Immunology of the neuromuscular junction and presynaptic nerve terminal

Current Opinion in Neurology

Volumn 12, Issue 5, 1999, Pages 545-551

  Vincent, Angela ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; CALCIUM; CALCIUM CHANNEL; CHOLINERGIC RECEPTOR;

ARTHROGRYPOSIS; EATON LAMBERT SYNDROME; FETUS DISEASE; HUMAN; IMMUNOLOGY; MORVAN SYNDROME; MYASTHENIA GRAVIS; MYOKYMIA; NEUROMUSCULAR SYNAPSE; REVIEW; SUBCLAVIAN STEAL SYNDROME; SYNAPTOSOME; T LYMPHOCYTE;

ANIMALS; DISEASE SUSCEPTIBILITY; HUMANS; IMMUNE SYSTEM; MYASTHENIA GRAVIS; NEUROMUSCULAR JUNCTION; PRESYNAPTIC TERMINALS;

EID: 0033372483     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019052-199910000-00008     Document Type: Review

References (66)

1. 1 Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetycholine receptor. Immunol Rev 1998; 163:89-120. This is a comprehensive review of the structure and antigenicity of the AChR in myasthenia gravis and in experimental autoimmune myasthenia gravis.
2. 2 Vincent A, Willcox N, Hill M, Curnow J, MacLennan C, Beeson D. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. Immunol Rev 1998; 164:157-168. A description is provided of the different subtypes of myasthenia gravis, along with a discussion of the role of the thymus in their aetiology, and the role of determinant spreading in shaping the immune responses to the AChR.
3. 3 Richman D. Myasthenia gravis and related diseases: disorders of the neuromuscular junction. Ann N Y Acad Sci 1998; 841:1-838. The proceedings of a conference held in Santa Monica, California, in 1997 are reported. Most of the groups active in the field were well represented and this volume provides a wide overview of their work.
4. 4 Robertson NP, Deans J, Compston DAS. Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 1998; 65:492-496. This paper provides contemporary epidemiological data obtained from multiple sources, confirming a high prevalence and incidence of myasthenia gravis, and describing clinical features in 100 cases.
5. 5 Aarli JA. Late-onset myasthenia gravis. Arch Neurol 1999; 56:25-27.
6. 6 Kleiner-Fisman G, Kott HS. Myathenia gravis mimicking stroke in elderly patients. Mayo Clin Proc 1998; 73:1077-1078.
7. 7 Huang D, Liu L, Noren K, Xia S, Trifunovic J, Pirskanen R, Lefvert AK. Genetic association of CTLA4 to myasthenia gravis with thymoma. J Neuroimmunol 1998; 88:192-198.
8. 8 Raknes G, Skeie GO, Gilhus NE, Aadland S, Vedeler C. Fc gamma RIIA and Fc gamma RIIIB polymorphisms in myasthenia gravis. J Neuroimmunol 1998; 81:173-176.
9. 9 Huang D, Zia S, Zhou Y, Pirskanen R, Liu L, Lefvert AK. No evidence for interleukin-4 gene conferring susceptibility to myasthenia gravis. J Neuroimmunol 1998; 92:208-211.
10. 10 Hjelmstrom P, Peacock CS, Giscombe R, Pirskanen R, Lefvert AK, Blackwell JM, Sanjeevi CB. Polymorphism in tumour necrosis factor genes associated with myasthenia gravis. J Neuroimmunol 1998: 88:137-143.
11. 11 Manz MG, Melms A, Sommer N, Muller CA. Myasthenia gravis and tumour necrosis factor beta polymorphisms: linkage disequilibrium but no association beyond HLA-B8. J Neuroimmunol 1998; 90:187-191.
12. 12 Ruff RL, Lennon VA. Endplate voltage-gated sodium channels are lost in clinical and experimental myasthenia gravis. Ann Neurol 1998; 43:370-379. This is an important paper that shows a reduction in sodium channel currents at the motor end-plates of patients with myasthenia gravis, and that a greater depolarization is required to initiate an action potential in the muscle. These results explain why there is failure of neuromuscular transmission in myesthenia gravis, even when earlier work had shown a compensatory increase in acetylcholine release.
