Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Constanze Breithaupt

Anna Schubart

Hilke Zander

Arne Skerra

Robert Huber

Christopher Linington

Uwe Jacob

^{Abteilung Strukturforschung, Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, 82152 Martinsried, Germany;}^{Abteilung Neuroimmunologie, Max-Planck-Institut für Neurobiologie, Am Klopferspitz 18a, 82152 Martinsried, Germany; and}^{Lehrstuhl für Biologische Chemie, Technische Universität München, 85350 Freising-Weihenstephan, Germany}

^{To whom correspondence should be addressed. E-mail:}ed.gpm.mehcoib@ahtierb.

^{Present address: Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.}

^{Present address: University of Aberdeen, Department of Medicine and Therapeutics, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.}

Contributed by Robert Huber, June 6, 2003

Abstract

Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG^{) at 1.45-Å resolution and the complex of MOG}^{with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-Å resolution. MOG}^{adopts an IgV like fold with the A′GFCC′C″ sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG with a surprisingly dominant contribution made by MOG residues 101–108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R}^DHSYQEE^{is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a}Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) associated with autoaggressive T and B cell responses to various myelin proteins. Myelin oligodendrocyte glycoprotein (MOG) was identified as a candidate autoantigen in MS because it induces a demyelinating antibody response in laboratory animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS (1). MOG is a quantitatively minor type I transmembrane CNS protein of unknown function with a single extracellular Ig-like domain (2). In contrast to other CNS proteins, MOG is found only in mammals and is highly conserved across species. It is expressed exclusively in the CNS by myelin-forming oligodendrocytes and is preferentially localized at the outermost surface of the myelin sheath thus directly exposed to autoantibodies in the extracellular milieu. MOG is the only antigen that can induce both a pathogenic demyelinating autoantibody response and an encephalitogenic T cell response in experimental animals (3). In MOG-induced EAE this combination of immune effector mechanisms reproduces the demyelinating pathology seen in the majority of patients with MS. The clinical relevance of autoimmune responses to MOG in MS is supported by reports that MS is associated with enhanced MOG-specific T and B cell responses and by the identification of MOG-specific antibodies associated with myelin debris in actively demyelinating MS lesions (4). Experimental evidence indicates that the autoantibody response to MOG is heterogeneous; demyelinating MOG-specific autoantibodies recognize purely conformation-dependent epitopes whereas MOG peptide-specific antibodies fail to recognize the native protein (5–7). To examine the structural basis of the pathogenic autoantibody response to MOG we determined the crystal structures of the extracellular domain of rat MOG (residues 1–126, MOG^{) and a complex of MOG}^{with the chimeric antigen-binding fragment (Fab) of the demyelinating MOG-specific monoclonal antibody 8-18C5 (}8).

Acknowledgments

We thank Gleb Bourenkov of the Deutsche Elektronen Synchrotron (Hamburg, Germany) for assistance during data collection. This work was supported by the European Union (Biomed 2: Contract BMH4-97-2027) and Deutsche Forschungsgemeinschaft Grant SFB571 (to C.L.).

Acknowledgments

Notes

Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org {PDB ID codes 1PKO (SeMetMOG^{) and 1PKQ [MOG}^{–(8-18C5)-Fab]}.}

Notes

Abbreviations: MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; MOG^{, extracellular domain of MOG; EAE, experimental autoimmune encephalomyelitis; SeMet, selenomethionine; CDR, complementarity-determining region.}Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org {PDB ID codes 1PKO (SeMetMOG^{) and 1PKQ [MOG}^{–(8-18C5)-Fab]}.}

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