Technical Report abstract
Nature Medicine 13, 211 - 217 (2007)
Published online: 12 January 2007 | doi:10.1038/nm1488
Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein
Kevin C O'Connor1,2,3,18, Katherine A McLaughlin3,4,18, Philip L De Jager1,2,3,5, Tanuja Chitnis1,2,3, Estelle Bettelli1,2,3, Chenqi Xu3,4, William H Robinson6,7, Sunil V Cherry1,2,3, Amit Bar-Or8, Brenda Banwell9, Hikoaki Fukaura10, Toshiyuki Fukazawa11, Silvia Tenembaum12, Susan J Wong13, Norma P Tavakoli13, Zhannat Idrissova14, Vissia Viglietta1,2,3, Kevin Rostasy15, Daniela Pohl15, Russell C Dale16, Mark Freedman17, Lawrence Steinman6,7, Guy J Buckle1,2,3, Vijay K Kuchroo1,2,3, David A Hafler1,2,3,4,18 & Kai W Wucherpfennig3,4,18
Abstract
The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.
- Center for Neurologic Diseases, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Room D1410, 44 Binney Street, Boston, Massachusetts 02115, USA.
- Broad Institute at Harvard University and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
- Division of Immunology and Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, 3801 University Street #111, Montreal, Quebec H3A 2B4, Canada.
- Department of Paediatrics (Neurology), Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
- Department of Neurology, Iwate Medical University, Uchimaru, Morioka, Iwate 020-8505, Japan.
- Hokuyukai Neurology Hospital, Hokkaido University, Kita 15, Nishi 7 Kita-ku, Sapporo 060-8638, Japan.
- Department of Pediatric Neurology, Dr. J.P. Garrahan National Pediatric Hospital, Calle Pichincha 1890, Ciudad Autónoma de Buenos Aires 1249, Argentina.
- Diagnostic Immunology Laboratory, Wadsworth Center, New York State Department of Health, PO Box 22002 Albany, New York 12201, USA.
- Department of Neurology, Kazakh National Medical University, Tole bi 88, 050012 Almaty, Kazakhstan.
- Department of Pediatrics and Pediatric Neurology, Georg-August-University, Robert Koch Strasse 40, Goettingen 37075, Germany.
- Department of Neurology, Great Ormond Street Hospital for Children, Great Ormond Street, London WC1N 3JH, UK.
- Department of Neurology, Ottawa-General Hospital, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
- These authors contributed equally to this work.
Correspondence to: Kai W Wucherpfennig3,4,18 e-mail: Kai_Wucherpfennig@dfci.harvard.edu
Correspondence to: David A Hafler1,2,3,4,18 e-mail: dhafler@rics.bwh.harvard.edu
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