Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2005 Oct;76(10):1431–1439. doi: 10.1136/jnnp.2004.052282

T cell reactivity to P0, P2, PMP-22, and myelin basic protein in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy

P Csurhes 1, A Sullivan 1, K Green 1, M Pender 1, P McCombe 1
PMCID: PMC1739377  PMID: 16170091

Abstract

Objectives: It has been suggested that autoimmunity to peripheral myelin proteins is involved in the pathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to compare reactivity of peripheral blood mononuclear cells (PBMC) to antigens of peripheral myelin proteins in patients with GBS and patients with CIDP with that of healthy controls and patients with other non-immune mediated neuropathies (ON).

Methods: We prepared PBMC from blood from 83 healthy controls and from 64 patients with GBS, 54 with CIDP, and 62 with ON. PBMC were tested in antigen specific proliferation assays against peptides from myelin proteins P0, P2, PMP22, and myelin basic protein (MBP), which is identical to myelin P1, and against whole human MBP. Interferon-gamma (IFN-γ) and interleukin (IL)-5 enzyme linked immunospot (ELISPOT) assays were also performed in some subjects to assess spontaneous and peripheral myelin antigen specific PBMC cytokine secretion.

Results: Antigen specific PBMC proliferation assays showed no significant elevation of peptide specific T cell responsiveness in patients with GBS or CIDP compared with healthy controls or patients with ON. Levels of spontaneous ELISPOT IFN-γ secretion were increased in patients with GBS and significantly increased in those with CIDP compared with healthy controls and patients with ON. No convincing differences in antigen specific ELISPOT IFN-γ secretion levels to individual peptides were detectable in patients with GBS. The proportion of patients with CIDP with an increased number of PBMC producing IFN-γ in response to peptide PMP-2251–64 was significantly increased compared with healthy controls and patients with ON. No significant differences in antigen specific ELISPOT IL-5 secretion levels were detectable in patients with GBS or CIDP compared with controls, but levels of spontaneous IL-5 secretion were significantly higher in patients with CIDP than in healthy controls or patients with ON.

Conclusions: Although the lack of significantly increased antigen specific PBMC proliferation in GBS and CIDP does not support a role for T cells, the more sensitive ELISPOT technique detected increased numbers of PBMC secreting IFN-γ spontaneously in 25% of patients with GBS, providing further evidence for a role of T cells in the immunopathology of GBS. Increased numbers of spontaneous IFN-γ and IL-5 secreting cells, and increased IFN-γ secretion in response to PMP-2251–64, in patients with CIDP provide further evidence for a role of myelin specific T cells in CIDP.

