Introduction - Approaches to Understanding Immune-Mediated Neurological Disorders: Measuring and Evaluating Autoantibodies to Neuronal Antigens

  • G. Martino
  • A. Vincent
Part of the Topics in Neuroscience book series (TOPNEURO)


There is increasing evidence of the relevance of the immune system to the pathogenesis of a variety of neurological disorders, including neuromuscular junction disorders, immune-mediated demyelinating disorders, and also some form of epilepsy, stroke, Alzheimer’s and Parkinsons’ diseases, and prion diseases. It is, therefore, particularly important to distinguish those conditions which are caused by dysfunction of the immune system, from those in which immune responses play a purely secondary role. In this chapter, we first provide an abbreviated introduction to neuroimmunology, and then discuss ways of measuring immune responses to neuronal antigens, and of approaches that evaluate their pathogenic roles.


Major Histocompatibility Complex Molecule Experimental Autoimmune Neuritis Major Histocompatibility Complex Expression Neuronal Antigen Deep Cervical Lymph Node 
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  1. 1.
    Barker CF, Billingham RE (1977) Immunologically privileged sites. Adv Immunol 25:1–54PubMedCrossRefGoogle Scholar
  2. 2.
    Cousins SW, McCabe MM, Danielpour D, Streilein JW (1991) Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci 32:2201–2211PubMedGoogle Scholar
  3. 3.
    Bradbury MW, Cole DF (1980) The role of the lymphatic system in drainage of cere-brospinal fluid and aqueous humour. J Physiol 299:353–365PubMedGoogle Scholar
  4. 4.
    Widner H, Moller G, Johansson BB (1988) Immune response in deep cervical lymph nodes and spleen in the mouse after antigen deposition in different intracerebral sites. Scand J Immunol 28:563–571PubMedCrossRefGoogle Scholar
  5. 5.
    Cserr HF, Harhng-Berg CJ, Knopf PM (1992) Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol 2:269–276PubMedCrossRefGoogle Scholar
  6. 6.
    Bradbury MW, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240:F329–336PubMedGoogle Scholar
  7. 7.
    Bradbury MW, Westrop RJ (1983) Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J Physiol 339:519–534PubMedGoogle Scholar
  8. 8.
    Hickey WF (1991) Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol 1:97–105PubMedCrossRefGoogle Scholar
  9. 9.
    Wekerle H, Engelhardt B, Risau W, Meyermann R (1991) Interaction of T lymphocytes with cerebral endothehal cells in vitro. Brain Pathol 1:107–114PubMedCrossRefGoogle Scholar
  10. 10.
    Raine CS, Cannella B, Duijvestijn AM, Cross AH (1990) Homing to central nervous system vasculature by antigen-specific lymphocytes. II. Lymphocyte/endothelial cell adhesion during the initial stages of autoimmune demyelination. Lab Invest 63:476–489PubMedGoogle Scholar
  11. 11.
    Wisniewski HM, Lossinsky AS (1991) Structural and functional aspects of the interaction of inflammatory cells with the blood-brain barrier in experimental brain inflammation. Brain Pathol 1:89–96PubMedCrossRefGoogle Scholar
  12. 12.
    Cross AH, Raine CS (1991) Central nervous system endothelial cell-polymorphonuclear cell interactions during autoimmune demyelination. Am J Pathol 139:1401–1409PubMedGoogle Scholar
  13. 13.
    Vass K, Lassmann H (1990) Intrathecal application of interferon gamma. Progressive appearance of MHC antigens within the rat nervous system. Am J Pathol 137:789–800PubMedGoogle Scholar
  14. 14.
    Neumann H, Cavalie A, Jenne DE, Wekerle H (1995) Induction of MHC class I genes in neurons. Science 269:549–552PubMedCrossRefGoogle Scholar
  15. 15.
    Pender MP, Nguyen KB, McCombe PA, Kerr JF (1991) Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci 104:81–87PubMedCrossRefGoogle Scholar
  16. 16.
    Schmied M, Breitschopf H, Gold R et al (1993) Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am J Pathol 143:446–452PubMedGoogle Scholar
  17. 17.
    Griffith TS, Ferguson TA (1997) The role of FasL-induced apoptosis in immune privilege. Immunol Today 18:240–244PubMedCrossRefGoogle Scholar
  18. 18.
    Weishaupt A, Gold R, Gaupp S et al (1997) Antigen therapy eliminates T cell inflammation by apoptosis: effective treatment of experimental autoimmune neuritis with recombinant myelin protein P2. Proc Natl Acad Sci USA 94:1338–1343PubMedCrossRefGoogle Scholar
  19. 19.
    Aloisi F, Ria F, Adorini L (2000) Regulation of T cell responses by central nervous APC: different roles for microglia and astrocytes. Immunol Today 21:141–147PubMedCrossRefGoogle Scholar
  20. 20.
    Martino G, Härtung HP (1999) Immunopathogenesis of multiple sclerosis: the role of T cells. Curr Opin Neurol 12:309–321PubMedCrossRefGoogle Scholar
  21. 21.
    Kieseier BC, Storch MK, Archelos JJ et al (1999) Effector pathways in immune mediated central nervous system demyelination. Curr Opin Neurol 12:323–336PubMedCrossRefGoogle Scholar
  22. 22.
    Parry SL, Hall FC, Olson J et al (1998) Bctivity versus autoaggression: a different perspective on human autoantigens. Curr Opin Immunol 10:663–668PubMedCrossRefGoogle Scholar
  23. 23.
    Zinkernagel RM (2000) What is missing in immunology to understand immunity? Nat Immunol 1:181–185PubMedCrossRefGoogle Scholar
  24. 24.
    Vincent A, Lily 0, Palace J (1999) Pathogenic autoantibodies to neuronal proteins in neurological disorders. J Neuroimmunol 100:169–180PubMedCrossRefGoogle Scholar
  25. 25.
    Vincent A (1999) Antibodies to ion channels in paraneoplastic disorders. Brain Pathol 9:285–291PubMedCrossRefGoogle Scholar
  26. 26.
    Archelos JJ, Härtung HP (2000) Pathogenetic role of autoantibodies in neurological diseases. Trends Neurosci 23:317–327PubMedCrossRefGoogle Scholar
  27. 27.
    Giometto B, Tavolato B, Graus F (1999) Autoimmunity in paraneoplastic neurological syndromes. Brain Pathol 9:261–273PubMedCrossRefGoogle Scholar
  28. 28.
    Lang B, Vincent A (1999) Autoimmunity to ion-channels and other proteins in paraneoplastic disorders. Curr Opin Immunol 8:865–871CrossRefGoogle Scholar
  29. 29.
    Vincent A, Honnorat J, Antoine JC et al (1998) Autoimmunity in paraneoplastic neurological disorders. J Neuroimmunol 84:105–109PubMedCrossRefGoogle Scholar
  30. 30.
    Moll JW, Antoine JC, Brashear HR et al (1995) Guidelines on the detection of paraneoplastic anti-neuronal-specific antibodies: report from the Workshop to the Fourth Meeting of the International Society of Neuro-Immunology on Paraneoplastic Neurological Disease, 22-23 October 1994, Rotterdam, The Netherlands. Neurology 45:1937–1941PubMedCrossRefGoogle Scholar
  31. 31.
    Leflcovits I (ed) (1996) Immunology methods manual: The comprehensive sourcebook of techniques. Academic Press, San DiegoGoogle Scholar
  32. 32.
    Berson SA, Yalow RS (1968) General principles of radioimmunoassay. Clin Chim Acta 22:51–69PubMedCrossRefGoogle Scholar
  33. 33.
    Engvall E, Perlman P (1971) Enzyme-linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G. Immunochemistry 8:871–874PubMedCrossRefGoogle Scholar
  34. 34.
    Schuurs AH, Van Weemen BK (1977) Enzyme-immunoassay. Clin Chim Acta 8:1–40CrossRefGoogle Scholar
  35. 35.
    Pataki G (1967) Thin-layer chromatography of amino acids. Chromatogr Rev 9:23–36PubMedCrossRefGoogle Scholar
  36. 36.
    Roda A, Pasini P, Guardigli M et al (2000) Bio- and chemiluminescence in bioanalysis. Fresenius J Anal Chem 366:752–759PubMedCrossRefGoogle Scholar
  37. 37.
    Hoch W, McConville J, Helms S et al (2001) Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7: 365–368PubMedCrossRefGoogle Scholar
  38. 38.
    Vincent A, Beeson D, Lang B (2000) Molecular targets for autoimmune and genetic disorders of neuromuscular transmission. Eur J Biochem. 267:6717–6728PubMedCrossRefGoogle Scholar
  39. 39.
    Roberts A, Perera S, Lang B et al (1985) Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma Hne. Nature 317:737–739PubMedCrossRefGoogle Scholar
  40. 40.
    Drachman DB, Adams RN, Josifek LF, Self SG (1982) Functional activities of autoanti bodies to acetylcholine receptors and the clinical severity of myasthenia gravis. N Engl J Med 307:769–775PubMedCrossRefGoogle Scholar
  41. 41.
    Yamamoto T, Vincent A, Ciulla TA et al (1991) Seronegative myasthenia gravis: a plasma factor inhibiting agonist-induced acetylcholine receptor function copurifles with IgM. Ann Neurol 30: 550–557PubMedCrossRefGoogle Scholar
  42. 42.
    Rogers SW, Andrews PI, Gahring LC et al (1994) Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 265:648–651PubMedCrossRefGoogle Scholar
  43. 43.
    Blaes F, Beeson D, Plested P et al (2000) IgG from “seronegative” myasthenia gravis patients binds to a muscle cell line, TE671, but not to human acetylcholine receptor. Ann Neurol 47:504–510PubMedCrossRefGoogle Scholar
  44. 44.
    Li M (2000) AppHcations of display technology in protein analysis. Nat Biotechnol 18:1251–1256PubMedCrossRefGoogle Scholar
  45. 45.
    Larrick JW, Fry KE (1991) Recombinant antibodies. Hum Antibodies Hybridomas 2:172–189PubMedGoogle Scholar
  46. 46.
    Graus YF, de Baets MH, Parren PW et al (1997) Human anti-nicotinic acetylcholine receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies. J Immunol 158:1919–1929PubMedGoogle Scholar
  47. 47.
    Farrar J, Portolano S, Willcox N et al (1997) Diverse Fab specific for acetylcholine receptor epitopes from a myasthenia gravis thymus combinatorial library. Int Immunol 9:1311–1318PubMedCrossRefGoogle Scholar
  48. 48.
    Matthews I, Farrar J, McLachlan S et al (1998) Production of Fab fragments against the human acetylcholine receptor from myasthenia gravis thymus lambda and kappa phage libraries. Ann N Y Acad Sci 841:418–421PubMedCrossRefGoogle Scholar
  49. 49.
    Toyka KV, Drachman DB, Griffin DE et al (1977) Myasthenia gravis: study of humoral immune mechanisms by passive transfer to mice. New Eng J Med 296:125–131PubMedCrossRefGoogle Scholar
  50. 50.
    Mossman S, Vincent A, Newsom-Davis J (1988) Passive transfer of myasthenia gravis by immunoglobulins: lack of correlation between antibody bound, acetylcholine receptor loss and transmission defect. J Neurol Sci 84:15–28PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2002

Authors and Affiliations

  • G. Martino
    • 1
  • A. Vincent
    • 2
  1. 1.Neuroimmunology Unit, Deptartment of Neuroscience, San Raffaele Scientific InstituteDIBITMilanItaly
  2. 2.Neurosciences Group, Department of Clinical Neurology, Institute of Molecular MedicineJohn Radcliffe HospitalOxfordUK

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