Myelin-Associated Oligodendrocytic Basic Protein: Identification of an Encephalitogenic Epitope and Association with Multiple Sclerosis

Abstract

Myelin-associated oligodendrocytic basic protein (MOBP) is an abundant myelin constituent expressed exclusively by oligodendrocytes, the myelin-forming cells of the CNS. We report that MOBP causes experimental allergic encephalomyelitis and is associated with multiple sclerosis. First, we note that purified recombinant MOBP inoculated into SJL/J mice produces CNS disease. Tests of overlapping peptides spanning the murine MOBP molecule map the encephalitogenic site to amino acids 37–60. MOBP-induced experimental allergic encephalomyelitis shows a severe clinical course and is characterized by a prominent CD4+ T lymphocyte infiltration and a lesser presence of CD8+ T cells and microglia/macrophages around vessels and in the white matter of the CNS. Second, PBL obtained from patients with relapsing/remitting multiple sclerosis mount a proliferative response to human MOBP, especially at amino acids 21–39. This response equals or exceeds the response to myelin basic protein and an influenza virus hemagglutinin peptide, both serving as internal controls. Thus, a novel myelin Ag, MOBP aa 37–60, plays a role in rodent autoimmune CNS disease, and its human MOBP counterpart is associated with the human demyelinating disease multiple sclerosis.

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

“…Our results expanded previous data (Holz et al, 2000;Kaye et al, 2000) showing that MOBP should also be considered as a target of CD4 + T cell responses in MS. The MS patients analyzed here had heterogeneous MHC class II types (see Table 1); yet PBMC from all of them reacted to at least one MOBP peptide at one or more time points.…”

“…MOBP peptides were synthesized at TSRI peptide core facility by standard FMOC synthesis chemistry and were >95% pure as judged by HPLC and by mass spectrometry. Earlier report showed that these selected overlapping MOBP peptides induced a lymphoproliferative response of MS patients' PBMC (Holz et al, 2000). Recombinant human IL-2 (50 U/ml) (Roche, Nutley, NJ) was added 5 days after the beginning of the incubation.…”

“…oligodendrocytes in brain and spinal cord (Holz et al, 1996;Yamamoto et al, 1994) and is the third most abundant myelin protein in the CNS after MBP and PLP (Yamamoto et al, 1994). Rodent MOBP, either as whole protein or peptides, could induce experimental autoimmune encephalomyelitis in susceptible mice (Holz et al, 2000;Maatta et al, 1998). Analysis of the human MOBP sequence (Yamamoto et al, 1994) identified the presence of putative peptide-binding motifs for the MS-associated human leucocyte antigen (HLA)-DR alleles (Holz et al, 2000).…”

“…Rodent MOBP, either as whole protein or peptides, could induce experimental autoimmune encephalomyelitis in susceptible mice (Holz et al, 2000;Maatta et al, 1998). Analysis of the human MOBP sequence (Yamamoto et al, 1994) identified the presence of putative peptide-binding motifs for the MS-associated human leucocyte antigen (HLA)-DR alleles (Holz et al, 2000). Further, peripheral blood mononuclear cells (PBMC) from several MS patients display a specific proliferative response to human MOBP peptides, when compared to healthy donors (Holz et al, 2000).…”

Thiopalmitoylation of Myelin Proteolipid Protein Epitopes Enhances Immunogenicity and Encephalitogenicity

“…When SJL/J mice are immunized with an equimolar mixture of nonacylated encephalitogenic peptides PLP 139 -151 and PLP 178 -191 , responses to both peptides are equally strong (10,23). By contrast, if EAE is induced by immunization of SJL/J mice with whole spinal cord homogenate, which contains many potential autoantigens (4,10,(43)(44)(45), including PLP with covalently attached fatty acids, the dominant immune response is to PLP 139 -151 (46). Additionally, if EAE is induced in SJL/J mice with another autoantigen such as MBP, or if these mice are infected with Theiler's murine encephalomyelitis virus and allowed to recover, PLP 139 -151 is the first new epitope against which autoreactivity subsequently develops (47,48).…”