28]. The objective of this study was to extend those findings, to investigate whether IFNAR dependency would be seen for other antibody specificities. We chose to test a monoclonal MOG-specific antibody. This required establishing that anti-MOG antibody is sufficient to induce primary demyelinating pathology and then to ask whether and how type I IFN signaling affects that pathology in mice with and without EAE.