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Molecular Mimicry between Neurons and an Intracerebral Pathogen Induces a CD8 T Cell-Mediated Autoimmune Disease¹

Monica Sanchez-Ruiz^*, Laura Wilden^*, Werner Müller^,, Werner Stenzel^*, Anna Brunn^*, Hrvoje Miletic^*, Dirk Schlüter^2, and Martina Deckert^2,*

^* Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln; Helmholtz Zentrum für Infektionsforschung, Experimentelle Immunologie, Braunschweig; Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany; and University of Manchester, Manchester, United Kingdom

To identify basic mechanisms of how infections may induce a neuron-specific autoimmune response, we generated mice expressing OVA as neuronal autoantigen under control of the neuron-specific enolase promoter (NSE-OVA mice). Intracerebral, but not systemic, infection with attenuated Listeria monocytogenes-secreting OVA induced an atactic-paretic neurological syndrome in NSE-OVA mice after bacterial clearance from the brain, whereas wild-type mice remained healthy. Immunization with attenuated Listeria monocytogenes-secreting OVA before intracerebral infection strongly increased the number of intracerebral OVA-specific CD8 T cells aggravating neurological disease. T cell depletion and adoptive transfer experiments identified CD8 T cells as decisive mediators of the autoimmune disease. Importantly, NSE-OVA mice having received OVA-specific TCR transgenic CD8 T cells developed an accelerated, more severe, and extended neurological disease. Adoptively transferred pathogenic CD8 T cells specifically homed to OVA-expressing MHC class I⁺ neurons and, corresponding to the clinical symptoms, 30% of neurons in the anterior horn of the spinal cord became apoptotic. Thus, molecular mimicry between a pathogen and neurons can induce a CD8 T cell-mediated neurological disease, with its severity being influenced by the frequency of specific CD8 T cells, and its induction, but not its symptomatic phase, requiring the intracerebral presence of the pathogen.

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 the Deutsche Forschungsgemeinschaft (Grant DE485/8-2) and the Zentrum für Molekulare Medizin Universität zu Köln (TV71).

² Address correspondence and reprint requests to Dr. Martina Deckert, Department of Neuropathology, University Hospital of Cologne, Kerpener Strasse 62, 50924 Köln, Germany. E-mail address: neuropatho{at}uni-koeln.de or Dr. Dirk Schlüter, Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail address: dirk.schlueter{at}medizin.uni-magdeburg.de

³ Abbreviations used in this paper: i.c., intracerebral; actA LMova, OVA-transgenic Listeria monocytogenes deleted of the actA gene; CNPase, 2',3'-cyclic nucleotide 3'-phosphodiesterase; GFAP, glial fibrillary acidic protein; LM, Listeria monocytogenes; LMova, Listeria monocytogenes-secreting OVA; LLO, listeriolysin O; NeuN, neuronal nuclei; NSE, neuron-specific enolase; p.i., postinfection; TfR, transferrin receptor; WT, wild type.