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  • Review Article
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Autoantibodies in neurological disease

Nature Reviews Immunology volume 21, pages 798–813 (2021)Cite this article

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Abstract

The realization that autoantibodies can contribute to dysfunction of the brain has brought about a paradigm shift in neurological diseases over the past decade, offering up important novel diagnostic and therapeutic opportunities. Detection of specific autoantibodies to neuronal or glial targets has resulted in a better understanding of central nervous system autoimmunity and in the reclassification of some diseases previously thought to result from infectious, ‘idiopathic’ or psychogenic causes. The most prominent examples, such as aquaporin 4 autoantibodies in neuromyelitis optica or NMDAR autoantibodies in encephalitis, have stimulated an entire field of clinical and experimental studies on disease mechanisms and immunological abnormalities. Also, these findings inspired the search for additional autoantibodies, which has been very successful to date and has not yet reached its peak. This Review summarizes this rapid development at a point in time where preclinical studies have started delivering fundamental new data for mechanistic understanding, where new technologies are being introduced into this field, and — most importantly — where the first specifically tailored immunotherapeutic approaches are emerging.

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Fig. 1: Diagnosing autoantibodies in neurological disease.
Fig. 2: Development of autoantibodies in neurological disease.
Fig. 3: Different disease mechanisms by pathogenic autoantibodies.
Fig. 4: Innovative immunotherapies in neurological antibody-mediated diseases.

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References

  1. Lennon, V. A., Kryzer, T. J., Pittock, S. J., Verkman, A. S. & Hinson, S. R. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 (2005).

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Dalmau, J. et al. Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36 (2007). This article presents the first identification of the NMDAR NR1 subunit as the target in a new type of autoimmune encephalitis, which has now become the most common antibody-mediated form.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Pollak, T. A. et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry 7, 93–108 (2019).

    PubMed  Google Scholar 

  4. Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016). This first international consensus paper on the clinical diagnostic criteria for autoimmune encephalitis symbolizes the transformation of this new development into clinical pathways.

    PubMed  PubMed Central  Google Scholar 

  5. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).

    PubMed  CAS  Google Scholar 

  6. Dalmau, J. et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 18, 1045–1057 (2019).

    PubMed  CAS  Google Scholar 

  7. Petit-Pedrol, M. et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 13, 276–286 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Lancaster, E. et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 9, 67–76 (2010).

    PubMed  CAS  Google Scholar 

  9. Haselmann, H. et al. Human autoantibodies against the AMPA receptor subunit GluA2 induce receptor reorganization and memory dysfunction. Neuron 100, 91–105.e9 (2018).

    PubMed  CAS  Google Scholar 

  10. Spatola, M. et al. Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 90, e1964–e1972 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  11. Sabater, L. et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 13, 575–586 (2014). This study identifies IgLON5 antibodies in a novel tauopathy, pointing to potentially broader overlapping mechanisms between antibody-mediated autoimmunity and neurodegenerative diseases.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Reindl, M. & Waters, P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat. Rev. Neurol. 15, 89–102 (2019).

    PubMed  CAS  Google Scholar 

  13. Fukata, Y. et al. LGI1–ADAM22–MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention. Proc. Natl Acad. Sci. USA 118, e2022580118 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Kornau, H. C. et al. Human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability. Ann. Neurol. 87, 405–418 (2020).

    PubMed  CAS  Google Scholar 

  15. Petit-Pedrol, M. et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 141, 3144–3159 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. Dawes, J. M. et al. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 97, 806–822.e10 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Dubey, D. et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann. Neurol. 83, 166–177 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  18. Gable, M. S., Sheriff, H., Dalmau, J., Tilley, D. H. & Glaser, C. A. The frequency of autoimmune N-methyl-d-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the california encephalitis project. Clin. Infect Dis. 54, 899–904 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Al-Diwani, A. et al. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry 6, 235–246 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. Irani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900 (2011).

    PubMed  Google Scholar 

  21. Fichtner, M. L., Jiang, R., Bourke, A., Nowak, R. J. & O’Connor, K. C. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front. Immunol. 11, 776 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Toyka, K. V., Brachman, D. B., Pestronk, A. & Kao, I. Myasthenia gravis: passive transfer from man to mouse. Science 190, 397–399 (1975).

    PubMed  CAS  Google Scholar 

  23. Newsom-Davis, J., Wilson, S. G., Vincent, A. & Ward, C. D. Long-term effects of repeated plasma exchange in myasthenia gravis. Lancet 1, 464–468 (1979).

