We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog−/−), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab–restricted epitope sequences of MOG35–55 and NF-M18–30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35–55–I-Ab–reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more than one autoantigen may have a role in spontaneously developing human autoimmune diseases.
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MogCre/Cre, Nefm−/−, 2D2 and Mog−/− mice were generously provided by A. Waisman (Johannes Gutenberg University of Mainz), J.-P. Julien (Laval University), V.K. Kuchroo (Harvard Medical School) and D. Pham-Dinh (INSERM UMR 546). We thank F. Lottspeich for granting us permission to use his mass spectrometer. We thank L. Penner and I. Arnold-Ammer for technical support. This project was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereiche (SFB) 571, Projects A1 and B6) and the Max Planck Society. H.S.D. is supported by a PhD fellowship (Portuguese Fundação para a Ciência ea Tecnologia (FCT) program SFRH/BD/15885/2005). Part of the study (conducted by H.W., R.L. and H.L.) was funded by the EU Project Neuropromise (PL 018637), and A.B.-N. was supported by the Israel Science Foundation and the National Multiple Sclerosis Society of New York (RG3195B8/2). A.B.-N. is an Alexander von Humboldt Prize Awardee.
Supplementary Figs. 1–13, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1029 kb)
Healthy 2D2 mouse. (MOV 2391 kb)
2D2 mouse with hind limb clasping phenotype. (MOV 2152 kb)
2D2 mouse with hind limb hyperextension (spasticity). (MOV 3284 kb)
Healthy 2D2 × Mog−/− mouse. (MOV 4442 kb)
2D2 × Mog−/− mouse with hind limb clasping. (MOV 3968 kb)
2D2 × Mog−/− mouse with hind limb clasping and hyperextension (spasticity). (MOV 3087 kb)
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Krishnamoorthy, G., Saxena, A., Mars, L. et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med 15, 626–632 (2009). https://doi.org/10.1038/nm.1975
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