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PMID: 8643438 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Review

Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 93 ·No. 10 ·1996-05-14 ·Pages 4529-36

Darnell RB

Abstract

Paraneoplastic neurologic disorders (PNDs) are believed to be autoimmune neuronal degenerations that develop in some patients with systemic cancer. A series of genes encoding previously undiscovered neuronal proteins have been cloned using antiserum from PND patients. Identification of these onconeural antigens suggests a reclassification of the disorders into four groups: those in which neuromuscular junction proteins, nerve terminal/vesicle-associated proteins, neuronal RNA binding proteins, or neuronal signal-transduction proteins serve as target antigens. This review considers insights into basic neurobiology, tumor immunology, and autoimmune neuronal degeneration offered by the characterization of the onconeural antigens.

MeSH Terms
Antigens, Neoplasm Autoimmune Diseases/etiology Humans Models, Neurological Nerve Degeneration/immunology Nerve Tissue Proteins/immunology Nervous System Diseases/classification,etiology Neuroimmunomodulation Paraneoplastic Syndromes/classification,etiology
Chemicals
Antigens, Neoplasm Nerve Tissue Proteins
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Darnell R B
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, 10021, USA.
References (100)
100 references, click to expand
  1. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome.
    Lancet. 1981 Aug 1;2(8240):224-6 PMID: 6114283
  2. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products.
    Nature. 1982 Jul 15;298(5871):240-4 PMID: 6283379
  3. Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing.
    Nature. 1983 Jul 14-20;304(5922):129-35 PMID: 6346105
  4. Plasma exchange and immunosuppressive drug treatment in the Lambert-Eaton myasthenic syndrome.
    Neurology. 1984 Apr;34(4):480-5 PMID: 6322050
  5. Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones.
    Proc Natl Acad Sci U S A. 1983 Dec;80(24):7636-40 PMID: 6584877
  6. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer.
    Neurology. 1985 Apr;35(4):538-43 PMID: 2984600
  7. Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons.
    Science. 1985 Apr 19;228(4697):346-8 PMID: 2580350
  8. Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line.
    Nature. 1985 Oct 24-30;317(6039):737-9 PMID: 2414666
  9. Autoimmune response of patients with paraneoplastic cerebellar degeneration to a Purkinje cell cytoplasmic protein antigen.
    Ann Neurol. 1985 Nov;18(5):592-600 PMID: 2416270
  10. Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor.
    Am J Med. 1986 Jan;80(1):45-52 PMID: 2417479
  11. Partial characterization of the Purkinje cell antigens in paraneoplastic cerebellar degeneration.
    Neurology. 1986 Sep;36(9):1163-8 PMID: 3528917
  12. Lambert-Eaton myasthenic syndrome: I. Early morphological effects of IgG on the presynaptic membrane active zones.
    Ann Neurol. 1987 Aug;22(2):193-9 PMID: 3662451
  13. Intraneuronal IgG in the central nervous system: uptake by retrograde axonal transport.
    Neurology. 1987 Nov;37(11):1780-4 PMID: 2444904
  14. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus.
    N Engl J Med. 1988 Apr 21;318(16):1012-20 PMID: 3281011
  15. An antineuronal autoantibody in paraneoplastic opsoclonus.
    Ann Neurol. 1988 May;23(5):528-31 PMID: 3389761
  16. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs.
    Science. 1988 Dec 16;242(4885):1570-2 PMID: 3144044
  17. Selective concentration of anti-Purkinje cell antibody in the CSF of two patients with paraneoplastic cerebellar degeneration.
    Acta Neurol Scand. 1988 Sep;78(3):210-3 PMID: 3227806
  18. Paraneoplastic cerebellar degeneration: clinical-immunological correlations.
    Ann Neurol. 1988 Oct;24(4):559-67 PMID: 3239956
  19. RNA-binding proteins as developmental regulators.
    Genes Dev. 1989 Apr;3(4):431-7 PMID: 2470643
  20. Sex in flies: the splice of life.
    Nature. 1989 Aug 17;340(6234):521-4 PMID: 2505080
  21. Cancer-associated retinopathy (CAR syndrome) with antibodies reacting with retinal, optic-nerve, and cancer cells.
    N Engl J Med. 1989 Dec 7;321(23):1589-94 PMID: 2555714
  22. Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes.