    PubMed  CAS  Google Scholar 

  24. Devinsky, O. et al. A cross-species approach to disorders affecting brain and behaviour. Nat. Rev. Neurol. 14, 677–686 (2018).

    PubMed  Google Scholar 

  25. Pakozdy, A. et al. Suspected limbic encephalitis and seizure in cats associated with voltage-gated potassium channel (VGKC) complex antibody. J. Vet. Intern. Med. 27, 212–214 (2013).

    PubMed  CAS  Google Scholar 

  26. Matsuki, N. et al. Prevalence of autoantibody in cerebrospinal fluids from dogs with various CNS diseases. J. Vet. Med. Sci. 66, 295–297 (2004).

    PubMed  Google Scholar 

  27. Fang, B. et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol. 73, 1297–1307 (2016).

    PubMed  Google Scholar 

  28. Prüss, H. et al. Anti-NMDA receptor encephalitis in the polar bear (Ursus maritimus) Knut. Sci. Rep. 5, 12805 (2015).

    PubMed  PubMed Central  Google Scholar 

  29. Pan, H. et al. Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. Mol. Psychiatry 24, 1489–1501 (2019).

    PubMed  CAS  Google Scholar 

  30. Honorat, J. A. et al. Autoimmune septin-5 cerebellar ataxia. Neurol. Neuroimmunol. Neuroinflamm 5, e474 (2018).

    PubMed  PubMed Central  Google Scholar 

  31. Scharf, M. et al. A spectrum of neural autoantigens, newly identified by histo-immunoprecipitation, mass spectrometry, and recombinant cell-based indirect immunofluorescence. Front. Immunol. 9, 1447 (2018).

    PubMed  PubMed Central  Google Scholar 

  32. 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 

  33. Zekeridou, A. et al. Phosphodiesterase 10A IgG: a novel biomarker of paraneoplastic neurologic autoimmunity. Neurology 93, e815–e822 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Honorat, J. A. et al. Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. Neurology 93, e954–e963 (2019).

    PubMed  PubMed Central  Google Scholar 

  35. Miske, R. et al. Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration. Neurol. Neuroimmunol. Neuroinflamm. 4, e307 (2016).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Berridge, G. et al. Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome. Neurology 91, e714–e723 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Flanagan, E. P. et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann. Neurol. 81, 298–309 (2017).

    PubMed  CAS  Google Scholar 

  39. Mandel-Brehm, C. et al. Kelch-like protein 11 antibodies in seminoma-associated paraneoplastic encephalitis. N. Engl. J. Med. 381, 47–54 (2019). This article identifies KLHL11 autoantibodies indicating both the continuously ongoing discovery of further autoantibodies and the increasing technical refinement to identify undetermined epitopes.

    PubMed  PubMed Central  CAS  Google Scholar 

  40. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    PubMed  CAS  Google Scholar 

  41. Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Cotzomi, E. et al. Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production. Brain 142, 1598–1615 (2019).

    PubMed  PubMed Central  Google Scholar 

  44. Rawlings, D. J., Metzler, G., Wray-Dutra, M. & Jackson, S. W. Altered B cell signalling in autoimmunity. Nat. Rev. Immunol. 17, 421–436 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Kreye, J. et al. Encephalitis patient derived monoclonal GABAA receptor antibodies cause catatonia and epileptic seizures. Preprint at bioRxiv https://doi.org/10.1101/2021.01.28.428602 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Brändle, S. M. et al. Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABAA receptor encephalitis. Proc. Natl Acad. Sci. USA 118, e1916337118 (2021).

    PubMed  PubMed Central  Google Scholar 

  47. Vinuesa, C. G., Sanz, I. & Cook, M. C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).

    PubMed  CAS  Google Scholar 

  48. Kreye, J. et al. Human cerebrospinal fluid monoclonal N-methyl-d-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis. Brain 139, 2641–2652 (2016). This article presents the first cloning and recombinant production of monoclonal human NMDAR NR1 autoantibodies, enabling understanding of antibody pathogenicity and immune mechanisms at a molecular level.

    PubMed  Google Scholar 

  49. Wenke, N. K. et al. N-Methyl-d-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit. Ann. Neurol. 85, 771–776 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  50. Malviya, M. et al. NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody. Ann. Clin. Transl Neurol. 4, 768–783 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  51. Fischer, A., Provot, J., Jais, J. P., Alcais, A. & Mahlaoui, N. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J. Allergy Clin. Immunol. 140, 1388–1393.e8 (2017).

    PubMed  CAS  Google Scholar 

  52. Akman, C. I., Patterson, M. C., Rubinstein, A. & Herzog, R. Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency. Dev. Med. Child. Neurol. 51, 563–567 (2009).

