Skip to main content
SpringerLink
Log in

Intestinal Bacterial Antigens, Toxin-Induced Pathogenesis and Immune Cross-Reactivity in Neuromyelitis Optica and Multiple Sclerosis

  • Chapter
  • First Online:
Neuro-Immuno-Gastroenterology

Abstract

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are chronic, potentially disabling, inflammatory autoimmune demyelinating diseases of the central nervous system. Although they share clinical, pathological and immunological features, MS and NMO are now considered two separate entities, and there is evidence that their pathogenesis is different. The latter is now known to be mediated by antibodies against the water channel, aquaporin-4, associated with complement-mediated damage. Environmental factors have been implicated in the pathogenesis of both of these conditions. Among these, infectious factors seem to play a key role. One mechanism whereby infection triggers autoimmunity is molecular mimicry resulting in immune cross-reactivity between infectious antigens and autoantigens. Recently, a number of studies have pointed to an immunological cross-reactivity between intestinal bacteria and aquaporin-4, providing a potential pathophysiological mechanism for NMO. The bacteria involved were Clostridium and E. coli. The immune cross-reactivity is not restricted to antibodies but also involves T cells against aquaporin-4 that also recognises clostridium epitopes. Interestingly, Clostridium perfringens and its immunological or direct neurotoxic effects (e.g. disruption of the blood-brain barrier) have also been implicated in MS. This chapter reviews the relevant data regarding the role of these gut bacteria and the immune responses they trigger in MS and NMO with some insights into the pathogenesis of these inflammatory demyelinating diseases.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17.

    Article  CAS  PubMed  Google Scholar 

  2. Mackenzie IS, Morant SV, Bloomfield GA, MacDonald TM, O'Riordan J. Incidence and prevalence of multiple sclerosis in the UK 1990–2010: a descriptive study in the General Practice Research Database. J Neurol Neurosurg Psychiatry. 2014;85(1):76–84. Pubmed Central PMCID: 3888639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. International Multiple Sclerosis Genetics C, Wellcome Trust Case Control C, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214–9. Pubmed Central PMCID: 3182531.

    Article  Google Scholar 

  4. Hartmann FJ, Khademi M, Aram J, Ammann S, Kockum I, Constantinescu C, et al. Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. Nat Commun. 2014;5:5056.

    Article  CAS  PubMed  Google Scholar 

  5. van Luijn MM, Kreft KL, Jongsma ML, Mes SW, Wierenga-Wolf AF, van Meurs M, et al. Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis. Brain. 2015;138(Pt 6):1531–47.

    Google Scholar 

  6. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol. 2007;61(6):504–13.

    Article  CAS  PubMed  Google Scholar 

  7. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61(4):288–99.

    Article  PubMed  Google Scholar 

  8. Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options Neurol. 2008;10(1):55–66.

    Article  PubMed  Google Scholar 

  9. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12.

    Article  CAS  PubMed  Google Scholar 

  10. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473–7. Pubmed Central PMCID: 2212860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology. 2007;69(24):2221–31.

    Article  CAS  PubMed  Google Scholar 

  12. Constantinescu CS, Gran B. The essential role of T cells in multiple sclerosis: a reappraisal. Biomed J. 2014;37(2):34–40.

    Article  PubMed  Google Scholar 

  13. Constantinescu CS, Wysocka M, Hilliard B, Ventura ES, Lavi E, Trinchieri G, et al. Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. J Immunol. 1998;161(9):5097–104.

    CAS  PubMed  Google Scholar 

  14. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;358(6382):155–7.

    Article  CAS  PubMed  Google Scholar 

  15. Nyirenda MH, Sanvito L, Darlington PJ, O'Brien K, Zhang GX, Constantinescu CS, et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol. 2011;187(5):2278–90.

    Article  CAS  PubMed  Google Scholar 

  16. Nyirenda M, Morandi E, Vinkemeier U, Constantin-Teodosiu D, Drinkwater S, King L, et al. Toll-like receptor 2 stimulation regulates the balance between Treg and Th17 function: a novel mechanism of reduced Treg function in multiple sclerosis. J Immunol. 2015;194(12):5761–74.

    Article  CAS  PubMed  Google Scholar 

  17. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995;80(5):695–705.

    Article  CAS  PubMed  Google Scholar 

  18. Ren Z, Wang Y, Duan T, Patel J, Liggett T, Loda E, et al. Cross-immunoreactivity between bacterial aquaporin-Z and human aquaporin-4: potential relevance to neuromyelitis optica. J Immunol. 2012;189(9):4602–11. Pubmed Central PMCID: 3586280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, Nelson PA, Stroud RM, Cree BA, et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol. 2012;72(1):53–64. Pubmed Central PMCID: 3405197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Uzawa A, Mori M, Arai K, Sato Y, Hayakawa S, Masuda S, et al. Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler. 2010;16(12):1443–52.

