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Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases


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.


  1. 1.

    Matute-Blanch, C., Montalban, X. & Comabella, M. Multiple sclerosis, and other demyelinating and autoimmune inflammatory diseases of the central nervous system. Handb. Clin. Neurol. 146, 67–84 (2017).

    PubMed  Google Scholar 

  2. 2.

    Korn, T. & Kallies, A. T cell responses in the central nervous system. Nat. Rev. Immunol. 17, 179–194 (2017).

    CAS  PubMed  Google Scholar 

  3. 3.

    Jarius, S., Wildemann, B. & Paul, F. Neuromyelitis optica: clinical features, immunopathogenesis and treatment. Clin. Exp. Immunol. 176, 149–164 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018).

    PubMed  Google Scholar 

  6. 6.

    Lassmann, H. The changing concepts in the neuropathology of acquired demyelinating central nervous system disorders. Curr. Opin. Neurol. 32, 313–319 (2019).

    CAS  PubMed  Google Scholar 

  7. 7.

    Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 15, 198–209 (2016).

    CAS  PubMed  Google Scholar 

  8. 8.

    Hohlfeld, R., Dornmair, K., Meinl, E. & Wekerle, H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 15, 317–331 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

    Planas, R. et al. GDP-l-fucose synthase is a CD4+ T cell-specific autoantigen in DRB3*02:02 patients with multiple sclerosis. Sci. Transl. Med. 10, eaat4301 (2018).

    PubMed  Google Scholar 

  10. 10.

    Jelcic, I. et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell 175, 85–100.e23 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat. Med. 6, 1167–1175 (2000).

    CAS  PubMed  Google Scholar 

  12. 12.

    Lassmann, H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front. Immunol. 9, 3116 (2018).

    CAS  PubMed  Google Scholar 

  13. 13.

    Mayer, M. C. et al. Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J. Immunol. 191, 3594–3604 (2013).

    CAS  PubMed  Google Scholar 

  14. 14.

    Meyer Zu Horste, G., Gross, C. C., Klotz, L., Schwab, N. & Wiendl, H. Next-generation neuroimmunology: new technologies to understand central nervous system autoimmunity. Trends Immunol. 41, 341–354 (2020).

    PubMed  Google Scholar 

  15. 15.

    Machado-Santos, J. et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141, 2066–2082 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Sulzer, D. et al. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Galiano-Landeira, J., Torra, A., Vila, M. & Bove, J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain 143, 3717–3733 (2020).

    PubMed  Google Scholar 

  18. 18.

    Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Seifert-Held, T. et al. Susac’s syndrome: clinical course and epidemiology in a Central European population. Int. J. Neurosci. 127, 776–780 (2017).

    PubMed  Google Scholar 

  20. 20.

    Dorr, J. et al. Characteristics of Susac syndrome: a review of all reported cases. Nat. Rev. Neurol. 9, 307–316 (2013).

    PubMed  Google Scholar 

  21. 21.

    Gross, C. C. et al. CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nat. Commun. 10, 5779 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Hardy, T. A. et al. Brain histopathology in three cases of Susac’s syndrome: implications for lesion pathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 86, 582–584 (2015).

    PubMed  Google Scholar 

  23. 23.

    Magro, C. M., Poe, J. C., Lubow, M. & Susac, J. O. Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies. Am. J. Clin. Pathol. 136, 903–912 (2011).

    CAS  PubMed  Google Scholar 

  24. 24.

    Li, R., Patterson, K. R. & Bar-Or, A. Reassessing B cell contributions in multiple sclerosis. Nat. Immunol. 19, 696–707 (2018).

    CAS  PubMed  Google Scholar 

  25. 25.

    Jarius, S. et al. Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study. J. Neuroinflammation 11, 46 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Varadkar, S. et al. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol. 13, 195–205 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Bien, C. G., Elger, C. E. & Wiendl, H. Advances in pathogenic concepts and therapeutic agents in Rasmussen’s encephalitis. Expert Opin. Invest. Drugs 11, 981–989 (2002).