    Neurology. 1990 Jul;40(7):1085-91 PMID: 2356009
  23. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis.
    Ann Neurol. 1990 May;27(5):544-52 PMID: 2163235
  24. Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal cell antibody from a patient with paraneoplastic cerebellar degeneration.
    Ann Neurol. 1990 Nov;28(5):692-8 PMID: 2260856
  25. A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy.
    J Cell Biol. 1991 Mar;112(5):981-9 PMID: 1999465
  26. Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration.
    Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3451-4 PMID: 2014264
  27. Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors.
    J Neurosci. 1991 May;11(5):1224-30 PMID: 1851215
  28. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer.
    Ann Neurol. 1991 Mar;29(3):241-51 PMID: 2042940
  29. Meiosis-specific RNA splicing in yeast.
    Cell. 1991 Sep 20;66(6):1257-68 PMID: 1840507
  30. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal.
    Cell. 1991 Oct 18;67(2):325-33 PMID: 1655278
  31. Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential effects of treatment.
    Neurology. 1991 Oct;41(10):1682-5 PMID: 1922820
  32. Antibody-mediated clearance of alphavirus infection from neurons.
    Science. 1991 Nov 8;254(5033):856-60 PMID: 1658936
  33. Autoantibodies in pathology and cell biology.
    Cell. 1991 Nov 29;67(5):841-2 PMID: 1959131
  34. Photoreceptor deactivation and retinal degeneration mediated by a photoreceptor-specific protein kinase C.
    Science. 1991 Dec 6;254(5037):1478-84 PMID: 1962207
  35. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.
    Science. 1991 Dec 13;254(5038):1643-7 PMID: 1840703
  36. Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
    J Exp Med. 1994 Apr 1;179(4):1317-30 PMID: 7511686
  37. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain.
    J Cell Biol. 1992 Jul;118(2):309-20 PMID: 1321158
  38. The cancer-associated retinopathy antigen is a recoverin-like protein.
    Invest Ophthalmol Vis Sci. 1992 Sep;33(10):2768-72 PMID: 1388144
  39. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients.
    Neurology. 1992 Oct;42(10):1931-7 PMID: 1407575
  40. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues.
    Am J Pathol. 1992 Oct;141(4):881-6 PMID: 1415481
  41. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies.
    Lancet. 1993 Jan 2;341(8836):21-2 PMID: 8093269
  42. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.
    Cell. 1992 Dec 24;71(7):1093-102 PMID: 1335364
  43. A role for synaptotagmin (p65) in regulated exocytosis.
    Cell. 1993 Jan 15;72(1):153-9 PMID: 8422678
  44. Paraneoplastic syndromes.
    Neurology. 1993 Jan;43(1):236 PMID: 8380908
  45. The protein Sex-lethal antagonizes the splicing factor U2AF to regulate alternative splicing of transformer pre-mRNA.
    Nature. 1993 Mar 11;362(6416):171-5 PMID: 7680770
  46. The neuronal nuclear antigen recognized by the human anti-Ri autoantibody is expressed in central but not peripheral nervous system neurons.
    Neurosci Lett. 1993 Feb 19;150(2):212-4 PMID: 8469424
  47. Spontaneous regression of small cell carcinoma of lung associated with severe neuropathy.
    Cancer Invest. 1993;11(3):306-9 PMID: 8387390
  48. Analysis of autoantibody binding to 52-kd paraneoplastic cerebellar degeneration-associated antigen expressed in recombinant proteins.
    Ann Neurol. 1993 Apr;33(4):373-80 PMID: 8489208
  49. Cloning and characterization of a Lambert-Eaton myasthenic syndrome antigen.
    Ann Neurol. 1993 Jan;33(1):113-20 PMID: 8494331
  50. Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs.
    Mol Cell Biol. 1993 Jun;13(6):3494-504 PMID: 8497264
  51. Gene elav of Drosophila melanogaster: a prototype for neuronal-specific RNA binding protein gene family that is conserved in flies and humans.