13. 13 Plomp JJ, Van Kempen GT, De Baets MB, Graus YM, Kuks JB, Molenaar PC. Acetylcholine release in myasthenia gravis: regulation at single endplate level. Ann Neurol 1995; 37:627-636.
14. 14 Guyon T, Wakkach A, Poea S, Mouly V, Klingel-Schmitt I, Levasseur P, et al. Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. J Clin Invest 1998; 102:249-263. A comprehensive study of AChR expression in human muscle biopsies from myasthenia gravis patients and in the TE671 cell line after application of antibodies to AChR. Demonstrates a possible compensatory mechanism to restore AChR numbers.
15. 15 Prakash YS, Sieck GC. Age related remodeling of the neuromuscular junctiions on type-identified diaphragm fibers. Muscle Nerve 1998; 21:887-895.
16. 6 Hoodemaekers A, Bessereau JL, Graus Y, Guyon T, Changeux J-P, Berrih-Aknin S, et al. Role of the target organ in determining susceptibility to experimental autoimmune myasthenia gravis. J Neuroimmunol 1998; 89:131-141.
17. 17 Sharshar T, Lacroix-Desmazes S, Mouthon L, Kaveri S, Gajdos P, Kazatchkine MD. Selective impairment of serum antibody repertoires toward muscle and thymus antigens in patients with seronegative and seropositive myasthenia gravis. Eur J Immunol 1998; 28:2344-2354. Antibody responses to muscle antigens differed between the two groups of patients, whereas antibody responses to thymic antigens did not, suggesting some differences in immune responses between seronegative and seropositive myasthenia gravis patients.
18. 18 Bufler J, Pitz R, Czep M, Wick M, Franke C. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibty blocks currents through nicotinic acetylcholine receptor channels. Ann Neruol 1998; 43:458-464. Using an ultrafast application system and mouse myotubes, immunoglobulin G of myasthenia gravis patients were tested for effects on fetal-type AChR function. A reversible block of acetylcholine-induced currents was found with all patients' immunoglobulin G preparations. The relationship between these antibodies and those detected by immunoprecipitation of human muscle AChR is unknown.
19. 19 Plested P, Newson-Davis J, Vincent A. Seronegative myasthenia plasmas and non-IgG fractions transiently inhibit nAChR function. Ann N Y Acad Sci 1998; 841:501-504.
20. 20 Xu B, Pirskanen R, Lefvert AK. Antibodies against beta1 and beta2 adrenergic receptors in myasthenia gravis. J Neurooimmunol 1998; 91:82-88. Predominantly immunoglobulin 2 and immunoglobulin 4 antibodies to β-adrenergic receptors were found in about 25% of myasthenia gravis patients, and appeared to correlate with the coexistence of heart disease in some elderly patients.
21. 21 Wintzen AR, Plomp JJ, Molenaar PC, can Dijk J, van Kempen GTH, Vos RM, et al. Acquired slow-channel syndrome: a form of myasthenia gravis with prolonged open time of the acetylcholine receptor channel. Ann Neurol 1998; 44: 657-664. This paper identifies an immune-mediated disorder associated with antibodies that are specific for the adult type of AChR and appear to alter AChR channel properties.
22. 22 Tzartos SJ, Remoundos M. Detection of antibodies directed against the cytoplasmic region of the human acetylcholine receptor in sera from myasthenia gravis patients. Clin Exp Immunol 1999; 116:146-152.
23. 23 Nagvekar N, Jacobson LW, Willcox N, Vincent A. Epitopes expressed in myasthenia gravis thymomas are not recognized by patients' T cells or autoantibodies. Clin Exp Immunol 1998; 112:17-20.
24. 24 Vernino S, Adamski J, Kryzer TJ, Fealey RD, Lennon VA. Neuronal nicotinic ACh receptor antibody in subacute autonomic neuropathy and cancer-related syndromes. Neurology 1998; 50:1806-1813.
25. 25 Jacobson L, Polizzi A, Morriss-Kay G, Vincent A. Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenita causes deformities in mice. J Clin Invest 1999; 103:1031-1038. This paper provides confirmation of the role of maternal antibodies against fetal AChR in causing this lethal condition, and establishes an animal model of maternal-to-fetal transfer that can be used to examine the role of maternal antibodies in other disorders.
26. 26 Salmon AM, Bruand C, Cardona A, Changeux JP, Berrih-Aknin S. An acetylcholine receptor alpha subunit promoter confers intrathymic expression in transgenic mice. J Clin Invest 1998; 101:2340-2350. This is an interesting paper that examines expression of β-galactosidase, under the control of two different AChR promoters in the thymus, and correlates the results with the animals' T-cell and B-cell responses to β-galactosidase. Reduced expression of this surrogate autoantigen appeared to lead to increased T-cell and B-cell responses to the antigen, whereas higher expression in the thymus lead to reduced antibody responses. These findings have general implications for understanding the relationship between thymic expression of autoantigens and immune responses in the periphery, but caution should be exercised when conclusions regarding the relevance to myasthenia gravis.
27. 27 Kusner LL, Mygland A, Kaminski HJ. Ryanodine receptor gene expression in thymomas. Muscle Nerve 1998; 21:1299-1303. The levels of expression of ryanodine receptor in thymomas from myasthenia gravis patients did not correlate with the patients' clinical features or antibodies to ryanodine receptor, suggesting that the ryanodine receptor is not an important inciting antigen in these cases.
28. 28 Lubke E, Freiburg A, Skeie GO, Kolmerer B, Labeit S, Aarli JA, et al. Striational autoantibodies in myasthenia gravis patients recognize I-band epitopes. J Neuroimmunol 1998; 81:98-108. Immunofluorescence microscopy on stretched single myofibrils demonstrates the location of the main site for binding of antibodies from patients with thymoma-associated myasthenia gravis on the giant titin molecule.
29. 29 Nenninger R, Schultz A, Hoffacker V, Helmreich M, Wilisch A, Vandekerckhove B, et al. Abnormal thymocyte development and generation of autoreactive T cells in mixed and cortical thymomas. Lab Invest 1998; 78:743-753. This study used fluorescent activated cell sorting analysis to look at the T cells produced by both types of thymomas. Relatively immature T cells were present in both types of thymomas, but with more in mixed thymomas, and there was some evidence that these T cells respond to AChR. These findings suggest that the thymomas generate potentially autoagressive T cells that could be immunized within the tumour to AChR or other muscle antigens.
30. 30 Marx A, Schultz A, Willisch A, Helmreich M, Nenninger R, Muller-Hermelink HK. Paraneoplastic autoimmunity in thymus tumours. Dev Immunol 1998; 6:129-140. An overview is provided of the role of different histological types of thymomas in inducing abnormal T-cell and B-cell responses in myasthenia gravis.
31. 31 Protti MP, Manfredi AA, Horton RM, Bellone M, Conti-Tronconi BM. Myasthenia gravis: recognition of a human autoantigen at the molecular level. Immunol Today 1993; 14:363-368.
32. 32 Wang ZY, Okita DK, Howard J, Conti-Fine BM. T cell recognitiion of muscle acetylcholine receptor subunits in generalised and ocular myasthenia gravis. Neurology 1993; 50:1045-1054.
33. + T cell repertoire on the epsilon subunit of muscle acetylcholine receptor in myasthenia gravis. J Neuroimmunol 1998; 91:33-42. Responses of T cells from 18 myasthenia gravis patients to ε-subunit peptides suggests the presence of several ε-specific T cell epitopes in myasthenia gravis, and relatively few and restricted epitopes in healthy individuals.
34. 34 Hawke S, Matsuo H, Nicolle M, Malcherek G, Melms A, Willcox N. Autoimmune T cells in myasthenia gravis: heterogeneity and potential for specific immunotargetting. Immunol Today 1996; 17:307-311.
35. 35 Hill M, Beeson D, Moss P, Jacobson L, Bond A, Corlett L, et al. Early onset myasthenia gravis: a recurring T cell epitope in the adult specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a. Ann Neurol 1999; 45:224-231. T-helper 1 T cells from four out of five myasthenia gravis patients, four of whom had early-onset myasthenia gravis, which recognized an epitope on the AChR ε-subunit, specific to adult AChR, presented by HLA-DR52a a possible immunodominant T-cell epitope for targeting in specific immunotherapies. Interestingly, antibodies in the patients' sera, however, bound better to fetal AChR than to adult AChR, suggesting that T-cell responses to adult AChR might then lead to antibody respones to fetal AChR.
36. •]), and expression of the class II molecules was particularly strong on antigen-presenting cells in the thymomas.
37. 37 Meager A, Willcox N, Vincent A, Newsom-Davis J. Spontaneous neutralising antibodies to interferon-alpha and interleukin-12 in thymoma-associated autoimmune disease. Lancet 1997; 350:1596-1597.
38. 38 Curnow SJ, Willcox N, Vincent A. Induction of primary immune responses by allogeneic human myoblasts: dissection of the cell types required for proliferation, IFN gamma secretion and cytotoxicity. J Neuroimmunol 1998; 86:53-62.
39. 39 Andersen LC, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neruol Scand 1998; 97:370-373.
40. 40 Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathiprine in myasthenia gravis. Neurology 1998; 50:1778-1783. This is a convincing demonstration of the ability of azathioprine to replace pednisolone in the long-term treatment of myasthenia gravis. Importantly, the effect of azathioprine took around 1 year to develop.
41. 41 Howard JF. Intravenous immunoglobulin for the treatment of acquired myasthenia gravis. Neurology 1998; 51 (Suppl. 5):S30-S36.
42. 42 Bond AP, Corlett L, Curnow SJ, Spack E, Willcox N, Newsom-Davis J. Diverse patterns of unresponsiveness in an acetylcholine receptor-specific T cell clone from a myasthenia gravis patient after engaging the T cell receptor with three different ligands. J Neuroimmunol 1998; 82:182-190. The effects of specific anti-Vβ antibody, specific peptide or class II-peptide complex on the subsequent survival and function of a specific T-cell clone from a myasthenia gravis patient showed that all three produced some lack of responsiveness, but only the class II-peptide complex produced significant T-cell death. These findings have implications for future specific immunotherapy of myasthenia gravis.
43. 43 Li H, Shi FD, He B, Bakheit M, Wahren B, Berglof A, et al. Experimental autoimmune myasthenia gravis induction in B cell deficient mice. Int Immunol 1998; 10:1359-1365. Similar T cell responses to AChR in B-cell deficient and control mice were identified, but no antibody was detected and no clinical experimental myasthenia gravis resulted.
44. 44 Dedhia V, Goluscko E, Wu B, Deng C, Chirstadoss P. The effect of B cell deficiency on the immune response to acetylcholine receptor and the development of experimental autoimmune myasthenia gravis. Clin Immunol Immunopathol 1998; 98:266-275. In contrast to conclusions from [38], these authors found that the absence of B cells did influence the early T-cell-dependent stages of the immune response to AChR.
45. 2a in the mouse).
46. 46 Balasa B, Deng C, Lee J, Christadoss P, Sarvetnick N. The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis. J Immunol 1998; 161:2856-2862. Pathogenic anti-AChR antibodies do not depend on interleukin-4-dependent T-helper 2 T-cell responses to AChR in the animal model of myasthenia gravis.
47. 47 Li HL, Shi FD, Bai XF, Huagn YM, van der Meidi PH, Xiao BG, Link H. Nasal tolerance to experimental autoimmune myasthenia gravis: tolerance reversal by nasal administration of minute amounts of interferon-gamma. Clin Immunol Immunopathol 1998; 87:15-22.
48. 48 Zhang GX, Shi FD, Zhu J, Ziao BG, Levi M, Wahren B, et al. Synthetic peptides fail to induce nasal tolerance to experimental autoimmune maysthenia gravis. J Neuroimmunol 1998; 85:96-101.
49. 49 Faber-Ellmann A, Paas-Rozner M, Sela M, Mozes E. Altered peptide ligands act as partial agonists by inhibiting phospholipase C activity induced by myasthenogenicT cell epitopes. Proc Natl Acad Sci USA 1998; 95:14320-14325. This is the first demonstration that altered peptide ligands of the AChR, that have previously been shown to reduce specific T-cell responses, inhibit AChR-induced phospholipase C activity in T cells.
50. 50 Katz-Levy Y, Dayan M, Wirguin I, Fridkin M, Sela M, Mozes E. Single amino acid analogs of a myasthenogenic peptide modulate specific T cell responses and prevent induction of experimental autoimmune myasthenia gravis. J Neuroimmunol 1998; 85:78-86.
