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C3d Binding to the Myelin Oligodendrocyte Glycoprotein Results in an Exacerbated Experimental Autoimmune Encephalomyelitis¹

Jean-François Jégou^*, Philippe Chan^*, Marie-Thérèse Schouft^*, Mark R. Griffiths, James W. Neal, Philippe Gasque^,, Hubert Vaudry^* and Marc Fontaine^2,*

^* Institut National de la Santé et de la Recherche Médicale U413, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, University of Rouen, Mont Saint-Aignan, France; Brain Inflammation and Immunity Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom; and Laboratoire de Biochimie et Génétique Moléculaire, EA 2526, University of La Reunion, Saint-Denis, La Reunion, France

The complement system is known to contribute to demyelination in multiple sclerosis and experimental autoimmune encephalomyelitis. However, there are few data concerning the natural adjuvant effect of C3d on the humoral response when it binds to myelin Ags. This study addresses the effect of C3d binding to the myelin oligodendrocyte glycoprotein (MOG) in the induction of experimental autoimmune encephalomyelitis in C57BL/6J mice. Immunization with human MOG coupled to C3d was found to accelerate the appearance of clinical signs of the disease and to enhance its severity compared with MOG-immunized mice. This finding was correlated with an increased infiltration of leukocytes into the central nervous system accompanied by increased complement activation and associated with areas of demyelination and axonal loss. Furthermore, B cell participation in the pathogenesis of the disease was determined by their increased capacity to act as APCs and to form germinal centers. Consistent with this, the production of MOG-specific Abs was found to be enhanced following MOG/C3d immunization. These results suggest that binding of C3d to self-Ags could increase the severity of an autoimmune disease by enhancing the adaptive autoimmune response.

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 Agence Nationale de Recherches sur le SIDA, Institut National de la Santé et de la Recherche Médicale (U413), the European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23), and the Conseil Régional de Haute-Normandie. J.-F.J. was a recipient of a fellowship from the French Ministry of Education.

² Address correspondence and reprint requests to Dr. Marc Fontaine, Institut National de la Santé et de la Recherche Médicale U413, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, Faculté des Sciences et Techniques, Université de Rouen, Place Emile Blondel, Mont Saint-Aignan Cedex, France. E-mail address: marc.fontaine{at}univ-rouen.fr

³ Abbreviations used in this paper: MS, multiple sclerosis; CIA, collagen-induced arthritis; CDI, cumulative disease index; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; FDC, follicular dendritic cell; GC, germinal center; HEL, hen egg lysozyme; LNC, lymph node cell; MMR, macrophage mannose receptor; MOG, myelin oligodendrocyte glycoprotein.