    J Neurobiol. 1993 Jun;24(6):723-39 PMID: 8331337
  52. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system.
    Neuron. 1993 Oct;11(4):657-72 PMID: 8398153
  53. Type IIa ('anti-Hu') antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro.
    Neurology. 1993 Oct;43(10):2049-54 PMID: 8413965
  54. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer.
    J Exp Med. 1993 Dec 1;178(6):2219-23 PMID: 8245793
  55. AU-rich intronic elements affect pre-mRNA 5' splice site selection in Drosophila melanogaster.
    Mol Cell Biol. 1993 Dec;13(12):7689-97 PMID: 8246985
  56. Synaptotagmin: a Lambert-Eaton myasthenic syndrome antigen that associates with presynaptic calcium channels.
    J Physiol Paris. 1993;87(1):37-41 PMID: 8305896
  57. Autoimmunity and apoptosis.
    J Exp Med. 1994 Apr 1;179(4):1083-6 PMID: 8145031
  58. Myasthenia gravis: passive transfer from man to mouse.
    Science. 1975 Oct 24;190(4212):397-9 PMID: 1179220
  59. [Plasmapheresis for myasthenia gravis].
    N Engl J Med. 1978 Feb 23;298(8):456-7 PMID: 622126
  60. Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits.
    Proc Natl Acad Sci U S A. 1980 Feb;77(2):755-9 PMID: 6153804
  61. A hippocampal protein associated with paraneoplastic neurologic syndrome and small cell lung carcinoma.
    Biochem Biophys Res Commun. 1994 Mar 30;199(3):1200-8 PMID: 7511893
  62. Mammalian homologs of Drosophila ELAV localized to a neuronal subset can bind in vitro to the 3' UTR of mRNA encoding the Id transcriptional repressor.
    J Neurosci. 1994 Apr;14(4):1943-52 PMID: 8158249
  63. Conserved structures and diversity of functions of RNA-binding proteins.
    Science. 1994 Jul 29;265(5172):615-21 PMID: 8036511
  64. Anti-Ri antibodies associated with opsoclonus and progressive encephalomyelitis with rigidity.
    Neurology. 1994 Aug;44(8):1521-2 PMID: 8058163
  65. Autoimmunity in the central nervous system: mechanisms of antigen presentation and recognition.
    Clin Immunol Immunopathol. 1994 Sep;72(3):293-306 PMID: 8062444
  66. Interactions between lymphocytes, macrophages, and central nervous system cells.
    J Leukoc Biol. 1994 Sep;56(3):407-15 PMID: 8083616
  67. AUUUA is not sufficient to promote poly(A) shortening and degradation of an mRNA: the functional sequence within AU-rich elements may be UUAUUUA(U/A)(U/A).
    Mol Cell Biol. 1994 Dec;14(12):7984-95 PMID: 7969138
  68. Selection of a subset of mRNAs from combinatorial 3' untranslated region libraries using neuronal RNA-binding protein Hel-N1.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11207-11 PMID: 7972035
  69. Neurologic paraneoplastic antibodies (anti-Yo; anti-Hu; anti-Ri): the case for a nomenclature based on antibody and antigen specificity.
    Neurology. 1994 Dec;44(12):2241-6 PMID: 7991105
  70. Immunological and pathological study of anti-Ri-associated encephalopathy.
    Ann Neurol. 1994 Dec;36(6):896-902 PMID: 7998777
  71. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer.
    Cancer. 1995 Jan 1;75(1):99-109 PMID: 7804984
  72. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome.
    J Neurol Neurosurg Psychiatry. 1995 Jan;58(1):85-7 PMID: 7823075
  73. Soma-specific expression and cloning of PSI, a negative regulator of P element pre-mRNA splicing.
    Genes Dev. 1995 Feb 1;9(3):269-83 PMID: 7867926
  74. Class I and II MHC expression and its implications for regeneration in the nervous system.
    Prog Brain Res. 1994;103:307-17 PMID: 7886215
  75. The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation.
    Mol Cell Biol. 1995 Apr;15(4):2219-30 PMID: 7891716
  76. Anti-Hu autoantibody associated sensory neuropathy/encephalomyelitis: a model of paraneoplastic syndrome.
    Perspect Biol Med. 1995 Winter;38(2):167-81 PMID: 7899054
  77. Cloning of a cDNA coding for the acetylcholine receptor alpha-subunit from a thymoma associated with myasthenia [correction of myastenia] gravis.
