HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harnesk, K. Articles by Piehl, F. Search for Related Content PubMed PubMed Citation Articles by Harnesk, K. Articles by Piehl, F. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene

Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis¹

Karin Harnesk^2,*, Maria Swanberg^2,3,*, Johan Öckinger^*, Margarita Diez^*, Olle Lidman^*, Erik Wallström^*, Anna Lobell^*,, Tomas Olsson^* and Fredrik Piehl^*

^* Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden; and Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Presentation of Ag bound to MHC class II (MHC II) molecules to CD4⁺ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVG^av1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN- in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVG^av1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVG^av1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVG^av1 and PVG^av1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.

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 6th Framework Program of the European Union, NeuroproMiSe, LSHM-CT-2005-018637 and EURATools, LSHG-CT-2005-019015, the Swedish Research Council, Wadsworth Foundation, the Swedish Society for Medical Research, the Nils and Bibbi Jenssen’s Foundation, the Montel William’s MS Foundation, the GV80 Foundation, the Söderbergs Foundation, and the Swedish Association of Persons with Neurological Disabilities.

² K.H. and M.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Maria Swanberg, Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine L8:04, Karolinska University Hospital, 171 76 Stockholm, Sweden. E-mail address: Maria.Swanberg{at}ki.se

⁴ Abbreviations used in this paper: MS, multiple sclerosis; RA, rheumatoid arthritis; MHC II, MHC class II; SNP, single nucleotide polymorphism; VRA, ventral root avulsion; EAE, experimental autoimmune encephalomyelitis; rMOG, recombinant myelin oligodendrocyte glycoprotein; Aif1, allograft inflammatory factor; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; lm, littermate control.