    PubMed  Google Scholar 

  53. Vogrig, A. et al. Central nervous system complications associated with immune checkpoint inhibitors. J. Neurol. Neurosurg. Psychiatry 91, 772–778 (2020).

    PubMed  Google Scholar 

  54. Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).

    PubMed  CAS  Google Scholar 

  55. Titulaer, M. J. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  56. Makuch, M. et al. N-Methyl-d-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann. Neurol. 83, 553–561 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Day, G. S., Laiq, S., Tang-Wai, D. F. & Munoz, D. G. Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol. 71, 717–724 (2014).

    PubMed  Google Scholar 

  58. Prüss, H. et al. N-Methyl-d-aspartate receptor antibodies in herpes simplex encephalitis. Ann. Neurol. 72, 902–911 (2012). This study shows a high rate of NMDAR autoantibodies in patients with herpes encephalitis and suggests a causal relationship related to virus-induced humoral autoimmunity.

    PubMed  PubMed Central  Google Scholar 

  59. Armangue, T. et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann. Neurol. 75, 317–323 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  60. Armangue, T. et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 17, 760–772 (2018). This prospective study demonstrates that 27% of patients with herpes encephalitis develop immunotherapy-responsive NMDAR encephalitis, usually within 2 months.

    PubMed  PubMed Central  Google Scholar 

  61. Linnoila, J. et al. Mouse model of anti-NMDA receptor post-herpes simplex encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 6, e529 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Linnoila, J. J., Binnicker, M. J., Majed, M., Klein, C. J. & McKeon, A. CSF herpes virus and autoantibody profiles in the evaluation of encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 3, e245 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. Prüss, H. Postviral autoimmune encephalitis: manifestations in children and adults. Curr. Opin. Neurol. 30, 327–333 (2017).

    PubMed  Google Scholar 

  64. Franke, C. et al. High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms. Brain Behav. Immun. 93, 415–419 (2020).

    PubMed  PubMed Central  Google Scholar 

  65. Kuraoka, M. et al. BCR and endosomal TLR signals synergize to increase AID expression and establish central B cell tolerance. Cell Rep. 18, 1627–1635 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  66. Kolhatkar, N. S. et al. Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott–Aldrich syndrome. J. Exp. Med. 212, 1663–1677 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. Sanderson, N. S. et al. Cocapture of cognate and bystander antigens can activate autoreactive B cells. Proc. Natl Acad. Sci. USA 114, 734–739 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  68. Kain, R. et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat. Med. 14, 1088–1096 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  69. Lafaille, F. G. et al. Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis. Nat. Med. 25, 1873–1884 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  70. Amara, K. et al. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 210, 445–455 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  71. Meyer, S. et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166, 582–595 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  72. Kearney, J. F., Patel, P., Stefanov, E. K. & King, R. G. Natural antibody repertoires: development and functional role in inhibiting allergic airway disease. Annu. Rev. Immunol. 33, 475–504 (2015).

    PubMed  CAS  Google Scholar 

  73. Schickel, J. N. et al. Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria. J. Exp. Med. 214, 1991–2003 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Burnett, D. L., Reed, J. H., Christ, D. & Goodnow, C. C. Clonal redemption and clonal anergy as mechanisms to balance B cell tolerance and immunity. Immunol. Rev. 292, 61–75 (2019).

    PubMed  CAS  Google Scholar 

  75. Varrin-Doyer, M. et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a TH17 bias and recognize Clostridium ABC transporter. Ann. Neurol. 72, 53–64 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Sagan, S. A. et al. Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4. Proc. Natl Acad. Sci. USA 113, 14781–14786 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  77. Zeka, B. et al. Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD. Acta Neuropathol. Commun. 4, 82 (2016).

    PubMed  PubMed Central  Google Scholar 

  78. Dabner, M. et al. Ovarian teratoma associated with anti-N-methyl d-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates. Int J. Gynecol. Pathol. 31, 429–437 (2012).

    PubMed  Google Scholar 

  79. Dao, L. M. et al. Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis. J. Neurol. https://doi.org/10.1007/s00415-020-10371-y (2021).

  80. Iversen, R. & Sollid, L. M. Autoimmunity provoked by foreign antigens. Science 368, 132–133 (2020).

    PubMed  CAS  Google Scholar 

  81. du Pre, M. F. et al. B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J. Exp. Med. 217, e20190860 (2020).

    PubMed  Google Scholar 

  82. Cree, B. A., Spencer, C. M., Varrin-Doyer, M., Baranzini, S. E. & Zamvil, S. S. Gut microbiome analysis in neuromyelitis optica reveals overabundance of Clostridium perfringens. Ann. Neurol. 80, 443–447 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  83. Herken, J. et al. Normal gut microbiome in NMDA receptor encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 6, e632 (2019).

    PubMed  PubMed Central  Google Scholar 

  84. Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).

    PubMed  CAS  Google Scholar 

  85. Zou, A., Ramanathan, S., Dale, R. C. & Brilot, F. Single-cell approaches to investigate B cells and antibodies in autoimmune neurological disorders. Cell Mol. Immunol. 18, 294–306 (2021).

    PubMed  CAS  Google Scholar 

  86. Takata, K. et al. Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients. JCI Insight 4, e127167 (2019).

    PubMed Central  Google Scholar 

  87. Bennett, J. L. et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann. Neurol. 66, 617–629 (2009). This study demonstrates cloning of intrathecal AQP4 autoantibodies, thereby paving the way for monoclonal human autoantibody technology to become state of the art in antibody-mediated neurological diseases.

    PubMed  PubMed Central  CAS  Google Scholar 

  88. Kreye, J. et al. A therapeutic non-self-reactive SARS-CoV-2 antibody protects from lung pathology in a COVID-19 hamster model. Cell 183, 1058–1069 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  89. Ramberger, M. et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 143, 1731–1745 (2020).

    PubMed  PubMed Central  Google Scholar 

  90. Jezequel, J. et al. Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients. Nat. Commun. 8, 1791 (2017). This study demonstrates different molecular mechanisms on synaptic transmission by NMDAR autoantibodies derived from patients with schizophrenia versus healthy controls.

    PubMed  PubMed Central  Google Scholar 

  91. Moscato, E. H. et al. Acute mechanisms underlying antibody effects in anti-N-methyl-d-aspartate receptor encephalitis. Ann. Neurol. 76, 108–119 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  92. Ladepeche, L. et al. NMDA receptor autoantibodies in autoimmune encephalitis cause a subunit-specific nanoscale redistribution of NMDA receptors. Cell Rep. 23, 3759–3768 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  93. Lai, M. et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann. Neurol. 65, 424–434 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  94. Peng, X. et al. Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies. Ann. Neurol. 77, 381–398 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  95. Crisp, S. J. et al. Glycine receptor autoantibodies disrupt inhibitory neurotransmission. Brain 142, 3398–3410 (2019).

    PubMed  PubMed Central  Google Scholar 

  96. Carvajal-Gonzalez, A. et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 137, 2178–2192 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Pettingill, P. et al. Antibodies to GABAA receptor α1 and γ2 subunits: clinical and serologic characterization. Neurology 84, 1233–1241 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  98. Gresa-Arribas, N. et al. Human neurexin-3α antibodies associate with encephalitis and alter synapse development. Neurology 86, 2235–2242 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  99. Landa, J. et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann. Neurol. 88, 1023–1027 (2020).

    PubMed  CAS  Google Scholar 

  100. Sabater, L., Planaguma, J., Dalmau, J. & Graus, F. Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J. Neuroinflammation 13, 226 (2016).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  102. Soltys, J. et al. Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica. J. Clin. Invest. 129, 2000–2013 (2019). This study analyses the molecular mechanisms that are required for AQP4 autoantibodies to activate complement, helping to understand organ-specific damage.

    PubMed  PubMed Central  Google Scholar 

  103. Pittock, S. J. et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N. Engl. J. Med. 381, 614–625 (2019).

    PubMed  CAS  Google Scholar 

  104. Piepgras, J. et al. Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons. Neurology 85, 890–897 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  105. Koneczny, I. A new classification system for IgG4 autoantibodies. Front. Immunol. 9, 97 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. Brilot, F. et al. Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol 66, 833–842 (2009).

    PubMed  CAS  Google Scholar 

  107. Asavapanumas, N. & Verkman, A. S. Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO-IgG and intracerebral needle injury. Acta Neuropathol. Commun. 2, 48 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. Shimizu, F. et al. Glucose-regulated protein 78 autoantibody associates with blood–brain barrier disruption in neuromyelitis optica. Sci. Transl Med. 9, eaai9111 (2017).

    PubMed  PubMed Central  Google Scholar 

  109. Shimizu, F. et al. GRP78 antibodies damage the blood–brain barrier and relate to cerebellar degeneration in Lambert–Eaton myasthenic syndrome. Brain 142, 2253–2264 (2019).