    CAS  Google Scholar 

  28. 28.

    Bien, C. G. et al. Diagnosis and staging of Rasmussen’s encephalitis by serial MRI and histopathology. Neurology 58, 250–257 (2002).

    CAS  PubMed  Google Scholar 

  29. 29.

    Bien, C. G. et al. Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia 54, 543–550 (2013).

    CAS  PubMed  Google Scholar 

  30. 30.

    Andermann, F. & Farrell, K. Early onset Rasmussen’s syndrome: a malignant, often bilateral form of the disorder. Epilepsy Res. 70 (Suppl. 1), S259–262 (2006).

    PubMed  Google Scholar 

  31. 31.

    Villani, F. et al. Adult-onset Rasmussen’s encephalitis: anatomical-electrographic-clinical features of 7 Italian cases. Epilepsia 47 (Suppl. 5), 41–46 (2006).

    PubMed  Google Scholar 

  32. 32.

    Bien, C. G. et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann. Neurol. 51, 311–318 (2002).

    CAS  PubMed  Google Scholar 

  33. 33.

    Schwab, N. et al. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain 132, 1236–1246 (2009).

    PubMed  Google Scholar 

  34. 34.

    Bauer, J. et al. Astrocytes are a specific immunological target in Rasmussen’s encephalitis. Ann. Neurol. 62, 67–80 (2007).

    PubMed  Google Scholar 

  35. 35.

    Schneider-Hohendorf, T. et al. CD8+ T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nat. Commun. 7, 11153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Troscher, A. R. et al. Microglial nodules provide the environment for pathogenic T cells in human encephalitis. Acta Neuropathol. 137, 619–635 (2019).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kebir, H. et al. Humanized mouse model of Rasmussen’s encephalitis supports the immune-mediated hypothesis. J. Clin. Invest. 128, 2000–2009 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Farrell, M. A. et al. Neuropathologic findings in cortical resections (including hemispherectomies) performed for the treatment of intractable childhood epilepsy. Acta Neuropathol. 83, 246–259 (1992).

    CAS  PubMed  Google Scholar 

  39. 39.

    Bien, C. G. et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 128, 454–471 (2005).

    CAS  PubMed  Google Scholar 

  40. 40.

    Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    CAS  PubMed  Google Scholar 

  41. 41.

    Takahashi, Y., Mine, J., Kubota, Y., Yamazaki, E. & Fujiwara, T. A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFα, and Granzyme B in CSF. Epilepsia 50, 1419–1431 (2009).

    CAS  PubMed  Google Scholar 

  42. 42.

    Owens, G. C. et al. Differential expression of interferon-gamma and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J. Neuroinflammation 10, 56 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Owens, G. C. et al. Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis. J. Neuroinflammation 12, 134 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Steinman, L. Blocking immune intrusion into the brain suppresses epilepsy in Rasmussen’s encephalitis model. J. Clin. Invest. 128, 1724–1726 (2018).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Di Liberto, G. et al. Neurons under T cell attack coordinate phagocyte-mediated synaptic stripping. Cell 175, 458–471.e19 (2018).

    PubMed  Google Scholar 

  46. 46.

    Shah, J. R. et al. Rasmussen encephalitis associated with Parry-Romberg syndrome. Neurology 61, 395–397 (2003).

    CAS  PubMed  Google Scholar 

  47. 47.

    Carreno, M. et al. Parry Romberg syndrome and linear scleroderma in coup de sabre mimicking Rasmussen encephalitis. Neurology 68, 1308–1310 (2007).

    CAS  PubMed  Google Scholar 

  48. 48.

    Straube, A., Padovan, C. S. & Seelos, K. Parry-Romberg syndrome and Rasmussen syndrome: only an incidental similarity? Nervenarzt 72, 641–646 (2001).

    CAS  PubMed  Google Scholar 

  49. 49.

    Longo, D. et al. Parry-Romberg syndrome and Rasmussen encephalitis: possible association. Clinical and neuroimaging features. J. Neuroimaging 21, 188–193 (2011).

    PubMed  Google Scholar 

  50. 50.

    Wilson, E. H., Weninger, W. & Hunter, C. A. Trafficking of immune cells in the central nervous system. J. Clin. Invest. 120, 1368–1379 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Hall, M. A., Reid, J. L. & Lanchbury, J. S. The distribution of human TCR junctional region lengths shifts with age in both CD4 and CD8 T cells. Int. Immunol. 10, 1407–1419 (1998).

    CAS  PubMed  Google Scholar 

  52. 52.

    Scammell, T. E. Narcolepsy. N. Engl. J. Med. 373, 2654–2662 (2015).

    CAS  PubMed  Google Scholar 

  53. 53.

    Jennum, P., Ibsen, R., Knudsen, S. & Kjellberg, J. Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. Sleep 36, 835–840 (2013).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Peyron, C. et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med. 6, 991–997 (2000).

    CAS  PubMed  Google Scholar 

  55. 55.

    Thannickal, T. C. et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474 (2000).

    CAS  Google Scholar 

  56. 56.

    Tafti, M. et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 37, 19–25 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Faraco, J. et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 9, e1003270 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Han, F. et al. HLA-DQ association and allele competition in Chinese narcolepsy. Tissue Antigens 80, 328–335 (2012).

    CAS  PubMed  Google Scholar 

  59. 59.

    Ollila, H. M. et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am. J. Hum. Genet. 96, 136–146 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Han, F. et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 9, e1003880 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    Han, F. et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann. Neurol. 70, 410–417 (2011).

    PubMed  Google Scholar 

  62. 62.

    Heier, M. S. et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 14, 867–871 (2013).

    CAS  PubMed  Google Scholar 

  63. 63.

    Nguyen, X. H., Saoudi, A. & Liblau, R. S. Vaccine-associated inflammatory diseases of the central nervous system: from signals to causation. Curr. Opin. Neurol. 29, 362–371 (2016).

    CAS  PubMed  Google Scholar 

  64. 64.

    Sarkanen, T. O., Alakuijala, A. P. E., Dauvilliers, Y. A. & Partinen, M. M. Incidence of narcolepsy after H1N1 influenza and vaccinations: systematic review and meta-analysis. Sleep Med. Rev. 38, 177–186 (2018).

    PubMed  Google Scholar 

  65. 65.

    Nishino, S., Ripley, B., Overeem, S., Lammers, G. J. & Mignot, E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39–40 (2000).

    CAS  PubMed  Google Scholar 

  66. 66.

    Clark, M., Kroger, C. J. & Tisch, R. M. Type 1 diabetes: a chronic anti-self-inflammatory response. Front. Immunol. 8, 1898 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Pugliese, A. Autoreactive T cells in type 1 diabetes. J. Clin. Invest. 127, 2881–2891 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Bernard-Valnet, R. et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc. Natl Acad. Sci. USA 113, 10956–10961 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Dauvilliers, Y. et al. Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 70, 1305–1310 (2013).

    PubMed  Google Scholar 

  70. 70.

    Pedersen, N. W. et al. CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nat. Commun. 10, 837 (2019).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Latorre, D. et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 562, 63–68 (2018).

    CAS  PubMed  Google Scholar 

  72. 72.

    Hartmann, F. J. et al. High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J. Exp. Med. 213, 2621–2633 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Nguyen, X. H. et al. Circulating follicular helper T cells exhibit reduced ICOS expression and impaired function in narcolepsy type 1 patients. J. Autoimmun. 94, 134–142 (2018).

    CAS  PubMed  Google Scholar 

  74. 74.

    Luo, G. et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc. Natl Acad. Sci. USA 115, E12323–E12332 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Ramberger, M. et al. CD4+ T-cell reactivity to orexin/hypocretin in patients with narcolepsy type 1. Sleep 40, zsw070 (2017).

    Google Scholar 

  76. 76.

    Cogswell, A. C. et al. Children with narcolepsy type 1 have increased T-cell responses to orexins. Ann. Clin. Transl. Neurol. 6, 2566–2572 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Siebold, C. et al. Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc. Natl Acad. Sci. USA 101, 1999–2004 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Liblau, R. S. Put to sleep by immune cells. Nature 562, 46–48 (2018).

    CAS  PubMed  Google Scholar 

  79. 79.

    Ahrends, T. et al. CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity 47, 848–861.e5 (2017).

    CAS  PubMed  Google Scholar 

  80. 80.

    Yshii, L. et al. IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration. JCI Insight 4, e127001 (2019).

    PubMed Central  Google Scholar 

  81. 81.

    Pardo, C. A. et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 45, 516–526 (2004).

    PubMed  Google Scholar 

  82. 82.

    Renia, L., Grau, G. E. & Wassmer, S. C. CD8+ T cells and human cerebral malaria: a shifting episteme. J. Clin. Invest. 130, 1109–1111 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Konradt, C. et al. Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system. Nat. Microbiol. 1, 16001 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Hasadsri, L., Lee, J., Wang, B. H., Yekkirala, L. & Wang, M. Anti-yo associated paraneoplastic cerebellar degeneration in a man with large cell cancer of the lung. Case Rep. Neurol. Med. 2013, 725936 (2013).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Fuller, C. E. in Atlas of Pediatric Brain Tumors (eds Adesina, A. M., Tihan, T., Fuller, C. E, & Poussaint, T. Y.) 303-306 (Springer International Publishing, 2016).

  86. 86.

    van der Valk, P. & Amor, S. Preactive lesions in multiple sclerosis. Curr. Opin. Neurol. 22, 207–213 (2009).

    PubMed  Google Scholar 

  87. 87.

    Singh, S. et al. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol. 125, 595–608 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    van Horssen, J. et al. Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J. Neuroinflammation 9, 156 (2012).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Bassetti, C. L. A. et al. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat. Rev. Neurol. 15, 519–539 (2019).

    PubMed  Google Scholar 

  90. 90.

    Bittner, S. et al. Rasmussen encephalitis treated with natalizumab. Neurology 81, 395–397 (2013).

    PubMed  Google Scholar 

  91. 91.

    Friedman, H., Ch’ien, L. & Parham, D. Virus in brain of child with hemiplegia, hemiconvulsions, and epilepsy. Lancet 2, 666 (1977).

    CAS  PubMed  Google Scholar 

  92. 92.

    Walter, G. F. & Renella, R. R. Epstein-Barr virus in brain and Rasmussen’s encephalitis. Lancet 1, 279–280 (1989).

    CAS  PubMed  Google Scholar 

  93. 93.

    Jay, V. et al. Chronic encephalitis and epilepsy (Rasmussen’s encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology 45, 108–117 (1995).

    CAS  PubMed  Google Scholar 

  94. 94.

    Power, C., Poland, S. D., Blume, W. T., Girvin, J. P. & Rice, G. P. Cytomegalovirus and Rasmussen’s encephalitis. Lancet 336, 1282–1284 (1990).

    CAS  PubMed  Google Scholar 

  95. 95.

    Casanova, J. L. & Abel, L. Lethal infectious diseases as inborn errors of immunity: toward a synthesis of the germ and genetic theories. Annu. Rev. Pathol. 16, 23–50 (2021).

    CAS  PubMed  Google Scholar 

  96. 96.

    Seifinejad, A. et al. Molecular codes and in vitro generation of hypocretin and melanin concentrating hormone neurons. Proc. Natl Acad. Sci. USA 116, 17061–17070 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Beltran, E. et al. Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis. J. Clin. Invest. 129, 4758–4768 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Schafflick, D. et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat. Commun. 11, 247 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kula, T. et al. T-scan: a genome-wide method for the systematic discovery of T cell epitopes. Cell 178, 1016–1028.e13 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Kim, S. M. et al. Analysis of the paired TCR alpha- and beta-chains of single human T cells. PLoS One 7, e37338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Siewert, K. et al. Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides. Nat. Med. 18, 824–828 (2012).

    CAS  PubMed  Google Scholar 

  102. 102.