Full Text

The Full Text of this article is available as a PDF (212.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aarli Johan A. Role of cytokines in neurological disorders. Curr Med Chem. 2003 Oct;10(19):1931–1937. doi: 10.2174/0929867033456918. [DOI] [PubMed] [Google Scholar]
  2. Asbury A. K. Diagnostic considerations in Guillain-Barré syndrome. Ann Neurol. 1981;9 (Suppl):1–5. doi: 10.1002/ana.410090703. [DOI] [PubMed] [Google Scholar]
  3. Bansil S., Mithen F. A., Cook S. D., Sheffet A., Rohowsky-Kochan C. Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barré syndrome. Neurology. 1991 Aug;41(8):1302–1305. doi: 10.1212/wnl.41.8.1302. [DOI] [PubMed] [Google Scholar]
  4. Dahle C., Ekerfelt C., Vrethem M., Samuelsson M., Ernerudh J. T helper type 2 like cytokine responses to peptides from P0 and P2 myelin proteins during the recovery phase of Guillain-Barré syndrome. J Neurol Sci. 1997 Dec 9;153(1):54–60. doi: 10.1016/s0022-510x(97)00178-0. [DOI] [PubMed] [Google Scholar]
  5. Dahle C., Vrethem M., Ernerudh J. T lymphocyte subset abnormalities in peripheral blood from patients with the Guillain-Barré syndrome. J Neuroimmunol. 1994 Sep;53(2):219–225. doi: 10.1016/0165-5728(94)90032-9. [DOI] [PubMed] [Google Scholar]
  6. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  7. Dyck P. J., Lais A. C., Ohta M., Bastron J. A., Okazaki H., Groover R. V. Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc. 1975 Nov;50(11):621–637. [PubMed] [Google Scholar]
  8. Gabriel C. M., Gregson N. A., Hughes R. A. Anti-PMP22 antibodies in patients with inflammatory neuropathy. J Neuroimmunol. 2000 May 1;104(2):139–146. doi: 10.1016/s0165-5728(99)00269-6. [DOI] [PubMed] [Google Scholar]
  9. Gabriel C. M., Hughes R. A., Moore S. E., Smith K. J., Walsh F. S. Induction of experimental autoimmune neuritis with peripheral myelin protein-22. Brain. 1998 Oct;121(Pt 10):1895–1902. doi: 10.1093/brain/121.10.1895. [DOI] [PubMed] [Google Scholar]
  10. Greer J. M., Csurhes P. A., Cameron K. D., McCombe P. A., Good M. F., Pender M. P. Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain. 1997 Aug;120(Pt 8):1447–1460. doi: 10.1093/brain/120.8.1447. [DOI] [PubMed] [Google Scholar]
  11. Hartung H. P., Hughes R. A., Taylor W. A., Heininger K., Reiners K., Toyka K. V. T cell activation in Guillain-Barré syndrome and in MS: elevated serum levels of soluble IL-2 receptors. Neurology. 1990 Feb;40(2):215–218. doi: 10.1212/wnl.40.2.215. [DOI] [PubMed] [Google Scholar]
  12. Hartung H. P., Reiners K., Schmidt B., Stoll G., Toyka K. V. Serum interleukin-2 concentrations in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy: comparison with other neurological diseases of presumed immunopathogenesis. Ann Neurol. 1991 Jul;30(1):48–53. doi: 10.1002/ana.410300110. [DOI] [PubMed] [Google Scholar]
  13. Hohnoki K., Inoue A., Koh C. S. Elevated serum levels of IFN-gamma, IL-4 and TNF-alpha/unelevated serum levels of IL-10 in patients with demyelinating diseases during the acute stage. J Neuroimmunol. 1998 Jul 1;87(1-2):27–32. doi: 10.1016/s0165-5728(98)00053-8. [DOI] [PubMed] [Google Scholar]
  14. Honavar M., Tharakan J. K., Hughes R. A., Leibowitz S., Winer J. B. A clinicopathological study of the Guillain-Barré syndrome. Nine cases and literature review. Brain. 1991 Jun;114(Pt 3):1245–1269. doi: 10.1093/brain/114.3.1245. [DOI] [PubMed] [Google Scholar]
  15. Horiuchi I., Kawano Y., Yamasaki K., Matsuo H., Minohara M., Nakamura T., Hashiguchi H., Ohyagi Y., Yamada T., Kira J. Heightened IgE response to mite antigens in inflammatory neuropathies. J Neurol Sci. 1999 Jul 1;166(2):77–80. doi: 10.1016/s0022-510x(99)00098-2. [DOI] [PubMed] [Google Scholar]