    PubMed  Google Scholar 

  110. Mintz, P. J. et al. Fingerprinting the circulating repertoire of antibodies from cancer patients. Nat. Biotechnol. 21, 57–63 (2003).

    PubMed  CAS  Google Scholar 

  111. Bartels, F. et al. Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Ann. Oncol. 30, 823–829 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  112. Werner, C. et al. Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. Brain 139, 365–379 (2016).

    PubMed  Google Scholar 

  113. Geis, C. et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 133, 3166–3180 (2010).

    PubMed  Google Scholar 

  114. Rocchi, A. et al. Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function. Cell Death Dis. 10, 864 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  115. Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  116. Sillevis Smitt, P. et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N. Engl. J. Med. 342, 21–27 (2000).

    PubMed  CAS  Google Scholar 

  117. Duan, T. & Verkman, A. S. Experimental animal models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders: progress and shortcomings. Brain Pathol. 30, 13–25 (2020).

    PubMed  Google Scholar 

  118. Planaguma, J. et al. Human N-methyl d-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94–109 (2015). This article presents the first experiments demonstrating reversible behavioural and memory changes in mice after intrathecal administration of NMDAR antibody-containing CSF.

    PubMed  Google Scholar 

  119. Wright, S. et al. Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model. Brain 138, 3159–3167 (2015).

    PubMed  Google Scholar 

  120. Wright, S. K. et al. In vitro characterisation and neurosteroid treatment of an N-methyl-d-aspartate receptor antibody-mediated seizure model. Preprint at bioRxiv https://doi.org/10.1101/2020.12.22.423962 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Sharma, R. et al. Monoclonal antibodies from a patient with anti-NMDA receptor encephalitis. Ann. Clin. Transl Neurol. 5, 935–951 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  122. Hillebrand, S. et al. Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat. Acta Neuropathol. 137, 467–485 (2019).

    PubMed  CAS  Google Scholar 

  123. Jones, B. E. et al. Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors. Sci. Transl Med. 11, eaaw0044 (2019). This article presents the first active immunization model of NMDAR encephalitis using conformationally stabilized NMDAR that resembles the human phenotype and may facilitate the development of new treatments.

    PubMed  PubMed Central  Google Scholar 

  124. Tsymala, I. et al. Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes. Acta Neuropathol. Commun. 8, 49 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  125. Gata-Garcia, A. & Diamond, B. Maternal antibody and ASD: clinical data and animal models. Front. Immunol. 10, 1129 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  126. Hacohen, Y. et al. Fetal acetylcholine receptor inactivation syndrome: a myopathy due to maternal antibodies. Neurol. Neuroimmunol. Neuroinflamm. 2, e57 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Lee, J. Y. et al. Neurotoxic autoantibodies mediate congenital cortical impairment of offspring in maternal lupus. Nat. Med. 15, 91–96 (2009).

    PubMed  CAS  Google Scholar 

  128. Braunschweig, D. et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J. Neuroimmunol. 252, 56–65 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  129. Brimberg, L. et al. Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol. Psychiatry 21, 1663–1671 (2016). This article shows that monoclonal CASPR2 autoantibodies generated from a mother of a child with ASD mimicked an ASD phenotype in mice and thus demonstrates the vast potential role of materno-fetal antibody transfer for lifelong neuropsychiatric morbidity.

    PubMed  PubMed Central  CAS  Google Scholar 

  130. Penagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  131. Coutinho, E. et al. Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero. Acta Neuropathol. 134, 567–583 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  132. Hammer, C. et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood–brain barrier integrity. Mol. Psychiatry 19, 1143–1149 (2013).

    PubMed  Google Scholar 

  133. Stefani, M. R. & Moghaddam, B. Transient N-methyl-d-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol. Psychiatry 57, 433–436 (2005).

    PubMed  CAS  Google Scholar 

  134. Jurek, B. et al. Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function. Ann. Neurol. 86, 656–670 (2019).

    PubMed  CAS  Google Scholar 

  135. Joubert, B. et al. Pregnancy outcomes in anti-NMDA receptor encephalitis: case series. Neurol. Neuroimmunol. Neuroinflamm. 7, e668 (2020).

    PubMed  PubMed Central  Google Scholar 

  136. Garcia-Serra, A. et al. Placental transfer of NMDAR antibodies causes reversible alterations in mice. Neurol. Neuroimmunol. Neuroinflamm. 8, e915 (2020).

    PubMed  PubMed Central  Google Scholar 

  137. Marquetand, J. et al. Slowly progressive LGI1 encephalitis with isolated late-onset cognitive dysfunction: a treatable mimic of Alzheimer’s disease. Eur. J. Neurol. 23, e28–e29 (2016).

