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 Google Scholar Articles by Breithaupt, C. Articles by Jacob, U. PubMed PubMed Citation Articles by Breithaupt, C. Articles by Jacob, U.

Demyelinating Myelin Oligodendrocyte Glycoprotein-Specific Autoantibody Response Is Focused on One Dominant Conformational Epitope Region in Rodents^1,2

Constanze Breithaupt^3,*, Beatrix Schäfer^*, Hannah Pellkofer^,, Robert Huber^*,,¶, Christopher Linington^|| and Uwe Jacob^#

^* Max-Planck-Institut für Biochemie, Abteilung Strukturforschung/Emeritusgruppe Huber, Martinsried, Germany; Max-Planck-Institut für Neurobiologie, Abteilung Neuroimmunologie, Martinsried, Germany; Institut für Klinische Neuroimmunologie, Klinikum Grosshadern, Ludwig Maximilians Universität, München, Germany; School of Biosciences, Cardiff University, Cardiff, United Kingdom; ^¶ Zentrum für Medizinische Biotechnologie, Universität Duisburg, Essen, Germany; ^|| Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; and ^# SuppreMol, Martinsried, Germany

Conformational epitopes of myelin oligodendrocyte glycoprotein (MOG) provide a major target for demyelinating autoantibodies in experimental autoimmune encephalomyelitis and recent studies indicate that a similar situation may exist in multiple sclerosis. We recently solved the crystal structure of the extracellular domain of MOG (MOG_ex) in complex with a Fab derived from the demyelinating mAb 8-18C5 and identified the conformational 8-18C5 epitope on MOG that is dominated by the surface exposed FG loop of MOG. To determine the importance of this epitope with regard to the polyclonal Ab response to MOG_ex we investigated the effects of mutating His¹⁰³ and Ser¹⁰⁴, the two central amino acids of the FG loop, on Ab binding. Mutation of these two residues reduced binding of a panel of eight demyelinating conformation-dependent mAbs to <20% compared with binding to wild-type MOG_ex, whereas substitution of amino acids that do not contribute to the 8-18C5 epitope had only a minor effect on Ab binding. The same restriction was observed for the polyclonal MOG-specific Ab response of MOG DNA-vaccinated BALB/c and SJL/J mice. Our data demonstrate that the pathogenic anti-MOG Ab response primarily targets one immunodominant region centered at the FG loop of MOG. Comparison of the structure of MOG_ex with the structures of related IgV-like domains yields a possible explanation for the focused Ab 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 The atomic coordinates and structure factors of DM2-MOG_ex presented in this article have been deposited in the Protein Data Bank (PDB; www.rcsb.org) with the PDB ID code 3CSP.

² This work was supported by the Gemeinnützige Hertie Stiftung (1.01.1/04/008, to U.J.).

³ Address correspondence and reprint requests to Dr. Constanze Breithaupt at the current address: Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt Mothes Strasse 3, 06120 Halle, Germany. E-mail address: constanze.breithaupt{at}biochemtech.uni-halle.de

⁴ Abbreviations used in this paper: MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis; MS, multiple sclerosis; MOG_ex, extracellular domain of MOG; hMOG, human MOG; BTN, butyrophilin; ERMAP, erythroid membrane-associated protein.