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Multi-proteomic Analysis Revealed Distinct Protein Profiles in Cerebrospinal Fluid of Patients Between Anti-NMDAR Encephalitis NORSE and Cryptogenic NORSE

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Abstract

New-onset refractory status epilepticus (NORSE) is rare but intractable. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and cryptogenic etiologies are the two major causes of NORSE with distinct clinical features. To elucidate the underlying mechanisms, 6 patients with anti-NMDAR encephalitis NORSE and 5 with cryptogenic NORSE (C-NORSE) were enrolled. Five patients of cerebrovascular disorders were used as controls. Quantitative proteomic analysis of the cerebrospinal fluid (CSF) samples of the patients revealed 101 and 56 proteins were changed, respectively. The average fold-change of the upregulated proteins, namely up-proteomic score in this study, was positively correlated with the severity and prognosis of the diseases, including ICU stay (r = 0.9308, P = 0.0035 in NMDAR group; r = 0.8977, P = 0.0193 in C-NORSE group), mRS score at discharge (r = 0.9710, P = 0.0111 in NMDAR group; r = 0.7071, P = 0.2000 in C-NORSE group), and time taken for patients awaking from a coma (r = 0.8823, P = 0.0100 in NMDAR group; r = 0.7906, P = 0.2000 in C-NORSE group). Pathways involved in humoral immune response, wound healing, and epigenetic regulation of transcription were upregulated in anti-NMDAR encephalitis NORSE. Pathways of innate and lymphocyte mediated immune response, synaptic functions, ubiquitination, and cell apoptosis were up-regulated in C-NORSE, which was consistent with a mouse model of status epilepticus. Fc receptor and B cell mediated immunity signaling pathways were downregulated in C-NORSE. Immunome microarray analysis demonstrated high autoantibody targeting 48 proteins in CSF samples of anti-NMDAR encephalitis NORSE. While the reaction was kept at a very low level in C-NORSE. There is no significant difference in inflammatory cytokine level between each group. The level of IL-4 (r = 0.7435, P = 0.0451), IL-13 (r = 0.7643, P = 0.0384), IFN-γ (r = 0.7973, P = 0.0287) and TNF-α (r = 0.8598, P = 0.0141) in NMDAR group, and IL-6 (r = 0.8479, P = 0.0348), IL-8 (r = 0.9076, P = 0.0166) in C-NORSE group were positively correlated with the up-proteomic score. The present study suggests that the up-proteomic score of CSF could be a promising indicator for assessment of the severity of anti-NMDAR encephalitis NORSE and C-NORSE. The distinct CSF proteomes imply different pathogenic mechanisms of the two diseases, and immunotherapy strategies as well.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Vezzani A, Dingledine R, Rossetti AO (2015) Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother 15(9):1081–1092. https://doi.org/10.1586/14737175.2015.1079130

    Article  CAS  Google Scholar 

  2. Mantoan Ritter L, Nashef L (2021) New-onset refractory status epilepticus (NORSE). Pract Neurol 21(2):119–127. https://doi.org/10.1136/practneurol-2020-002534

    Article  Google Scholar 

  3. Hirsch LJ, Gaspard N, van Baalen A, Nabbout R, Demeret S, Loddenkemper T, Navarro V, Specchio N et al. (2018) Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 59(4):739–744. https://doi.org/10.1111/epi.14016

    Article  Google Scholar 

  4. Gaspard N, Foreman BP, Alvarez V, Kang CC, Probasco JC, Jongeling AC, Meyers E, Espinera A et al. (2015) New-onset refractory status epilepticus: etiology, clinical features, and outcome. Neurology 85(18):1604–1613. https://doi.org/10.1212/WNL.0000000000001940

    Article  Google Scholar 

  5. Iizuka T, Kanazawa N, Kaneko J, Tominaga N, Nonoda Y, Hara A, Onozawa Y, Asari H et al. (2017) Cryptogenic NORSE: its distinctive clinical features and response to immunotherapy. Neurol Neuroimmunol Neuroinflamm 4(6):e396. https://doi.org/10.1212/NXI.0000000000000396

    Article  Google Scholar 

  6. Specchio N, Pietrafusa N (2020) New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome. Dev Med Child Neurol 62(8):897–905

    Article  Google Scholar 

  7. Jang Y, Kim DW, Yang KI, Byun J-I, Seo J-G, No YJ, Kang KW, Kim D et al. (2020) Clinical approach to autoimmune epilepsy. j clin neurol 16(4):519. https://doi.org/10.3988/jcn.2020.16.4.519

    Article  Google Scholar 

  8. Gall CRE, Jumma O, Mohanraj R (2013) Five cases of new onset refractory status epilepticus (NORSE) syndrome: outcomes with early immunotherapy. Seizure 22(3):217–220. https://doi.org/10.1016/j.seizure.2012.12.016

    Article  Google Scholar 

  9. Li J, Saldivar C, Maganti RK (2013) Plasma exchange in cryptogenic new onset refractory status epilepticus. Seizure 22(1):70–73. https://doi.org/10.1016/j.seizure.2012.09.011

    Article  CAS  Google Scholar 

  10. Kodama S, Arai N, Hagiwara A, Kimura A, Takeuchi S (2018) A favorable outcome of intensive immunotherapies for new-onset refractory status epilepticus (NORSE). J Intensive Care 6 (1). https://doi.org/10.1186/s40560-018-0315-7

  11. Gaspard N, Hirsch LJ, Sculier C, Loddenkemper T, van Baalen A, Lancrenon J, Emmery M, Specchio N et al. (2018) New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia 59(4):745–752. https://doi.org/10.1111/epi.14022

    Article  Google Scholar 

  12. Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, de Curtis M, Perucca P (2018) Epilepsy. Nat Rev Dis Primers 4 (1). https://doi.org/10.1038/nrdp.2018.24

  13. Staley K (2015) Molecular mechanisms of epilepsy. Nat Neurosci 18(3):367–372. https://doi.org/10.1038/nn.3947

    Article  CAS  Google Scholar 

  14. Xu X, Lu Q, Huang Y, Fan S, Zhou L, Yuan J, Yang X, Ren H et al. (2020) Anti-NMDAR encephalitis: a single-center, longitudinal study in China. Neurol Neuroimmunol Neuroinflamm 7 (1). https://doi.org/10.1212/NXI.0000000000000633

  15. Wang D, Pan Y, Huang K, Lin Z, Xie Z, Liu G, Wu Y, Wang S (2020) Is rat hippocampus section immunostaining an indicator for immunotherapy in cryptogenic adult new-onset refractory status epilepticus (NORSE)? Seizure 76:131–136. https://doi.org/10.1016/j.seizure.2020.01.022

    Article  Google Scholar 

  16. Chen X, Liu K, Lin Z, Huang K, Pan S (2020) Knockout of transient receptor potential melastatin 4 channel mitigates cerebral edema and neuronal injury after status epilepticus in mice. J Neuropathol Exp Neurol 79(12):1354–1364. https://doi.org/10.1093/jnen/nlaa134

    Article  CAS  Google Scholar 

  17. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology 10(1):63–74. https://doi.org/10.1016/S1474-4422(10)70253-2

    Article  CAS  Google Scholar 

  18. Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F, Gleichman AJ, Balice-Gordon R et al. (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13(2):167–177. https://doi.org/10.1016/s1474-4422(13)70282-5

    Article  CAS  Google Scholar 

  19. Cartagena AM, Young GB, Lee DH, Mirsattari SM (2014) Reversible and irreversible cranial MRI findings associated with status epilepticus. Epilepsy Behav 33:24–30. https://doi.org/10.1016/j.yebeh.2014.02.003

    Article  CAS  Google Scholar 

  20. Liu CY, Zhu J, Zheng XY, Ma C, Wang X (2017) Anti-N-methyl-D-aspartate receptor encephalitis: a severe, potentially reversible autoimmune encephalitis. Mediators Inflamm 2017:6361479. https://doi.org/10.1155/2017/6361479

    Article  CAS  Google Scholar 

  21. Terrone G, Frigerio F, Balosso S, Ravizza T, Vezzani A (2019) Inflammation and reactive oxygen species in status epilepticus: biomarkers and implications for therapy. Epilepsy Behav 101:106275. https://doi.org/10.1016/j.yebeh.2019.04.028

    Article  Google Scholar 

  22. Simoni MGD, Perego C, Ravizza T, Moneta D, Conti M, Marchesi F, Luigi AD, Garattini S, Vezzani A (2000) Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur J Neurosci 12:2623–2633