    PubMed  CAS  Google Scholar 

  138. McKeon, A. et al. Potassium channel antibody associated encephalopathy presenting with a frontotemporal dementia like syndrome. Arch. Neurol. 64, 1528–1530 (2007).

    PubMed  Google Scholar 

  139. Reintjes, W., Romijn, M. D., Hollander, D., Ter Bruggen, J. P. & van Marum, R. J. Reversible dementia: two nursing home patients with voltage-gated potassium channel antibody-associated limbic encephalitis. J. Am. Med. Dir. Assoc. 16, 790–794 (2015).

    PubMed  Google Scholar 

  140. Tomczak, A. et al. A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism. Mult. Scler. Relat. Disord. 39, 101900 (2019).

    PubMed  Google Scholar 

  141. Schumacher, H., Meyer, T. & Prüss, H. GABAB receptor encephalitis in a patient diagnosed with amyotrophic lateral sclerosis. BMC Neurol. 19, 41 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. Maat, P. et al. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt–Jakob disease. Neurol. Neuroimmunol. Neuroinflamm. 2, e178 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. May, C. et al. Highly immunoreactive IgG antibodies directed against a set of twenty human proteins in the sera of patients with amyotrophic lateral sclerosis identified by protein array. PLoS ONE 9, e89596 (2014).

    PubMed  PubMed Central  Google Scholar 

  144. Liu, J. & Wang, F. Role of neuroinflammation in amyotrophic lateral sclerosis: cellular mechanisms and therapeutic implications. Front. Immunol. 8, 1005 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  147. Tüzün, E. et al. LRP4 antibody positive amyotrophic lateral sclerosis patients display neuropil-reactive IgG and enhanced serum complement levels. Immunol. Lett. 203, 54–56 (2018).

    PubMed  Google Scholar 

  148. Gaig, C. et al. Clinical manifestations of the anti-IgLON5 disease. Neurology 88, 1736–1743 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  149. Honorat, J. A. et al. IgLON5 antibody: neurological accompaniments and outcomes in 20 patients. Neurol. Neuroimmunol. Neuroinflamm. 4, e385 (2017).

    PubMed  PubMed Central  Google Scholar 

  150. Doyle, K. P. & Buckwalter, M. S. Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia? Brain Behav. Immun. 64, 1–8 (2017).

    PubMed  CAS  Google Scholar 

  151. Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    PubMed  CAS  Google Scholar 

  152. Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  153. Brudek, T. et al. Autoimmune antibody decline in Parkinson’s disease and multiple system atrophy; a step towards immunotherapeutic strategies. Mol. Neurodegener. 12, 44 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. Pascual, G. et al. Immunological memory to hyperphosphorylated tau in asymptomatic individuals. Acta Neuropathol. 133, 767–783 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  155. Maier, M. et al. A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis. Sci. Transl Med. 10, eaah3924 (2018).

    PubMed  CAS  Google Scholar 

  156. Albus, A., Jordens, M., Moller, M. & Dodel, R. Encoding the sequence of specific autoantibodies against β-amyloid and α-synuclein in neurodegenerative diseases. Front. Immunol. 10, 2033 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  157. Frontzek, K. et al. Autoantibodies against the prion protein in individuals with PRNP mutations. Neurology 95, e2028–e2037 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  158. Cabral-Marques, O. et al. GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nat. Commun. 9, 5224 (2018). This study analyses GPCR-specific autoantibodies, and strengthens the concept that a ‘network’ of functionally related autoantibodies can provide homeostatic functions, which may also apply to anti-neuronal autoantibodies.

    PubMed  PubMed Central  CAS  Google Scholar 

  159. Neiman, M. et al. Individual and stable autoantibody repertoires in healthy individuals. Autoimmunity 52, 1–11 (2019).

    PubMed  CAS  Google Scholar 

  160. Finke, C. et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol. 74, 50–59 (2017).

    PubMed  Google Scholar 

  161. Damato, V., Evoli, A. & Iorio, R. Efficacy and safety of rituximab therapy in neuromyelitis optica spectrum disorders: a systematic review and meta-analysis. JAMA Neurol. 73, 1342–1348 (2016).

    PubMed  Google Scholar 

  162. Lee, W. J. et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology 86, 1683–1691 (2016).

    PubMed  CAS  Google Scholar 

  163. Graf, J. et al. Targeting B cells to modify MS, NMOSD, and MOGAD: Part 1. Neurol. Neuroimmunol. Neuroinflamm. 8, e918 (2021).

