Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Single-cell approaches to investigate B cells and antibodies in autoimmune neurological disorders

Cellular & Molecular Immunology volume 18, pages 294–306 (2021)Cite this article

Subjects

Abstract

Autoimmune neurological disorders, including neuromyelitis optica spectrum disorder, anti-N-methyl-D-aspartate receptor encephalitis, anti-MOG antibody-associated disorders, and myasthenia gravis, are clearly defined by the presence of autoantibodies against neurological antigens. Although these autoantibodies have been heavily studied for their biological activities, given the heterogeneity of polyclonal patient samples, the characteristics of a single antibody cannot be definitively assigned. This review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological disorders. High-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody production. Ultimately, several factors, including epitope specificity and binding affinity, finely regulate the pathogenic potential of an autoantibody, and a deeper appreciation of these factors may progress the development of targeted immunotherapies for patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hozumi, N. & Tonegawa, S. Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc. Natl Acad. Sci. USA 73, 3628–3632 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Brack, C., Hirama, M., Lenhard-Schuller, R. & Tonegawa, S. A complete immunoglobulin gene is created by somatic recombination. Cell 15, 1–14 (1978).

    CAS  PubMed  Google Scholar 

  3. Ramanathan, S. et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J. Neurol. Neurosurg. Psychiatry 89, 127–137 (2018).

    PubMed  Google Scholar 

  4. Huda, S. et al. Neuromyelitis optica spectrum disorders. Clin. Med. 19, 169–176 (2019).

    Google Scholar 

  5. Ramanathan, S., Dale, R. C. & Brilot, F. Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmun. Rev. 15, 307–324 (2016).

    CAS  PubMed  Google Scholar 

  6. Gilhus, N. E. Myasthenia Gravis. N. Engl. J. Med 375, 2570–2581 (2016).

    CAS  PubMed  Google Scholar 

  7. Spadaro, M. et al. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann. Neurol. 84, 315–328 (2018).

    CAS  PubMed  Google Scholar 

  8. Reindl, M. et al. International multicenter examination of MOG antibody assays. Neurol. Neuroimmunol. Neuroinflamm. 7, e674 (2020).

  9. Tea, F. et al. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination. Acta Neuropathol. Commun. 7, 145 (2019).

    PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Winklmeier, S. et al. Identification of circulating MOG-specific B cells in patients with MOG antibodies. Neurol. Neuroimmunol. Neuroinflamm. 6, 625 (2019).

    PubMed  PubMed Central  Google Scholar 

  12. Klein, A. M. et al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell 161, 1187–1201 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Jiang, R. et al. Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses. Preprint at https://www.biorxiv.org/content/10.1101/840389v2.full (2019).

  15. Wang, X., He, Y., Zhang, Q., Ren, X. & Zhang, Z. Direct comparative analysis of 10X genomics chromium and smart-seq2. Preprint at https://www.biorxiv.org/content/10.1101/615013v1 (2019).

  16. Baran-Gale, J., Chandra, T. & Kirschner, K. Experimental design for single-cell RNA sequencing. Brief. Funct. Genomics 17, 233–239 (2018).

    CAS  PubMed  Google Scholar 

  17. Tiller, T. et al. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Huijbers, M. G. et al. MuSK myasthenia gravis monoclonal antibodies: valency dictates pathogenicity. Neurol. Neuroimmunol. Neuroinflamm. 6, e547 (2019).

    PubMed  PubMed Central  Google Scholar 

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

  21. Wilson, R. et al. Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica. Brain 141, 1063–1074 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. Ramberger, M. et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 143, 1731–1744 (2020).

  23. Sabatino, J. J. Jr., Probstel, A. K. & Zamvil, S. S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat. Rev. Neurosci. 20, 728–745 (2019).

    CAS  PubMed  Google Scholar 

  24. 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 

  25. Bennett, J. L. et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann. Neurol. 66, 617–629 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Chihara, N. et al. Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica. PLoS One 8, e83036 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. Chihara, N. et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc. Natl Acad. Sci. USA 108, 3701–3706 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim, S. H. et al. Less frequent rituximab retreatment maintains remission of neuromyelitis optica spectrum disorder, following long-term rituximab treatment. J. Neurol. Neurosurg. Psychiatry 90, 486–487 (2019).

    PubMed  Google Scholar 

  29. Durozard, P. et al. Comparison of the response to rituximab between myelin oligodendrocyte glycoprotein and aquaporin-4 antibody diseases. Ann. Neurol. 87, 256–266 (2020).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Araki, M. et al. Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod. Rheumatol. 23, 827–831 (2013).

    CAS  PubMed  Google Scholar 

  32. Araki, M. et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 82, 1302–1306 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ayzenberg, I. et al. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol. 70, 394–397 (2013).

    PubMed  Google Scholar 

  34. Ringelstein, M. et al. Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol. 72, 756–763 (2015).

    PubMed  Google Scholar 

  35. Kieseier, B. C. et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol. 70, 390–393 (2013).

    PubMed  Google Scholar 

  36. Lauenstein, A. S., Stettner, M., Kieseier, B. C. & Lensch, E. Treating neuromyelitis optica with the interleukin-6 receptor antagonist tocilizumab. BMJ Case Rep 2014, bcr2013202939 (2014).

  37. Trebst, C. et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J. Neurol. 261, 1–16 (2014).

    CAS  PubMed  Google Scholar 

  38. Igawa, T. et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat. Biotechnol. 28, 1203–1207 (2010).

    CAS  PubMed  Google Scholar 

  39. Traboulsee, A. et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 19, 402–412 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Cree, B. A. et al. An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64, 1270–1272 (2005).

    CAS  PubMed  Google Scholar 

  41. Jacob, A. et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch. Neurol. 66, 1128–1133 (2009).

    PubMed  Google Scholar 

  42. Costanzi, C. et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology 77, 659–666 (2011).

    CAS  PubMed  Google Scholar 

  43. Diaz-Manera, J. et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 78, 189–193 (2012).

    CAS  PubMed  Google Scholar 

  44. Willcox, H. N., Newsom-Davis, J. & Calder, L. R. Cell types required for anti-acetylcholine receptor antibody synthesis by cultured thymocytes and blood lymphocytes in myasthenia gravis. Clin. Exp. Immunol. 58, 97–106 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Stathopoulos, P., Kumar, A., Nowak, R. J. & O’Connor, K. C. Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight 2, e94263 (2017).

  46. Hachiya, Y. et al. Rituximab ameliorates anti-N-methyl-D-aspartate receptor encephalitis by removal of short-lived plasmablasts. J. Neuroimmunol. 265, 128–130 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  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).

    PubMed  Google Scholar 

  49. 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 

  50. Lee, J. Y. et al. Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Ann. Clin. Transl. Neurol. 3, 443–454 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Meffre, E. & Wardemann, H. B-cell tolerance checkpoints in health and autoimmunity. Curr. Opin. Immunol. 20, 632–638 (2008).

    CAS  PubMed  Google Scholar 

  52. Yurasov, S. et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med 201, 703–711 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Samuels, J., Ng, Y. S., Coupillaud, C., Paget, D. & Meffre, E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J. Exp. Med 201, 1659–1667 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Stucci, S. et al. Immune-related adverse events during anticancer immunotherapy: pathogenesis and management. Oncol. Lett. 14, 5671–5680 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. Suarez-Almazor, M. E., Kim, S. T., Abdel-Wahab, N. & Diab, A. Review: immune-related adverse events with use of checkpoint inhibitors for immunotherapy of cancer. Arthritis Rheumatol. 69, 687–699 (2017).

    PubMed  Google Scholar 

  56. Sandigursky, S. & Mor, A. Immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Curr. Rheumatol. Rep. 20, 65 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. Kowarik, M. C. et al. CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. Ann. Clin. Transl. Neurol. 4, 369–380 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sinmaz, N. et al. Autoantibodies in movement and psychiatric disorders: updated concepts in detection methods, pathogenicity, and CNS entry. Ann. N. Y. Acad. Sci. 1351, 22–38 (2015).

    CAS  PubMed  Google Scholar 

  59. Tang, X., Huang, Y., Lei, J., Luo, H. & Zhu, X. The single-cell sequencing: new developments and medical applications. Cell Biosci. 9, 53 (2019).

    PubMed  PubMed Central  Google Scholar 

  60. Ma, S., Wang, C., Mao, X. & Hao, Y. B cell dysfunction associated with aging and autoimmune diseases. Front Immunol. 10, 318 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Rubin, S. J. S., Bloom, M. S. & Robinson, W. H. B cell checkpoints in autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 15, 303–315 (2019).

    PubMed  Google Scholar 

  62. Wardemann, H. & Nussenzweig, M. C. B-cell self-tolerance in humans. Adv. Immunol. 95, 83–110 (2007).

    CAS  PubMed  Google Scholar 

  63. Elluru, S. R., Kaveri, S. V. & Bayry, J. The protective role of immunoglobulins in fungal infections and inflammation. Semin Immunopathol. 37, 187–197 (2015).

    CAS  PubMed  Google Scholar 

  64. Nacu, A., Andersen, J. B., Lisnic, V., Owe, J. F. & Gilhus, N. E. Complicating autoimmune diseases in myasthenia gravis: a review. Autoimmunity 48, 362–368 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  66. Kinnunen, T. et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J. Clin. Invest. 123, 2737–2741 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Massey, J. C., Sutton, I. J., Ma, D. D. F. & Moore, J. J. Regenerating immunotolerance in multiple sclerosis with autologous hematopoietic stem cell transplant. Front. Immunol. 9, 410 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Meffre, E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann. N. Y. Acad. Sci. 1246, 1–10 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Owens, G. P. et al. Mutagenesis of the aquaporin 4 extracellular domains defines restricted binding patterns of pathogenic neuromyelitis optica IgG. J. Biol. Chem. 290, 12123–12134 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Takahashi, T. et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130, 1235–1243 (2007).

    PubMed  Google Scholar 

  72. Kinzel, S. & Weber, M. S. The role of peripheral CNS-directed antibodies in promoting inflammatory CNS demyelination. Brain Sci. 7, 70 (2017).

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

    CAS  PubMed  Google Scholar 

  74. Dujmovic, I. et al. Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders. J. Neuroimmunol. 234, 124–130 (2011).

    CAS  PubMed  Google Scholar 

  75. Kowarik, M. C. et al. The cerebrospinal fluid immunoglobulin transcriptome and proteome in neuromyelitis optica reveals central nervous system-specific B cell populations. J. Neuroinflammation 12, 19 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. Fenton, K. et al. Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice. PLoS One 4, e8474 (2009).

    PubMed  PubMed Central  Google Scholar 

  77. Yung, S. & Chan, T. M. Anti-DNA antibodies in the pathogenesis of lupus nephritis-the emerging mechanisms. Autoimmun. Rev. 7, 317–321 (2008).

    CAS  PubMed  Google Scholar 

  78. DeGiorgio, L. A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).

    CAS  PubMed  Google Scholar 

  79. Kowal, C. et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl Acad. Sci. USA 103, 19854–19859 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cohen-Solal, J. & Diamond, B. Lessons from an anti-DNA autoantibody. Mol. Immunol. 48, 1328–1331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Tradtrantip, L. et al. Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. 26, 2197–2208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tradtrantip, L. et al. Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann. Neurol. 71, 314–322 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  Google Scholar 

  84. Cobo-Calvo, A. et al. Evaluation of treatment response in adults with relapsing MOG-Ab-associated disease. J. Neuroinflammation 16, 134 (2019).

    PubMed  PubMed Central  Google Scholar 

  85. Hacohen, Y. et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol. 75, 478–487 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gleichman, A. J., Spruce, L. A., Dalmau, J., Seeholzer, S. H. & Lynch, D. R. Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J. Neurosci. 32, 11082–11094 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kalev-Zylinska, M. L., Symes, W., Young, D. & During, M. J. Knockdown and overexpression of NR1 modulates NMDA receptor function. Mol. Cell Neurosci. 41, 383–396 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wasterlain, C. G., Naylor, D. E., Liu, H., Niquet, J. & Baldwin, R. Trafficking of NMDA receptors during status epilepticus: therapeutic implications. Epilepsia 54, 78–80 (2013). Suppl 6.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  91. Ly, L. T. et al. Affinities of human NMDA receptor autoantibodies: implications for disease mechanisms and clinical diagnostics. J. Neurol. 265, 2625–2632 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Melchers, F. Checkpoints that control B cell development. J. Clin. Invest 125, 2203–2210 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. Hinson, S. R. et al. Prediction of neuromyelitis optica attack severity by quantitation of complement-mediated injury to aquaporin-4-expressing cells. Arch. Neurol. 66, 1164–1167 (2009).

    PubMed  Google Scholar 

  94. Soltys, J. et al. Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica. J. Clin. Invest 129, 2000–2013 (2019).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  96. Huijbers, M. G. et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc. Natl Acad. Sci. USA 110, 20783–20788 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Koneczny, I., Cossins, J., Waters, P., Beeson, D. & Vincent, A. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. PLoS One 8, e80695 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Otsuka, K. et al. Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Sci. Rep. 5, 13928 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. Hughes, E. G. et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30, 5866–5875 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Tuzun, E. & Christadoss, P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun. Rev. 12, 904–911 (2013).

    CAS  PubMed  Google Scholar 

  101. Engel, A. G. & Fumagalli, G. Mechanisms of acetylcholine receptor loss from the neuromuscular junction. Ciba Found Symp. 197–224 (1982).

  102. Frenzel, A., Hust, M. & Schirrmann, T. Expression of recombinant antibodies. Front Immunol. 4, 217 (2013).

    PubMed  PubMed Central  Google Scholar 

  103. Peschke, B., Keller, C. W., Weber, P., Quast, I. & Lunemann, J. D. Fc-galactosylation of human immunoglobulin gamma isotypes improves C1q binding and enhances complement-dependent cytotoxicity. Front. Immunol. 8, 646 (2017).

