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* Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and
Clinical Institute of Neurology and
Center for Brain Research, Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research grants from the Israel Science Foundation, the National Multiple Sclerosis Society of New York, the Israel Ministry of Health, and the William Sahm Foundation. A.B.-N. is the incumbent of the Eugene and Marcia Applebaum Professorial Chair.
2 N.K. and M.-C.Z. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Avraham Ben-Nun, Department of Immunology, The Weizmann Institute of Science, P.O. Box 26, Rehovot 76000, Israel. E-mail address: avraham.ben-nun{at}weizmann.ac.il
4 Abbreviations used in this paper: MS, multiple sclerosis; βAPP, β-amyloid precursor protein; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; LNC, lymph node cells; MBP, myelin basic protein; MOBP, myelin-associated oligodendrocytic basic protein; MOG, myelin oligodendrocyte glycoprotein; OSP, oligodendrocyte-specific protein; smOSP, recombinant soluble mouse OSP; pmOSP, mouse OSP peptide; PLP, proteolipid protein.
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