    Thymus. 1994;23(2):103-13 PMID: 7725386
  78. The appendage domain of alpha-adaptin is a high affinity binding site for dynamin.
    J Biol Chem. 1995 Apr 28;270(17):10079-83 PMID: 7730311
  79. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes.
    N Engl J Med. 1995 Jun 1;332(22):1467-74 PMID: 7739683
  80. Acetylcholine receptor alpha-subunit and myogenin mRNAs in thymus and thymomas.
    Am J Pathol. 1995 Jun;146(6):1320-4 PMID: 7778671
  81. Hu antigens: reactivity with Hu antibodies, tumor expression, and major immunogenic sites.
    Ann Neurol. 1995 Jul;38(1):102-10 PMID: 7541976
  82. CD1: presenting unusual antigens to unusual T lymphocytes.
    Science. 1995 Jul 14;269(5221):185-6 PMID: 7542402
  83. Induction of MHC class I genes in neurons.
    Science. 1995 Jul 28;269(5223):549-52 PMID: 7624779
  84. Induction of anti-Purkinje cell antibodies in vivo by immunizing with a recombinant 52-kDa paraneoplastic cerebellar degeneration-associated protein.
    J Neuroimmunol. 1995 Jul;60(1-2):135-41 PMID: 7642741
  85. Three-dimensional location of the main immunogenic region of the acetylcholine receptor.
    Neuron. 1995 Aug;15(2):323-31 PMID: 7544140
  86. Beta-NAP, a cerebellar degeneration antigen, is a neuron-specific vesicle coat protein.
    Cell. 1995 Sep 8;82(5):773-83 PMID: 7671305
  87. CD1 and the expanding universe of T cell antigens.
    J Immunol. 1995 Oct 15;155(8):3709-10 PMID: 7561071
  88. Traffic of hematogenous cells through the central nervous system.
    Curr Top Microbiol Immunol. 1995;202:221-45 PMID: 7587365
  89. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice.
    Neurology. 1995 Oct;45(10):1873-8 PMID: 7477985
  90. A role for CD95 ligand in preventing graft rejection.
    Nature. 1995 Oct 19;377(6550):630-2 PMID: 7566174
  91. Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo.
    J Exp Med. 1995 Nov 1;182(5):1201-12 PMID: 7595191
  92. The enigma of the natural killer cell.
    Nature. 1995 Nov 16;378(6554):245-8 PMID: 7477341
  93. Fas ligand-induced apoptosis as a mechanism of immune privilege.
    Science. 1995 Nov 17;270(5239):1189-92 PMID: 7502042
  94. A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):331-5 PMID: 8552632
  95. The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies.
    J Neurosci. 1996 Feb 1;16(3):1114-22 PMID: 8558240
  96. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein.
    Cell. 1993 Jul 30;74(2):291-8 PMID: 7688265
  97. Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model.
    J Neurol Sci. 1991 Nov;106(1):82-7 PMID: 1779243
  98. Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients.
    Medicine (Baltimore). 1992 Mar;71(2):59-72 PMID: 1312211
  99. The synaptic vesicle protein synaptotagmin associates with calcium channels and is a putative Lambert-Eaton myasthenic syndrome antigen.
    Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3625-9 PMID: 1314395
  100. Retinal degeneration is rescued in transgenic rd mice by expression of the cGMP phosphodiesterase beta subunit.
    Proc Natl Acad Sci U S A. 1992 May 15;89(10):4422-6 PMID: 1350091
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.93.10.4529
Published
1996-05-14
Pages
4529-36
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC39311
Subset
IM
Grants
NINDS NIH HHS · R01 NS34389 · United States
External Links
PubMed source DOI: 10.1073/pnas.93.10.4529 PMC Full Text View journal details
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