  16. Horiuchi I., Ochi H., Murai H., Osoegawa M., Minohara M., Furuya H., Kira J. Th2 shift in mononeuritis multiplex and increase of Th2 cells in chronic inflammatory demyelinating polyneuropathy: an intracellular cytokine analysis. J Neurol Sci. 2001 Dec 15;193(1):49–52. doi: 10.1016/s0022-510x(01)00603-7. [DOI] [PubMed] [Google Scholar]
  17. Hughes R. A., Hadden R. D., Gregson N. A., Smith K. J. Pathogenesis of Guillain-Barré syndrome. J Neuroimmunol. 1999 Dec;100(1-2):74–97. doi: 10.1016/s0165-5728(99)00195-2. [DOI] [PubMed] [Google Scholar]
  18. Inoue A., Iwahashi T., Koh C. S., Yanagisawa N. [A study on subpopulation of helper T cells in chronic inflammatory demyelinating polyneuropathy]. Arerugi. 1994 Oct;43(10):1270–1276. [PubMed] [Google Scholar]
  19. Kadlubowski M., Hughes R. A. Identification of the neuritogen for experimental allergic neuritis. Nature. 1979 Jan 11;277(5692):140–141. doi: 10.1038/277140a0. [DOI] [PubMed] [Google Scholar]
  20. Khalili-Shirazi A., Atkinson P., Gregson N., Hughes R. A. Antibody responses to P0 and P2 myelin proteins in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol. 1993 Jul;46(1-2):245–251. doi: 10.1016/0165-5728(93)90255-w. [DOI] [PubMed] [Google Scholar]
  21. Khalili-Shirazi A., Hughes R. A., Brostoff S. W., Linington C., Gregson N. T cell responses to myelin proteins in Guillain-Barré syndrome. J Neurol Sci. 1992 Sep;111(2):200–203. doi: 10.1016/0022-510x(92)90069-w. [DOI] [PubMed] [Google Scholar]
  22. Kieseier Bernd C., Dalakas Marinos C., Hartung Hans-Peter. Immune mechanisms in chronic inflammatory demyelinating neuropathy. Neurology. 2002 Dec 24;59(12 Suppl 6):S7–12. doi: 10.1212/wnl.59.12_suppl_6.s7. [DOI] [PubMed] [Google Scholar]
  23. Kleyweg R. P., van der Meché F. G., Schmitz P. I. Interobserver agreement in the assessment of muscle strength and functional abilities in Guillain-Barré syndrome. Muscle Nerve. 1991 Nov;14(11):1103–1109. doi: 10.1002/mus.880141111. [DOI] [PubMed] [Google Scholar]
  24. Koga Michiaki, Yuki Nobuhiro, Tsukada Yukiko, Hirata Koichi, Matsumoto Yoh. CDR3 spectratyping analysis of the T cell receptor repertoire in Guillain-Barré and Fisher syndromes. J Neuroimmunol. 2003 Aug;141(1-2):112–117. doi: 10.1016/s0165-5728(03)00212-1. [DOI] [PubMed] [Google Scholar]
  25. Kwa M. S., van Schaik I. N., Brand A., Baas F., Vermeulen M. Investigation of serum response to PMP22, connexin 32 and P(0) in inflammatory neuropathies. J Neuroimmunol. 2001 Jun 1;116(2):220–225. doi: 10.1016/s0165-5728(01)00307-1. [DOI] [PubMed] [Google Scholar]
  26. Lafaille J. J. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev. 1998 Jun;9(2):139–151. doi: 10.1016/s1359-6101(98)00009-4. [DOI] [PubMed] [Google Scholar]
  27. Leneman F. The Guillain-Barré syndrome. Definition, etiology, and review of 1,100 cases. Arch Intern Med. 1966 Aug;118(2):139–144. doi: 10.1001/archinte.118.2.139. [DOI] [PubMed] [Google Scholar]
  28. Liblau R. S., Singer S. M., McDevitt H. O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995 Jan;16(1):34–38. doi: 10.1016/0167-5699(95)80068-9. [DOI] [PubMed] [Google Scholar]
  29. Lin J. T., Rowe V., Brostoff S. W., Abdou N. I. Lymphocyte studies in a patient with chronic polyradiculoneuropathy. Neurology. 1982 Oct;32(10):1127–1132. doi: 10.1212/wnl.32.10.1127. [DOI] [PubMed] [Google Scholar]
  30. Linington C., Izumo S., Suzuki M., Uyemura K., Meyermann R., Wekerle H. A permanent rat T cell line that mediates experimental allergic neuritis in the Lewis rat in vivo. J Immunol. 1984 Oct;133(4):1946–1950. [PubMed] [Google Scholar]