    Arakawa, A. et al. Melanocyte antigen triggers autoimmunity in human psoriasis. J. Exp. Med. 212, 2203–2212 (2015).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Bahi-Buisson, N. et al. [Recent advances in pathogenic concepts and therapeutic strategies in Rasmussen’s encephalitis]. Rev. Neurol. 161, 395–405 (2005).

    CAS  PubMed  Google Scholar 

  104. 104.

    Agamanolis, D. P. et al. Brain microvascular pathology in Susac syndrome: an electron microscopic study of five cases. Ultrastruct. Pathol. 43, 229–236 (2019).

    PubMed  Google Scholar 

  105. 105.

    Kleffner, I. et al. Diagnostic criteria for Susac syndrome. J. Neurol. Neurosurg. Psychiatry 87, 1287–1295 (2016).

    PubMed  Google Scholar 

  106. 106.

    Petty, G. W., Matteson, E. L., Younge, B. R., McDonald, T. J. & Wood, C. P. Recurrence of Susac syndrome (retinocochleocerebral vasculopathy) after remission of 18 years. Mayo Clin. Proc. 76, 958–960 (2001).

    CAS  PubMed  Google Scholar 

  107. 107.

    Lucchinetti, C. F. et al. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol. 24, 83–97 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Hoftberger, R. et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol. 139, 875–892 (2020).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Kortvelyessy, P. et al. Complement-associated neuronal loss in a patient with CASPR2 antibody-associated encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 2, e75 (2015).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135, 1622–1638 (2012).

    PubMed  Google Scholar 

  111. 111.

    Kuehn, J. C. et al. A 64-year-old patient with a mesiotemporal mass and symptomatic epilepsy. Brain Pathol. 30, 413–414 (2020).

    PubMed  Google Scholar 

  112. 112.

    Bracher, A. et al. An expanded parenchymal CD8+ T cell clone in GABAA receptor encephalitis. Ann. Clin. Transl. Neurol. 7, 239–244 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Popkirov, S. et al. Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis. Acta Neuropathol. Commun. 5, 40 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Pitsch, J. et al. Drebrin autoantibodies in patients with seizures and suspected encephalitis. Ann. Neurol. 87, 869–884 (2020).

    CAS  PubMed  Google Scholar 

  115. 115.

    Kuhlmann, T. et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 133, 13–24 (2017).

    CAS  PubMed  Google Scholar 

  116. 116.

    Law, L. Y. et al. The spectrum of immune-mediated and inflammatory lesions of the brainstem: clues to diagnosis. Neurology 93, 390–405 (2019).

    PubMed  Google Scholar 

  117. 117.

    Susac, J. O. et al. MRI findings in Susac’s syndrome. Neurology 61, 1783–1787 (2003).

    CAS  PubMed  Google Scholar 

  118. 118.

    White, M. L., Zhang, Y. & Smoker, W. R. Evolution of lesions in Susac syndrome at serial MR imaging with diffusion-weighted imaging and apparent diffusion coefficient values. AJNR 25, 706–713 (2004).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Kleffner, I. et al. Diffusion tensor imaging demonstrates fiber impairment in Susac syndrome. Neurology 70, 1867–1869 (2008).

    CAS  PubMed  Google Scholar 

  120. 120.

    Susac, J. O. Susac’s syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 44, 591–593 (1994).

    CAS  PubMed  Google Scholar 

  121. 121.

    O’Halloran, H. S., Pearson, P. A., Lee, W. B., Susac, J. O. & Berger, J. R. Microangiopathy of the brain, retina, and cochlea (Susac syndrome). A report of five cases and a review of the literature. Ophthalmology 105, 1038–1044 (1998).

    PubMed  Google Scholar 

  122. 122.

    Foldvary-Schaefer, N., Grigg-Damberger, M. & Mehra, R. Sleep disorders – A Case a Week from the Cleveland Clinic. 2nd Edn (Oxford University Press, 2019).

Download references


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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Public T cell clones

T cell clones that target a specific epitope and that are shared by different individuals.

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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).

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