    Article  Google Scholar 

  23. Zou C, Pei S, Yan W, Lu Q, Zhong X, Chen Q, Pan S, Wang Z et al. (2020) Cerebrospinal fluid osteopontin and inflammation-associated cytokines in patients with anti-N-methyl-D-aspartate receptor encephalitis. Front Neurol 11.https://doi.org/10.3389/fneur.2020.519692

  24. Huang Y-Q, Xiong H (2021) Anti-NMDA receptor encephalitis: a review of mechanistic studies. Int J Physiol Pathophysiol Pharmacol 13 (1)

  25. Thomas A, Farah K, Millis RM (2022) Epigenetic influences on wound healing and hypertrophic-keloid scarring: a review for basic scientists and clinicians. Cureus 14(3):e23503. https://doi.org/10.7759/cureus.23503

    Article  Google Scholar 

  26. Migdał M, Tralle E, Nahia KA, Bugajski Ł, Kędzierska KZ, Garbicz F, Piwocka K, Winata CL et al. (2021) Multi-omics analyses of early liver injury reveals cell-type-specific transcriptional and epigenomic shift. BMC Genomics 22(1):904. https://doi.org/10.1186/s12864-021-08173-1

    Article  CAS  Google Scholar 

  27. AEA S, CM H (2019) The role of epigenetics in autoimmune/inflammatory disease. Front Immunol 10 (1525). https://doi.org/10.3389/fimmu.2019.01525

  28. Pastar I, Marjanovic J, Stone RC, Chen V, Burgess JL, Mervis JS, Tomic-Canic M (2021) Epigenetic regulation of cellular functions in wound healing. Exp Dermatol 30(8):1073–1089. https://doi.org/10.1111/exd.14325

    Article  CAS  Google Scholar 

  29. Smith MM (1991) Histone structure and function. Curr Opin Cell Biol 3(3):429–437. https://doi.org/10.1016/0955-0674(91)90070-F

    Article  CAS  Google Scholar 

  30. Smith BJ, Carregari VC (2022) Histone modifications in neurological disorders. Adv Exp Med Biol 1382:95–107. https://doi.org/10.1007/978-3-031-05460-0_7

  31. Su H, Na N, Zhang X, Zhao Y (2017) The biological function and significance of CD74 in immune diseases. Inflamm Res 66(3):209–216. https://doi.org/10.1007/s00011-016-0995-1

    Article  CAS  Google Scholar 

  32. Fagan AM, Bu G, Sun Y, Daugherty A, Holtzman DM (1996) Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem 271(47):30121–30125

    Article  CAS  Google Scholar 

  33. Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, Nelson MR, Rao A et al. (2021) Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease. Nat Neurosci 24(6):786–798. https://doi.org/10.1038/s41593-021-00851-3

    Article  CAS  Google Scholar 

  34. Böhm JK, Schaeben V, Schäfer N, Güting H, Lefering R, Thorn S, Schöchl H, Zipperle J et al. (2022) Extended coagulation profiling in isolated traumatic brain injury: a CENTER-TBI analysis. Neurocrit Care 36(3):927–941. https://doi.org/10.1007/s12028-021-01400-3

    Article  CAS  Google Scholar 

  35. Cesca F, Baldelli P, Valtorta F, Benfenati F (2010) The synapsins: key actors of synapse function and plasticity. Prog Neurobiol 91(4):313–348. https://doi.org/10.1016/j.pneurobio.2010.04.006

    Article  CAS  Google Scholar 

  36. Nguyen DK, Rouleau I, Sénéchal G, Ansaldo AI, Gravel M, Benfenati F, Cossette P (2015) X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome. Epilepsia 56(7):1098–1108. https://doi.org/10.1111/epi.13042

    Article  CAS  Google Scholar 

  37. Garcia CC, Blair HJ, Seager M, Coulthard A, Tennant S, Buddles M, Curtis A, Goodship JA (2004) Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J Med Genet 41(3):183–186

    Article  CAS  Google Scholar 

  38. Fassio A, Patry L, Congia S, Onofri F, Piton A, Gauthier J, Pozzi D, Messa M et al. (2011) SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet 20(12):2297–2307. https://doi.org/10.1093/hmg/ddr122

    Article  CAS  Google Scholar 

  39. Sakurada K, Kato H, Nagumo H, Hiraoka H, Furuya K, Ikuhara T, Yamakita Y, Fukunaga K et al. (2002) Synapsin I is phosphorylated at Ser603 by p21-activated kinases (PAKs) in vitro and in PC12 cells stimulated with bradykinin. J Biol Chem 277(47):45473–45479

    Article  CAS  Google Scholar 

  40. Nikolić M (2008) The Pak1 kinase: an important regulator of neuronal morphology and function in the developing forebrain. Mol Neurobiol 37(2–3):187–202. https://doi.org/10.1007/s12035-008-8032-1

    Article  CAS  Google Scholar 

  41. Xia Z, Storm DR (2005) The role of calmodulin as a signal integrator for synaptic plasticity. Nat Rev Neurosci 6(4):267–276

    Article  CAS  Google Scholar 

  42. Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83(5):495–502. https://doi.org/10.1136/jnnp-2011-301779

    Article  Google Scholar 

  43. Kilka S, Erdmann F, Migdoll A, Fischer G, Weiwad M (2009) The proline-rich N-terminal sequence of calcineurin Abeta determines substrate binding. Biochemistry 48(9):1900–1910. https://doi.org/10.1021/bi8019355

    Article  CAS  Google Scholar 

  44. Ambrozkiewicz MC, Borisova E, Schwark M, Ripamonti S, Schaub T, Smorodchenko A, Weber AI, Rhee HJ et al. (2021) The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc. Mol Psychiatry 26(6):1980–1995. https://doi.org/10.1038/s41380-020-0714-8

    Article  CAS  Google Scholar 

  45. Shah IM, Di Napoli M (2007) The ubiquitin-proteasome system and proteasome inhibitors in central nervous system diseases. Cardiovasc Hematol Disord Drug Targets 7(4):250–273

    Article  CAS  Google Scholar 

  46. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q et al. (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286):712–716. https://doi.org/10.1126/science.aad8373

    Article  CAS  Google Scholar 

  47. Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, Stevens B, McCarroll SA et al. (2021) Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci 24(2):214–224. https://doi.org/10.1038/s41593-020-00763-8

    Article  CAS  Google Scholar 

  48. Bien CG, Vincent A, Barnett MH, Becker AJ, Blumcke I, Graus F, Jellinger KA, Reuss DE et al. (2012) Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135(5):1622–1638. https://doi.org/10.1093/brain/aws082

    Article  Google Scholar 

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Acknowledgements

We would like to thank enrolled patients for their participation in the study. We also thank the colleagues of our Neurology Department and Laboratory of Diagnosis of Neurological Disorders and Neuroprotection Research for their advice and support through the course of this work.

Funding

This work was supported by National Key R&D Program of China (2020YFC2006400 to Gao), Key-Area Research and Development Program of Guangdong Province (2021B0101420005 to Gao), National Natural Science Foundation of China (82171602 to Xu, 82071484 to Wu), President Foundation of Nanfang Hospital (2019B007 to Wang, 2020B008 to Xu), Medical Science and Technology Foundation of Guangdong Province (A2021151 to Xu) and Natural Science Foundation of Guangdong Province (2019A1515011760 to Wu).

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Author notes

  1. Dongmei Wang, Yongming Wu, Yue Pan, and Shengnan Wang contributed equally to the present study.

Authors and Affiliations

  1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Dongmei Wang, Yongming Wu, Yue Pan, Shengnan Wang, Guanghui Liu & Kaibiao Xu

  2. Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China

    Yibo Gao

  3. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yibo Gao

  4. Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yibo Gao

  5. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yibo Gao

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  1. Dongmei Wang
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Contributions

DW, YG, and KX are responsible for concepts and design. YP, KX, YW, and SW are responsible for data collecting and statistical analysis. GL and YP are responsible for immunostaining tests of all the patients. All authors acquired, analyzed, and interpreted the data. All authors contributed intellectually. The manuscript was prepared by DW and KX. All authors read and approved the final manuscript.

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Correspondence to Yibo Gao or Kaibiao Xu.

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This study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University (Permit No. NFEC-2021–001).

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Wang, D., Wu, Y., Pan, Y. et al. Multi-proteomic Analysis Revealed Distinct Protein Profiles in Cerebrospinal Fluid of Patients Between Anti-NMDAR Encephalitis NORSE and Cryptogenic NORSE. Mol Neurobiol 60, 98–115 (2023). https://doi.org/10.1007/s12035-022-03011-1

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