  31. Linington C., Lassmann H., Ozawa K., Kosin S., Mongan L. Cell adhesion molecules of the immunoglobulin supergene family as tissue-specific autoantigens: induction of experimental allergic neuritis (EAN) by P0 protein-specific T cell lines. Eur J Immunol. 1992 Jul;22(7):1813–1817. doi: 10.1002/eji.1830220721. [DOI] [PubMed] [Google Scholar]
  32. Milner P., Lovelidge C. A., Taylor W. A., Hughes R. A. P0 myelin protein produces experimental allergic neuritis in Lewis rats. J Neurol Sci. 1987 Jul;79(3):275–285. doi: 10.1016/0022-510x(87)90235-8. [DOI] [PubMed] [Google Scholar]
  33. Pender M. P., Csurhes P. A., Greer J. M., Mowat P. D., Henderson R. D., Cameron K. D., Purdie D. M., McCombe P. A., Good M. F. Surges of increased T cell reactivity to an encephalitogenic region of myelin proteolipid protein occur more often in patients with multiple sclerosis than in healthy subjects. J Immunol. 2000 Nov 1;165(9):5322–5331. doi: 10.4049/jimmunol.165.9.5322. [DOI] [PubMed] [Google Scholar]
  34. Pollard J. D., Baverstock J., McLeod J. G. Class II antigen expression and inflammatory cells in the Guillain-Barré syndrome. Ann Neurol. 1987 Apr;21(4):337–341. doi: 10.1002/ana.410210404. [DOI] [PubMed] [Google Scholar]
  35. Pollard J. D., McCombe P. A., Baverstock J., Gatenby P. A., McLeod J. G. Class II antigen expression and T lymphocyte subsets in chronic inflammatory demyelinating polyneuropathy. J Neuroimmunol. 1986 Dec;13(2):123–134. doi: 10.1016/0165-5728(86)90059-7. [DOI] [PubMed] [Google Scholar]
  36. Pollard J. D., Westland K. W., Harvey G. K., Jung S., Bonner J., Spies J. M., Toyka K. V., Hartung H. P. Activated T cells of nonneural specificity open the blood-nerve barrier to circulating antibody. Ann Neurol. 1995 Apr;37(4):467–475. doi: 10.1002/ana.410370409. [DOI] [PubMed] [Google Scholar]
  37. Press R., Deretzi G., Zou L. P., Zhu J., Fredman P., Lycke J., Link H. IL-10 and IFN-gamma in Guillain-Barré syndrome. Network Members of the Swedish Epidemiological Study Group. J Neuroimmunol. 2001 Jan 1;112(1-2):129–138. doi: 10.1016/s0165-5728(00)00388-x. [DOI] [PubMed] [Google Scholar]
  38. Press Rayomand, Ozenci V., Kouwenhoven M., Link H. Non-T(H)1 cytokines are augmented systematically early in Guillain-Barré syndrome. Neurology. 2002 Feb 12;58(3):476–478. doi: 10.1212/wnl.58.3.476. [DOI] [PubMed] [Google Scholar]
  39. Prineas J. W., McLeod J. G. Chronic relapsing polyneuritis. J Neurol Sci. 1976 Apr;27(4):427–458. doi: 10.1016/0022-510x(76)90213-6. [DOI] [PubMed] [Google Scholar]
  40. Prineas J. W. Pathology of the Guillain-Barré syndrome. Ann Neurol. 1981;9 (Suppl):6–19. doi: 10.1002/ana.410090704. [DOI] [PubMed] [Google Scholar]
  41. Quarles R. H., Ilyas A. A., Willison H. J. Antibodies to gangliosides and myelin proteins in Guillain-Barré syndrome. Ann Neurol. 1990;27 (Suppl):S48–S52. doi: 10.1002/ana.410270713. [DOI] [PubMed] [Google Scholar]
  42. Quarles R. H. Myelin sheaths: glycoproteins involved in their formation, maintenance and degeneration. Cell Mol Life Sci. 2002 Nov;59(11):1851–1871. doi: 10.1007/PL00012510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ritz M. F., Lechner-Scott J., Scott R. J., Fuhr P., Malik N., Erne B., Taylor V., Suter U., Schaeren-Wiemers N., Steck A. J. Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies. J Neuroimmunol. 2000 May 1;104(2):155–163. doi: 10.1016/s0165-5728(99)00250-7. [DOI] [PubMed] [Google Scholar]
  44. Robinson Douglas S. T-cell cytokines: what we have learned from human studies. Paediatr Respir Rev. 2004;5 (Suppl A):S53–S58. doi: 10.1016/s1526-0542(04)90011-5. [DOI] [PubMed] [Google Scholar]