    PubMed  PubMed Central  Google Scholar 

  104. Quast, I. et al. Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J. Clin. Invest. 125, 4160–4170 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. Klooster, R. et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 135, 1081–1101 (2012).

    PubMed  Google Scholar 

  106. van der Neut Kolfschoten, M. et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317, 1554–1557 (2007).

    PubMed  Google Scholar 

  107. Fujihara, K. Neuromyelitis optica spectrum disorders: still evolving and broadening. Curr. Opin. Neurol. 32, 385–394 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lennon, V. A. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 (2004).

    CAS  PubMed  Google Scholar 

  110. Saadoun, S. et al. Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 133, 349–361 (2010).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  112. 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 

  113. Dalmau, J. et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Pruss, H. et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 75, 1735–1739 (2010).

    CAS  PubMed  Google Scholar 

  115. Mikasova, L. et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 135, 1606–1621 (2012).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Planaguma, J. et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138, 94–109 (2015).

    PubMed  Google Scholar 

  118. Ramanathan, S., Mohammad, S. S., Brilot, F. & Dale, R. C. Autoimmune encephalitis: recent updates and emerging challenges. J. Clin. Neurosci. 21, 722–730 (2014).

    CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Vincent, A. ANTIBODIES AND RECEPTORS: from neuromuscular junction to central nervous system. Neuroscience 439, 48–61 (2020).

  121. Lindstrom, J. M., Seybold, M. E., Lennon, V. A., Whittingham, S. & Duane, D. D. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 26, 1054–1059 (1976).

    CAS  PubMed  Google Scholar 

  122. Vincent, A., Palace, J. & Hilton-Jones, D. Myasthenia gravis. Lancet 357, 2122–2128 (2001).

    CAS  PubMed  Google Scholar 

  123. Nowak, R. J., Dicapua, D. B., Zebardast, N. & Goldstein, J. M. Response of patients with refractory myasthenia gravis to rituximab: a retrospective study. Ther. Adv. Neurol. Disord. 4, 259–266 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. McLaughlin, K. A. et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J. Immunol. 183, 4067–4076 (2009).

    CAS  PubMed  Google Scholar 

  125. O’Connor, K. C. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13, 211–217 (2007).

    PubMed  PubMed Central  Google Scholar 

  126. 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).

    CAS  PubMed  Google Scholar 

  127. Ramanathan, S., Al-Diwani, A., Waters, P. & Irani, S. R. The autoantibody-mediated encephalitides: from clinical observations to molecular pathogenesis. J. Neurol. 1–9 (2019).

  128. Lopez-Chiriboga, A. S. et al. LGI1 and CASPR2 neurological autoimmunity in children. Ann. Neurol. 84, 473–480 (2018).

    CAS  PubMed  Google Scholar 

  129. van Sonderen, A., Petit-Pedrol, M., Dalmau, J. & Titulaer, M. J. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat. Rev. Neurol. 13, 290–301 (2017).

    PubMed  Google Scholar 

  130. Thompson, J. et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 141, 348–356 (2018).

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Australian National Health and Medical Research Council [APP1078643 and APP1183968] (NHRMC, Australia), Multiple Sclerosis Research Australia, and a Sydney Research Excellence Initiative grant (University of Sydney, Australia).

Author information

Authors and Affiliations

  1. Brain Autoimmunity Group, Kids Neuroscience Centre, Kids Research at the Children’s Hospital at Westmead, Sydney, NSW, Australia

    Alicia Zou, Sudarshini Ramanathan, Russell C. Dale & Fabienne Brilot

  2. Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    Alicia Zou, Sudarshini Ramanathan, Russell C. Dale & Fabienne Brilot

  3. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia

    Russell C. Dale & Fabienne Brilot

  4. School of Medical Sciences, Discipline of Applied Medical Science, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    Fabienne Brilot

Authors
  1. Alicia Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sudarshini Ramanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Russell C. Dale
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabienne Brilot
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.Z. and F.B. designed the study. A.Z. wrote the first draft of the manuscript and prepared the figures and tables. A.Z., S.R., R.C.D., and F.B. reviewed the draft before submission.

Corresponding author

Correspondence to Fabienne Brilot.

Ethics declarations

Competing interests

A.Z. reports funding from the University of Sydney Postgraduate Award (UPA, Australia) and declares no other competing interests. S.R. is a consultant on an advisory board for UCB on the treatment of MOG antibody-associated demyelination. R.C.D. and F.B. have received honoraria from Biogen Idec and Merck Serono as invited speakers.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zou, A., Ramanathan, S., Dale, R.C. et al. Single-cell approaches to investigate B cells and antibodies in autoimmune neurological disorders. Cell Mol Immunol 18, 294–306 (2021). https://doi.org/10.1038/s41423-020-0510-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-0510-z

Keywords

This article is cited by

Search

Advanced search

Quick links