    PubMed  Google Scholar 

  164. Chamberlain, N. et al. Rituximab does not reset defective early B cell tolerance checkpoints. J. Clin. Invest. 126, 282–287 (2016).

    PubMed  Google Scholar 

  165. Yamamura, T. et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N. Engl. J. Med. 381, 2114–2124 (2019).

    PubMed  CAS  Google Scholar 

  166. Cree, B. A. C. et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 394, 1352–1363 (2019).

    PubMed  CAS  Google Scholar 

  167. Zhang, C. et al. Safety and efficacy of bortezomib in patients with highly relapsing neuromyelitis optica spectrum disorder. JAMA Neurol. 74, 1010–1012 (2017). This article presents the successful depletion of long-lived plasma cells by proteasome inhibition, demonstrating the potential as a new treatment in antibody-mediated neurological diseases.

    PubMed  PubMed Central  Google Scholar 

  168. Scheibe, F. et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology 88, 366–370 (2017).

    PubMed  CAS  Google Scholar 

  169. Wickel, J. et al. Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis. Trials 21, 625 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  170. Scheibe, F. et al. Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis. J. Neurol. 267, 317–323 (2020).

    PubMed  CAS  Google Scholar 

  171. Ratuszny, D. et al. Case report: daratumumab in a patient with severe refractory anti-NMDA receptor encephalitis. Front. Neurol. 11, 602102 (2020).

    PubMed  PubMed Central  Google Scholar 

  172. Tradtrantip, L., Asavapanumas, N. & Verkman, A. S. Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase. Mol. Pharmacol. 83, 1268–1275 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  173. Tradtrantip, L., Ratelade, J., Zhang, H. & Verkman, A. S. Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann. Neurol. 73, 77–85 (2013).

    PubMed  CAS  Google Scholar 

  174. Bril, V. et al. Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis: a phase 2 randomized control trial. Neurology 96, e853–e865 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  175. Howard, J. F. Jr. et al. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology 92, e2661–e2673 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  176. Karnell, J. L. et al. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity. Sci. Transl Med. 11, eaar6584 (2019).

    PubMed  Google Scholar 

  177. Kansal, R. et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci. Transl Med. 11, eaav1648 (2019).

    PubMed  PubMed Central  Google Scholar 

  178. Burt, R. K. et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA 321, 165–174 (2019).

    PubMed  PubMed Central  Google Scholar 

  179. Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016). This article presents the development of CAAR T cells to treat a DSG3 antibody-mediated skin disease, indicating that the CAAR concept should also be explored to specifically deplete autoantibodies that cause neurological diseases.

    PubMed  PubMed Central  CAS  Google Scholar 

  180. Parvathaneni, K. & Scott, D. W. Engineered FVIII-expressing cytotoxic T cells target and kill FVIII-specific B cells in vitro and in vivo. Blood Adv. 2, 2332–2340 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  181. Duan, T., Tradtrantip, L., Phuan, P. W., Bennett, J. L. & Verkman, A. S. Affinity-matured ‘aquaporumab’ anti-aquaporin-4 antibody for therapy of seropositive neuromyelitis optica spectrum disorders. Neuropharmacology 162, 107827 (2020).

    PubMed  CAS  Google Scholar 

  182. Cheng, Q. et al. Selective depletion of plasma cells in vivo based on the specificity of their secreted antibodies. Eur. J. Immunol. 50, 284–291 (2020).

    PubMed  CAS  Google Scholar 

  183. Steinman, L. et al. Restoring immune tolerance in neuromyelitis optica: Part I. Neurol. Neuroimmunol. Neuroinflamm. 3, e276 (2016).

    PubMed  PubMed Central  Google Scholar 

  184. Irani, S. R. et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133, 2734–2748 (2010).

    PubMed  PubMed Central  Google Scholar 

  185. Lai, M. et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 9, 776–785 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  186. Hutchinson, M. et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 71, 1291–1292 (2008).

    PubMed  CAS  Google Scholar 

  187. Lancaster, E. et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 77, 1698–1701 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  188. Boronat, A. et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann. Neurol. 73, 120–128 (2013).

    PubMed  CAS  Google Scholar 

  189. Dale, R. C. et al. Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 135, 3453–3468 (2012).

    PubMed  Google Scholar 

  190. Folli, F. et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N. Engl. J. Med. 328, 546–551 (1993).

    PubMed  CAS  Google Scholar 

  191. Piepgras, J. et al. Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis. Neurol. Neuroimmunol. Neuroinflamm. 2, e169 (2015).