  45. Röcken M., Racke M., Shevach E. M. IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease. Immunol Today. 1996 May;17(5):225–231. doi: 10.1016/0167-5699(96)80556-1. [DOI] [PubMed] [Google Scholar]
  46. Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Taylor W. A., Brostoff S. W., Hughes R. A. P2 specific lymphocyte transformation in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neurol Sci. 1991 Jul;104(1):52–55. doi: 10.1016/0022-510x(91)90215-s. [DOI] [PubMed] [Google Scholar]
  48. Taylor W. A., Hughes R. A. T lymphocyte activation antigens in Guillain-Barré syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol. 1989 Sep;24(1-2):33–39. doi: 10.1016/0165-5728(89)90095-7. [DOI] [PubMed] [Google Scholar]
  49. Winer J. B., Gray I. A., Gregson N. A., Hughes R. A., Leibowitz S., Shepherd P., Taylor W. A., Yewdall V. A prospective study of acute idiopathic neuropathy. III. Immunological studies. J Neurol Neurosurg Psychiatry. 1988 May;51(5):619–625. doi: 10.1136/jnnp.51.5.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Winer J. B., Hughes R. A., Anderson M. J., Jones D. M., Kangro H., Watkins R. P. A prospective study of acute idiopathic neuropathy. II. Antecedent events. J Neurol Neurosurg Psychiatry. 1988 May;51(5):613–618. doi: 10.1136/jnnp.51.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wood J. G., Dawson R. M. Some properties of a major structural glycoprotein of sciatic nerve. J Neurochem. 1974 May;22(5):627–630. doi: 10.1111/j.1471-4159.1974.tb04273.x. [DOI] [PubMed] [Google Scholar]
  52. Yan W. X., Archelos J. J., Hartung H. P., Pollard J. D. P0 protein is a target antigen in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001 Sep;50(3):286–292. doi: 10.1002/ana.1129. [DOI] [PubMed] [Google Scholar]
  53. Yuki N. Infectious origins of, and molecular mimicry in, Guillain-Barré and Fisher syndromes. Lancet Infect Dis. 2001 Aug;1(1):29–37. doi: 10.1016/S1473-3099(01)00019-6. [DOI] [PubMed] [Google Scholar]
  54. Zhu J., Link H., Mix E., Olsson T., Huang W. X. Th1-like cell responses to peripheral nerve myelin components over the course of experimental allergic neuritis in Lewis rats. Acta Neurol Scand. 1994 Jul;90(1):19–25. doi: 10.1111/j.1600-0404.1994.tb02674.x. [DOI] [PubMed] [Google Scholar]
  55. Zhu J., Mix E., Olsson T., Link H. Cellular mRNA expression of interferon-gamma, IL-4 and transforming growth factor-beta (TGF-beta) by rat mononuclear cells stimulated with peripheral nerve myelin antigens in experimental allergic neuritis. Clin Exp Immunol. 1994 Nov;98(2):306–312. doi: 10.1111/j.1365-2249.1994.tb06142.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zhu J., Pelidou S. H., Deretzi G., Levi M., Mix E., van der Meide P., Winblad B., Zou L. P. P0 glycoprotein peptides 56-71 and 180-199 dose-dependently induce acute and chronic experimental autoimmune neuritis in Lewis rats associated with epitope spreading. J Neuroimmunol. 2001 Mar 1;114(1-2):99–106. doi: 10.1016/s0165-5728(01)00245-4. [DOI] [PubMed] [Google Scholar]
  57. Zweiman B., Rostami A., Lisak R. P., Moskovitz A. R., Pleasure D. E. Immune reactions to P2 protein in human inflammatory demyelinative neuropathies. Neurology. 1983 Feb;33(2):234–237. doi: 10.1212/wnl.33.2.234. [DOI] [PubMed] [Google Scholar]
  58. van der Meché F. G., van Doorn P. A. Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy: immune mechanisms and update on current therapies. Ann Neurol. 1995 May;37 (Suppl 1):S14–S31. doi: 10.1002/ana.410370704. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES