Epitope Specificity of Autoreactive T and B Cells Associated with Experimental Autoimmune Encephalomyelitis and Optic Neuritis Induced by Oligodendrocyte-Specific Protein in SJL/J Mice

Abstract

The encephalitogenic potential of oligodendrocyte-specific protein (OSP) in mice, its specific localization in the intralamellar tight junctions in CNS myelin, and the detection of autoreactivity against OSP in multiple sclerosis (MS) strongly suggest the relevance of autoreactivity against OSP in the pathogenesis of MS. In this study, we have characterized the autoimmune T and B cells that are associated with clinicopathological manifestations of OSP-induced MS-like disease in mice by using recombinant soluble mouse OSP (smOSP) and synthetic overlapping peptides spanning smOSP. SJL/J mice immunized with smOSP developed chronic relapsing clinical experimental autoimmune encephalomyelitis accompanied with intense perivascular and parenchymal inflammatory infiltrates, widespread demyelination, axonal loss, and remarkable optic neuritis. The smOSP-primed lymph node cells reacted predominantly against OSP55–80 and to a lesser extent also to OSP22–46 and OSP179–207. Unexpectedly, in vitro selection with smOSP resulted in pathogenic smOSP-specific CD4+ T cells that reacted equally well against OSP55–80, OSP22–46, OSP45–66, and OSP179–207. Fine analysis of the anti-OSP autoimmunity revealed that the disease is primarily associated with CD4+ T cells directed against the major (OSP55–80) and the minor (OSP179–207) encephalitogenic regions that were further delineated, both in vitro and in vivo, to OSP55–66 and OSP194–207, respectively. In contrast, the OSP-induced Abs were predominantly directed against OSP22–46; these Abs were mostly of IgG1 isotype, but high levels of IgG2a and IgG2b and significant levels of IgE were also observed. The reactivity of pathogenic T cells to two encephalitogenic regions, OSP55–80 and OSP179–207, and their diverse TCRVβ gene repertoire may impose difficulties for epitope-directed or TCR-targeting approaches to immune-specific modulation of OSP-related pathogenesis.

Oligodendrocyte‐specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve

“…This would be in line with OSP-induced EAE in mice, which has been shown to be T cell dependent and class II-restricted [24,25]. OSP is encephalitogenic in C3H.SW, C57BL/6J and SJL/J mice, but not in ABH, BALB/c and PL/J mice [22,23,25]. Peptide data from these studies indicate that OSP p52-71 and OSP p179-207 have potent immunogenic and/or encephalitogenic potential [22,24].…”

“…Our model shares clinical and pathological features with the recently published OSP-induced EAE in the SJL/J mouse model [22]. Interestingly, clinical features and neuropathology of OSPinduced EAE in rhesus monkeys were markedly different from EAE induced by other myelin antigens in rhesus macaques [27].…”

“…OSP is encephalitogenic in C3H.SW, C57BL/6J and SJL/J mice, but not in ABH, BALB/c and PL/J mice [22,23,25]. Peptide data from these studies indicate that OSP p52-71 and OSP p179-207 have potent immunogenic and/or encephalitogenic potential [22,24]. Recently, it has been reported that in C57BL/6J mice the minimal encephalitogenic epitope is p191-199, with a particular restriction on 192Y [26].…”

“…OSP is primarily expressed in oligodendrocytes of the CNS and in Sertoli cells of testes [19][20][21]. Experiments in rodents have established that immunoreactivity to OSP induces experimental autoimmune encephalomyelitis (EAE), and suggest a pathogenic potential for autoreactive T cells recognizing OSP in MS patients [22][23][24][25][26].…”

Correlation of Blood T Cell and Antibody Reactivity to Myelin Proteins with HLA Type and Lesion Localization in Multiple Sclerosis

“…Studies on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, show that the distribution of lesions in the nervous system varies, depending on the Ag and immunization protocol used to induce EAE, and on the MHC and non-MHC genes carried by the animal (3)(4)(5)(6)(7)(8)(9)(10)(11). In MS, the distribution of demyelinated lesions in the CNS can vary from one patient to another, and there is currently no way of predicting where they will develop.…”