51. 51 Nishimura Y, Chen YZ, Kanai T, Yokomizo H, Matsuoka T, Matsushita S. Modification of human T cell responses by altered peptide ligands a new approach to antigen-specific modification. Intern Med 1998; 37:804-817.
52. 52 McIntosh KR, Linsley PS, Bacha PA, Drachman DB. Immunotherpay of experimental autoimmune myasthenia gravis: selective effects of CTLA4Ig and synergistic combination of IL-2-diphtheria toxin fusion protein. J Neuroimmunol 1998; 87:136-146. The combined effect of these two agents in an experimental model of myasthenia gravis produced substantial inhibition of anti-AChR antibodies and reduced clinical evidence of disease in Lewis rat model of myasthenia gravis, even during ongoing disease.
53. 53 Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert Eaton myasthenic syndrome and small cell lung cancer. Lancet 1999; 353:117-118. An analysis of survival rates in patients with small cell lung cancer with or without LEMS shows that the presence of the autoimmune disease is associated with better prognosis.
54. 54 Xu YF, Hewett SJ, Atchison WD. Passive transfer of Lambert Eaton myasthenic syndrome induces dihydropyridine sensitivity of Ica in mouse motor nerve terminals. J Neurophysiol 1998; 80:1056-1069. Evidence is provided that chronic exposure of motor nerve terminals to LEMS autoantibodies can unmask or upregulate dihydropyridine-sensitive channels, which are not usually involved in calcium-induced acetylcholine release at the neuromuscular junction.
55. 1a-subunit.
56. •], derived from work on the contribution of different calcium channels to acetylcholine release, and the effect of LEMS antibodies.
57. 57 Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997; 42:147-156.
58. 58 Mason WP, Graus F, Lang B, Honnorat J, Delattre JY, Valldeoriola F, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and Lambert Eaton myasthenic syndrome. Brain 1997; 120:1279-1300.
59. 59 Hart I, Waters C, Vincent A, Newland C, Beeson D, Pongs O, et al. Autoantibodies detected to expressed K channels are implicated in neuromyotonia. Ann Neurol 1997; 41:238-246.
60. 60 Sonoda Y, Arimura K, Kurono A, Suehara M, Kameyama M, Minato S, et al. Serum of Isaacs' syndrome suppresses potassium channels in PC-12 cell lines. Muscle Nerve 1996; 19:1439-1446.
61. 61 Magnani G, Nemni R, Leocani L, Amadio S, Locatelli T, Maderna L, et al. Neuromyotonia, systemic lupus erythematosus and acetylcholine receptor antibodies. J Neurol 1998; 245:182-185.
62. 62 Lee EK, Maselli RA, Ellis WG, Agius MA. Morvan's fibrillary chorea: a paraneoplastic manifestation of thymoma. J Neurol Neurosurg Psychiatry 1998; 65:857-862. Antibodies to AChR, titin and N-type VGCC were detected in a patient with thymoma-associated Morvan's syndrome.
63. 63 Heidenreich F, Vincent A. Antibodies to ion-channel proteins in thymoma with myasthenia, neuromyotonia and peripheral neuropathy. Neurology 1998; 50:1483-1485.
64. 64 Roberts M, Willison HJ, Vincent A, Newsom-Davis J. Serum factor in Miller-Fisher variant of Guillain-Barre syndrome and neurotransmitter release. Lancet 1994; 343:454-455.
65. 65 Plomp JJ, Molenaar PC, O'Hanlon GM, Jacobs BC, Veitch J, Daha MR, et al. Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor endplates. Ann Neurol 1999; 45:189-199. This is a detailed study of the direct effects of anti-GQ1b antibodies at the neuromuscular junction. Massive transmitter release occurred within minutes of applying serum or immunoglobulin G, but only in the presence of complement. The effects were very similar to those found with α-latrotoxin, a spider toxin that depletes motor nerve terminals of ACh.
66. 66 Yuki N, Wakabayashi K, Yamada M, Seki K. Overlap of Guillain-Barre syndrome and Bickerstaff's brainstem encephalitis. J Neurol Sci 1997; 145:119-121.