    Article  CAS  PubMed  Google Scholar 

  21. Lindstrom M, Heikinheimo A, Lahti P, Korkeala H. Novel insights into the epidemiology of Clostridium perfringens type A food poisoning. Food Microbiol. 2011;28(2):192–8.

    Article  PubMed  Google Scholar 

  22. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485–98. Pubmed Central PMCID: 2796826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vaishnav RA, Liu R, Chapman J, Roberts AM, Ye H, Rebolledo-Mendez JD, et al. Aquaporin 4 molecular mimicry and implications for neuromyelitis optica. J Neuroimmunol. 2013;260(1–2):92–8. Pubmed Central PMCID: 3682654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rumah KR, Linden J, Fischetti VA, Vartanian T. Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease. PLoS One. 2013;8(10):e76359. Pubmed Central PMCID: 3797790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Finnie JW. Ultrastructural changes in the brain of mice given Clostridium perfringens type D epsilon toxin. J Comp Pathol. 1984;94(3):445–52.

    Article  CAS  PubMed  Google Scholar 

  26. Finnie JW. Histopathological changes in the brain of mice given Clostridium perfringens type D epsilon toxin. J Comp Pathol. 1984;94(3):363–70.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu C, Ghabriel MN, Blumbergs PC, Reilly PL, Manavis J, Youssef J, et al. Clostridium perfringens prototoxin-induced alteration of endothelial barrier antigen (EBA) immunoreactivity at the blood–brain barrier (BBB). Exp Neurol. 2001;169(1):72–82.

    Article  CAS  PubMed  Google Scholar 

  28. Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004;55(4):458–68.

    Article  PubMed  Google Scholar 

  29. Kurtzke JF. Epidemiology in multiple sclerosis: a pilgrim's progress. Brain J Neurol. 2013;136(Pt 9):2904–17.

    Article  Google Scholar 

  30. Murrell TG, O'Donoghue PJ, Ellis T. A review of the sheep-multiple sclerosis connection. Med Hypotheses. 1986;19(1):27–39.

    Article  CAS  PubMed  Google Scholar 

  31. Xu MQ, Cao HL, Wang WQ, Wang S, Cao XC, Yan F, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol WJG. 2015;21(1):102–11. Pubmed Central PMCID: 4284325.

    Article  CAS  PubMed  Google Scholar 

  32. Yokote H, Miyake S, Croxford JL, Oki S, Mizusawa H, Yamamura T. NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora. Am J Pathol. 2008;173(6):1714–23. Pubmed Central PMCID: 2626383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cantarel BL, Waubant E, Chehoud C, Kuczynski J, DeSantis TZ, Warrington J, et al. Gut microbiota in multiple sclerosis: possible influence of immunomodulators. J Invest Med 63(5):729–34.

    Google Scholar 

  34. Viaud S, Daillere R, Boneca IG, Lepage P, Langella P, Chamaillard M, et al. Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ. 2015;22(2):199–214. Pubmed Central PMCID: 4291500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70.

    Article  CAS  PubMed  Google Scholar 

  36. Awad A, Stuve O. Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2(6):50–61. Pubmed Central PMCID: 3002608.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. Jama. 2015;313(3):275–84.

    Article  PubMed  Google Scholar 

  38. Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain J Neurol. 2013;136(Pt 9):2888–903. Pubmed Central PMCID: 3754461.

    Article  Google Scholar 

  39. Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8(3):244–53.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

Work in Prof. Constantinescu’s laboratory relevant to this chapter has been supported by the MS Society of Great Britain and Northern Ireland, an unrestricted educational grant from Biogen and the Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Author information

Authors and Affiliations

  1. Department of Clinical Neuroscience, University of Nottingham, University Hospital, Queen’s Medical Centre, Nottingham, UK

    Cris S. Constantinescu MD, PhD

  2. Clinical Neurology, University of Nottingham, Queen’s Medical Centre, Nottingham, UK

    I-Jun Chou MD

  3. Department of Paediatric Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    I-Jun Chou MD

Authors
  1. Cris S. Constantinescu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I-Jun Chou MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cris S. Constantinescu MD, PhD .

Editor information

Editors and Affiliations

  1. Neurology, C Floor South Block, University of Nottingham, Nottingham, United Kingdom

    Cris Constantinescu

  2. Atlantic Digestive Health Institute, Morristown Medical Center, Columbus, Ohio, USA

    Razvan Arsenescu

  3. Armedica LLC, Columbus, Ohio, USA

    Violeta Arsenescu

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Constantinescu, C.S., Chou, IJ. (2016). Intestinal Bacterial Antigens, Toxin-Induced Pathogenesis and Immune Cross-Reactivity in Neuromyelitis Optica and Multiple Sclerosis. In: Constantinescu, C., Arsenescu, R., Arsenescu, V. (eds) Neuro-Immuno-Gastroenterology. Springer, Cham. https://doi.org/10.1007/978-3-319-28609-9_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-28609-9_13

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-28607-5

  • Online ISBN: 978-3-319-28609-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation