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.
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Acknowledgements
We thank M. Kozak (University of Medicine and Dentistry of New Jersey) for providing the modified pSP64 plasmid vector. These studies were supported by grants from the US National Institutes of Health to K.W.W. (P01 AI045757) and D.A.H. (U01DK6192601, R01NS2424710, P01AI39671 and P01NS38037); grants from the National Multiple Sclerosis Society to D.A.H. (RG2172C9 and RG3308A10); a Career Transition Fellowship awarded to K.C.O. by the National Multiple Sclerosis Society (TA 3000A2/1); and a National Multiple Sclerosis Society Pediatric Multiple Sclerosis Center Program Project Grant to T.C. P.L.D. is a William C. Fowler scholar in Multiple Sclerosis and is supported by a National Institutes of Health National Institute of Neurological Disorders and Stroke K08 grant. P.L.D. is also supported by the Clinical Investigator Training Program (Harvard-MIT Health Sciences and Technology, Beth Israel Deaconess Medical Center, and Pfizer).
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K.C.O. performed the initial analysis of ADEM serum samples and coordinated specimen collection. K.A.M. generated the MOG tetramer, performed most of the RIA experiments and generated the MOG transfectant. D.A.H. and K.W.W. coinitiated and cosupervised the entire project, and K.W.W. conceived the tetramer approach. P.L.D. and T.C. compiled and analyzed clinical data. Other authors contributed specimens, clinical information or key reagents.
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Supplementary information
Supplementary Fig. 1
Comparison of RIA and ELISA for detection of monoclonal versus polyclonal antibodies to MOG. (PDF 704 kb)
Supplementary Fig. 2
FACS analysis of MOG-GFP transfectant labeled with ADEM and pediatric MS sera (PDF 836 kb)
Supplementary Table 1
Classification of “Other” CSF samples (PDF 13 kb)
Supplementary Table 2
Treatment of MS and CIS patients (PDF 12 kb)
Supplementary Table 3
Detection of antibodies to MOG by FACS (% of positive cells) (PDF 25 kb)
Supplementary Table 4
Comparison of RIA and FACS (PDF 9 kb)
Supplementary Table 5
Comparison of RIA and ELISA (PDF 13 kb)
Supplementary Table 6
Comparison of MOG+ and MOG− ADEM (PDF 49 kb)
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O'Connor, K., McLaughlin, K., De Jager, P. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 13, 211–217 (2007). https://doi.org/10.1038/nm1488
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DOI: https://doi.org/10.1038/nm1488
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