    PubMed  PubMed Central  Google Scholar 

  192. Sun, B., Ramberger, M., O’Connor, K. C., Bashford-Rogers, R. J. M. & Irani, S. R. The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nat. Rev. Neurol. 16, 481–492 (2020).

    PubMed  CAS  Google Scholar 

  193. Reiber, H., Ungefehr, S. & Jacobi, C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult. Scler. 4, 111–117 (1998).

    PubMed  CAS  Google Scholar 

  194. Prüss, H. et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 75, 1735–1739 (2010). This retrospective analysis of archived CSF demonstrates that NMDAR encephalitis can account for 1% of young patients on a neuro-ICU. The study suggests that patients with other yet to be defined autoantibodies may still be overlooked.

    PubMed  Google Scholar 

  195. Gresa-Arribas, N. et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 13, 167–177 (2014).

    PubMed  CAS  Google Scholar 

  196. van Sonderen, A. et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology 87, 1449–1456 (2016).

    PubMed  Google Scholar 

  197. Dendrou, C. A., Petersen, J., Rossjohn, J. & Fugger, L. HLA variation and disease. Nat. Rev. Immunol. 18, 325–339 (2018).

    PubMed  CAS  Google Scholar 

  198. Mueller, S. H. et al. Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Ann. Neurol. 83, 863–869 (2018).

    PubMed  CAS  Google Scholar 

  199. Binks, S. et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain 141, 2263–2271 (2018).

    PubMed  PubMed Central  Google Scholar 

  200. Estrada, K. et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat. Commun. 9, 1929 (2018).

    PubMed  PubMed Central  Google Scholar 

  201. Yoshimura, S. et al. Distinct genetic and infectious profiles in Japanese neuromyelitis optica patients according to anti-aquaporin 4 antibody status. J. Neurol. Neurosurg. Psychiatry 84, 29–34 (2013).

    PubMed  Google Scholar 

  202. Shu, Y. et al. HLA class II allele DRB1*16:02 is associated with anti-NMDAR encephalitis. J. Neurol. Neurosurg. Psychiatry 90, 652–658 (2019).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany

    Harald Prüss

  2. Department of Neurology and Experimental Neurology, Charité — Universitätsmedizin Berlin, Berlin, Germany

    Harald Prüss

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Glossary

Neuromyelitis optica

(NMO). An autoimmune inflammatory disorder predominantly affecting the optic nerves and spinal cord, caused by autoantibodies to the water channel aquaporin 4 (AQP4).

Neuropil

A dense unmyelinated fibre network of neuronal processes in the brain, containing synapses, axons and dendrites, and making up large parts of the brain’s grey matter.

NMDAR encephalitis

The most common autoimmune encephalitis. Inflammation in the brain is caused by autoantibodies to the N-methyl-d-aspartate receptor (NMDAR) and can lead to psychosis, amnesia, epileptic seizures, abnormal movements and reduced levels of consciousness.

Faciobrachial dystonic seizures

Characteristic abnormal involuntary movements associated with leucine-rich glioma-inactivated protein 1 (LGI1) autoantibodies, typically as frequent, brief stereotyped seizures predominantly affecting one arm and the ipsilateral face.

Paraneoplastic neurological syndromes

Diverse neurological abnormalities in the context of cancer, caused by cytotoxic T cells (and to a lesser degree by antibodies) cross-reacting with antigens in the nervous system that are ectopically expressed in the tumour.

Blood–brain barrier

The border between blood vessels and brain parenchyma, composed of a dense network of endothelial cells, pericytes and astrocytes. The intact blood–brain barrier prevents soluble molecules, such as (auto)antibodies, entering the brain.

Post-stroke dementia

Largely unexplained progressive cognitive decline affecting 30% of stroke survivors and being an important health issue. A potential relation to anti-neuronal autoantibodies is under investigation.

‘Brain antibody-omics’

A term coined by the author that underlies the (yet to be proven) hypothesis that autoantibodies are present also in the healthy brain, and that their composition and fluctuations can contribute to several brain diseases including dementia.

Conformational epitopes

Structures composed of different parts of a protein, in contrast to linear epitopes composed of continuous amino acids in a line. Many pathogenic anti-neuronal autoantibodies bind only conformational epitopes.

Therapeutic apheresis

Extracorporeal elimination of antibodies in autoimmune diseases, either with plasma exchange (blood plasma is removed and replaced) or immunoadsorption (antibodies removed with an adsorber column and blood reinfused).

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Prüss, H. Autoantibodies in neurological disease. Nat Rev Immunol 21, 798–813 (2021). https://doi.org/10.1038/s41577-021-00543-w

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