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In Trans T Cell Tolerance Diminishes Autoantibody Responses and Exacerbates Experimental Allergic Encephalomyelitis¹

J. Jeremiah Bell^2,*, Rohit D. Divekar^*, Jason S. Ellis^*, Jason A. Cascio^*, Cara L. Haymaker^*, Renu Jain^*, Danielle M. Tartar^*, Christine M. Hoeman^*, John C. Hardaway^* and Habib Zaghouani^3,*,

^* Department of Molecular Microbiology and Immunology, and Department of Child Health, School of Medicine, University of Missouri, Columbia, MO 65212

A number of Ag-specific approaches have been developed that ameliorate experimental allergic encephalomyelitis (EAE), an animal model for the human autoimmune disease multiple sclerosis. Translation to humans, however, remains a consideration, justifying the search for more insight into the mechanism underlying restoration of self-tolerance. Ig-proteolipid protein (PLP) 1 and Ig-myelin oligodendrocyte glycoprotein (MOG) are Ig chimeras carrying the encephalitogenic PLP 139–151 and MOG 35–55 amino acid sequence, respectively. Ig-PLP1 ameliorates EAE in SJL/J (H-2^s) mice while Ig-MOG modulates the disease in C57BL/6 (H-2^b) animals. In this study, we asked whether the chimeras would suppress EAE in F₁ mice expressing both parental MHC alleles and representing a polymorphism with more relevance to human circumstances. The results show that Ig-MOG modulates both PLP1 and MOG peptide-induced EAE in the F₁ mice, whereas Ig-PLP1 counters PLP1 EAE but exacerbates MOG-induced disease. This in trans aggravation of MOG EAE by Ig-PLP1 operates through induction of PLP1-specific T cells producing IL-5 that sustained inhibition of MOG-specific Abs leading to exacerbation of EAE. Thus, in trans T cell tolerance, which should be operative in polymorphic systems, can aggravate rather than ameliorate autoimmunity. This phenomenon possibly takes place through interference with protective humoral immunity.

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 Grants 2RO1 NS37406 and RO1 AI48541 (to H.Z.) from the National Institutes of Health. J.J.B., J.S.E., and C.M.H. were supported by the Predoctoral Training Grant T32 GM08396-13 from National Institute of General Medical Sciences. D.M.T., J.A.C., and J.C.H. were supported by a Life Science Fellowship from the University of Missouri (Columbia, MO).

² Current address: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

³ Address correspondence and reprint requests to Dr. Habib Zaghouani, Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, M616 Medical Sciences Building, Columbia, MO 65212. E-mail address: zaghouanih{at}health.missouri.edu

⁴ Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; MS, multiple sclerosis; PLP, proteolipid protein; agg, aggregated; MOG, myelin oligodendrocyte glycoprotein; MBP, myelin basic protein; HA, hemagglutinin; SP, spleen; LN, lymph node.

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The JI 2008 180: 1291-1292. [Full Text]