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Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases

Abstract

The pathophysiology of complex neuroimmunological diseases, such as multiple sclerosis and autoimmune encephalitis, remains puzzling — various mechanisms that are difficult to dissect seem to contribute, hampering the understanding of the processes involved. Some rare neuroimmunological diseases are easier to study because their presentation and pathogenesis are more homogeneous. The investigation of these diseases can provide fundamental insights into neuroimmunological pathomechanisms that can in turn be applied to more complex diseases. In this Review, we summarize key mechanistic insights into three such rare but paradigmatic neuroimmunological diseases — Susac syndrome, Rasmussen encephalitis and narcolepsy type 1 — and consider the implications of these insights for the study of other neuroimmunological diseases. In these diseases, the combination of findings in humans, different modalities of investigation and animal models has enabled the triangulation of evidence to validate and consolidate the pathomechanistic features and to develop diagnostic and therapeutic strategies; this approach has provided insights that are directly relevant to other neuroimmunological diseases and applicable in other contexts. We also outline how next-generation technologies and refined animal models can further improve our understanding of pathomechanisms, including cell-specific and antigen-specific CNS immune responses, thereby paving the way for the development of targeted therapeutic approaches.

Key points

  • Susac syndrome, Rasmussen encephalitis and narcolepsy type 1 are more homogeneous than other more common neuroimmunological diseases and can therefore serve as paradigms for the study of fundamental neuroimmunological mechanisms.

  • The study of Susac syndrome, Rasmussen encephalitis and narcolepsy type 1 has demonstrated that cytotoxic CD8+ T cells play a major role in the pathophysiology of neuroinflammatory disease.

  • The triangulation of evidence from human and animal studies has provided insight into the pathomechanisms of Susac syndrome, Rasmussen encephalitis, and narcolepsy type 1 and could be applied to other neuroimmunological diseases.

  • Refined animal models and next-generation technologies are likely to provide further mechanistic insight into paradigmatic neuroimmunological diseases, enabling the development of innovative therapeutic approaches.

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Fig. 1: Imaging and histopathological features of Susac syndrome and Rasmussen encephalitis.
Fig. 2: Pathophysiology of Susac syndrome, Rasmussen encephalitis and narcolepsy type 1.
Fig. 3: Use of animal models of rare neuroimmunological diseases.
Fig. 4: Triangulation of evidence.
Fig. 5: Strategies for the identification of disease-specific antigens.

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Acknowledgements

The authors thank Prof. Christian G. Bien (Epilepsy Center Bethel, Krankenhaus Mara, Bielefeld Germany) for providing an MRI scan of a patient with Rasmussen encephalitis and Prof. Brigitte Wildemann (University Hospital Heidelberg, Germany), Prof. Nicholas Schwab and Dr. Nico Melzer (both University Hospital Münster, Germany) for discussions on AQP4+ neuromyelitis optica spectrum disorders, MOG antibody-associated disease, Rasmussen encephalitis, and autoimmune encephalitis. The authors are supported by the German Research Foundation (DFG grants CRC SFB TR-128 A09 to H.W. and C.C.G., SFB1009 A03 to H.W., and GR3946-3/1 to C.C.G.) and the Interdisciplinary Center for Clinical Studies (IZKF grant Kl3/010/19 to C.C.G.), the Austrian Science Fund (FWF Project P26936-B27) to J.B., and the Narcomics ERA-Net, ImmunitySleep ANR, RHU BETPSY and ARSEP grants to R.L.

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H.W. provided the initial idea, outlined the content of the manuscript, wrote sections of the manuscript and designed Fig. 2. C.C.G. wrote sections of the manuscript, designed and created Box 1, Fig. 3, Fig. 4, Fig. 5, Table 1, and Supplementary Tables 1 and 2, and edited the manuscript. J.B. created Fig. 2 and Table 1 and provided histology data for Fig. 1. R.L. wrote sections of the manuscript. All authors contributed to the development of the manuscript, critically revised the manuscript, approved the final version, and are responsible for the content.

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Correspondence to Heinz Wiendl.

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Competing interests

H.W. receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma, and Sanofi-Aventis and receives speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma, Genzyme, Teva, and WebMD Global. He is also a paid consultant for Abbvie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis and the Swiss Multiple Sclerosis Society. His research is funded by Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme. C.C.G. has received speaker honoraria from Bayer Health Care, MyLan and Genzyme, and travel expenses for attending meetings from Bayer Health Care, Biogen, Euroimmun, Genzyme, MyLan and Novartis Pharma. She recieves research funding from Biogen, Roche, and Novartis. R.L. has received grant support from BMS, GlaxoSmithKline and Pierre Fabre. He has received speaker or scientific board honoraria from Biogen, Novartis, Sanofi-Genzyme, and Servier and currently has grants from ANR, ARSEP, Cancer Research Institute, French Cancer research foundation (ARC), ERA-Net Narcomics, GlaxoSmithKline, Rare Diseases Foundation, and RHU BETPSY.

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Nature Reviews Neurology thanks J. Kira, M. Reindl and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Wiendl, H., Gross, C.C., Bauer, J. et al. Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases. Nat Rev Neurol 17, 433–447 (2021). https://doi.org/10.1038/s41582-021-00496-7

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