Skip to main content
SpringerLink
Log in

Pathophysiological Bases of Autoimmune-Initiated/Mediated Neurodegeneration

  • Protocol
  • First Online:
Translational Methods for Multiple Sclerosis Research

Part of the book series: Neuromethods ((NM,volume 166))

Abstract

Neurodegeneration in inflammatory conditions in the central nervous system follows a basic pathway, mediated by pro-inflammatory cytokines and macrophage and microglia activation, which leads to tissue injury through oxidative stress, mitochondrial injury, and ionic imbalance in glia, axons, and neurons. In inflammatory diseases of the brain and spinal cord, however, this downstream mechanism can be triggered and modified by a variety of different primary mechanisms of the adaptive immune system, engaging CD4+ Th1 or Th17 cells, CD8+ cytotoxic T-cells, tissue resident memory T-cells, B-cells, and autoantibodies. These different triggers result in distinct pathological entities and are reflected in different inflammatory diseases in humans. Their specific features are discussed in this chapter.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353:777–783

    Article  CAS  PubMed  Google Scholar 

  2. Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59

    Article  CAS  PubMed  Google Scholar 

  3. Lassmann H, Bradl M (2017) Multiple sclerosis: experimental models and reality. Acta Neuropathol 133:223–244

    Article  CAS  PubMed  Google Scholar 

  4. Flügel A, Berkowicz T, Ritter T et al (2001) Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. Immunity 14:547–560

    Article  PubMed  Google Scholar 

  5. Wolf Y, Shemer A, Levy-Efrati L et al (2018) Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination. Eur J Immunol 48:1308–1318

    Article  CAS  PubMed  Google Scholar 

  6. Nikic I, Merkler D, Sorbara C et al (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–499

    Article  CAS  PubMed  Google Scholar 

  7. Aboul-Enein F, Weiser P, Hoftberger R et al (2006) Transient axonal injury in the absence of demyelination: a correlate of clinical disease in acute experimental autoimmune encephalomyelitis. Acta Neuropathol 111:539–547

    Article  PubMed  Google Scholar 

  8. Mendiola AS, Ryu JK, Bardehle S et al (2020) Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation. Nat Immunol 21:513–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ryu JK, Rafalski VA, Meyer-Franke A et al (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212–1223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boscia F, De Rosa V, Cammarota M et al (2020) The Na+/Ca2+ exchangers in demyelinating diseases. Cell Calcium 85:102130

    Article  CAS  PubMed  Google Scholar 

  11. Friese MA, Schattling B, Fugger L (2014) Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 10:225–238

    Article  CAS  PubMed  Google Scholar 

  12. Andhavarapu S, Mubariz F, Arvas M et al (2019) Interplay between ER stress and autophagy: a possible mechanism in multiple sclerosis pathology. Exp Mol Pathol 108:183–190

    Article  CAS  PubMed  Google Scholar 

  13. Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193

    Article  CAS  PubMed  Google Scholar 

  14. Lassmann H, Van Horssen J (2016) Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta 1862:506–510

    Article  CAS  PubMed  Google Scholar 

  15. Ben-Nun A, Wekerle H, Cohen IR (1981) The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 11:195–199

    Article  CAS  PubMed  Google Scholar 

  16. Korn T, Mitsdoerffer M, Croxford AL et al (2008) IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc Natl Acad Sci 105:18460–18465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wimmer I, Scharler C, Zrzavy T et al (2019) Microglia pre-activation and neurodegeneration precipitate neuroinflammation without exacerbating tissue injury in experimental autoimmune encephalomyelitis. Acta Neuropathol Commun 7:1–13

    Article  Google Scholar 

  18. Becher B, Tugues S, Greter M (2016) GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45:963–973

    Article  CAS  PubMed  Google Scholar 

  19. Basso AS, Frenkel D, Quintana FJ et al (2008) Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest 118:1532–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tabira T, Itoyama Y, Kuroiwa Y (1984) Necessity of continuous antigenic stimulation by the locally retained antigens in chronic relapsing experimental allergic encephalomyelitis. J Neurol Sci 66:97–106

    Article  CAS  PubMed  Google Scholar 

  21. Alvord E Jr (1970) In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 9. North Holland, Amsterdam

    Google Scholar 

  22. Saxena A, Bauer J, Scheikl T et al (2008) Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol 181:1617–1621

    Article  CAS  PubMed  Google Scholar 

  23. Na SY, Cao Y, Toben C et al (2008) Naive CD8 T-cells initiate spontaneous autoimmunity to a sequestered model antigen of the central nervous system. Brain 131:2353–2365

    Article  PubMed  Google Scholar 

  24. Na SY, Hermann A, Sanchez-Ruiz M et al (2012) Oligodendrocytes enforce immune tolerance of the uninfected brain by purging the peripheral repertoire of autoreactive CD8+ T cells. Immunity 37:134–146

    Article  CAS  PubMed  Google Scholar 

  25. Cabarrocas J, Bauer J, Piaggio E et al (2003) Effective and selective immune surveillance of the brain by MHC class I-restricted cytotoxic T lymphocytes. Eur J Immunol 33:1174–1182

    Article  CAS  PubMed  Google Scholar 

  26. Scheikl T, Pignolet B, Dalard C et al (2012) Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus. J Immunol 188:4731–4735

    Article  CAS  PubMed  Google Scholar 

  27. Gross CC, Meyer C, Bhatia U et al (2019) CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nat Commun 10:1–19

    Article  CAS  Google Scholar 

  28. Smolders J, Heutinck KM, Fransen NL et al (2018) Tissue-resident memory T cells populate the human brain. Nat Commun 9:4593

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Van Nierop GP, Van Luijn MM, Michels SS et al (2017) Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. Acta Neuropathol 134:383–401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  31. Steinbach K, Vincenti I, Merkler D (2018) Resident-memory T cells in tissue-restricted immune responses: for better or worse? Front Immunol 9:2827

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Weber MS, Prod’homme T, Patarroyo JC et al (2010) B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. Ann Neurol 68:369–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hausler D, Hausser-Kinzel S, Feldmann L et al (2018) Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease. Proc Natl Acad Sci U S A 115:9773–9778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Lisak RP, Benjamins JA, Nedelkoska L et al (2012) Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol 246:85–95

    Article  CAS  PubMed  Google Scholar 

  36. Fillatreau S (2018) Natural regulatory plasma cells. Curr Opin Immunol 55:62–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Appel SH, Bornstein MB (1964) The application of tissue culture to the study of experimental allergic encephalomyelitis. II Serum factors responsible for demyelination. J Exp Med 119:303–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lassmann H, Kitz K, Wisniewski H (1981) In vivo effect of sera from animals with chronic relapsing experimental allergic encephalomyelitis on central and peripheral myelin. Acta Neuropathol 55:297–306

    Article  CAS  PubMed  Google Scholar 

  39. Linington C, Bradl M, Lassmann H et al (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130:443–454

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Mathey EK, Derfuss T, Storch MK et al (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204:2363–2372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Bradl M, Misu T, Takahashi T et al (2009) Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 66:630–643

    Article  CAS  PubMed  Google Scholar 

  43. Spadaro M, Winklmeier S, Beltran E et al (2018) Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol 84:315–328

    Article  CAS  PubMed  Google Scholar 

  44. Höftberger R, Lassmann H (2018) Immune-mediated disorders. In: Handbook of clinical neurology. Elsevier, pp 285–299

    Google Scholar 

  45. Jurynczyk M, Messina S, Woodhall MR et al (2017) Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 140:3128–3138

    Article  PubMed  Google Scholar 

  46. Bradl M, Lassmann H (2016) Neurologic autoimmunity: mechanisms revealed by animal models. Handb Clin Neurol 133:121–143

    Article  PubMed  Google Scholar 

  47. Geis C, Planaguma J, Carreno M et al (2019) Autoimmune seizures and epilepsy. J Clin Invest 129:926–940

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Hans Lassmann

Authors
  1. Hans Lassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans Lassmann .

Editor information

Editors and Affiliations

  1. Department of Neurology and Neuroimaging Center (NIC) of the Focus Program Translational Neuroscience (FTN), University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany

    Sergiu Groppa

  2. Department of Neurology, University of Düsseldorf, Düsseldorf, Germany

    Sven G. Meuth

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Lassmann, H. (2021). Pathophysiological Bases of Autoimmune-Initiated/Mediated Neurodegeneration. In: Groppa, S., G. Meuth, S. (eds) Translational Methods for Multiple Sclerosis Research. Neuromethods, vol 166. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1213-2_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1213-2_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1212-5

  • Online ISBN: 978-1-0716-1213-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation