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* Experimental Neuroimmunology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany;
Department of Clinical Neuroscience, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;
Redoxis, Göteborg, Sweden;
Section for Medical Inflammation Research, Biomedical Center, Lund University, Sweden; and
¶ Section for Medical Inflammation Research, Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
We here present the first genetic fine mapping of experimental autoimmune neuritis (EAN), the animal model of Guillain-Barré syndrome, in a rat advanced intercross line. We identified and refined a total of five quantitative trait loci on rat chromosomes 4, 10, and 12 (RNO4, RNO10, RNO12), showing linkage to splenic IFN-
secretion and disease severity. All quantitative trait loci were shared with other models of complex inflammatory diseases. The quantitative trait locus showing strongest linkage to clinical disease was Ean6 and spans 4.3 Mb on RNO12, harboring the neutrophil cytosolic factor 1 (Ncf1) among other genes. Polymorphisms in Ncf1, a member of the NADPH oxidase complex, have been associated with disease regulation in experimental arthritis and encephalomyelitis. We therefore tested the Ncf1 pathway by treating rats with a NADPH oxidase complex activator and ameliorated EAN compared the oil-treated control group. By proving the therapeutic effect of stimulating the NADPH oxidase complex, our data strongly suggest the first identification of a gene regulating peripheral nervous system inflammation. Taken together with previous reports, our findings suggest a general role of Ncf1 and oxidative burst in pathogenesis of experimental autoimmune animal models.
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 study was supported by the German Research Foundation (DFG We 1947/4-1/2) to R.W. and European Rat Tools for Functional Genomics (European Commission contract no. LSHG-CT-2005-019015) and Neuroprotective Strategies for Multiple Sclerosis (European Commission contract no. LSHM-CT-2005-01863) to T.O.
2 A.H. and A.D.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Robert Weissert, Department of Neurosciences, Division of Neurology, Geneva University Hospital, Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. E-mail address: robert.weissert{at}hcuge.ch
4 Abbreviations used in this paper: GBS, Guillain-Barré syndrome; AIDP, acute inflammatory demyelinating polyradiculoneuropathy; AIL, advanced intercross line; bPMN, bovine peripheral nerve myelin; CI, confidence interval; EA, experimental arthritis; EAE, experimental autoimmune encephalomyelitis; EAN, allergic autoimmune neuritis; LOD, logarithm of the likelihood ratio; MNC, mononuclear cell; MOG, myelin oligodendrocyte glycoprotein; Ncf1, neutrophil cytosolic factor 1; p.i., postimmunization; PIA, pristine-induced arthritis; PNM, peripheral nerve myelin; QTL, quantitative trait locus; RNO, rat chromosome; RT1, MHC of rat.
5 The online version of this article contains supplemental material.
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  K. Hagenow, K. A. Gelderman, M. Hultqvist, P. Merky, J. Backlund, O. Frey, T. Kamradt, and R. Holmdahl Ncf1-Associated Reduced Oxidative Burst Promotes IL-33R+ T Cell-Mediated Adjuvant-Free Arthritis in Mice J. Immunol., July 15, 2009; 183(2): 874 - 881. [Abstract] [Full Text] [PDF]
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