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PMID: 24501693 Published · ppublish English Review Research Support, Non-U.S. Gov't

Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies: A beneficial antitumor immune response going awry.

Oncoimmunology ·Vol. 2 ·No. 12 ·2013-12-01 ·Pages e27384

Pignolet BS, Gebauer CM, Liblau RS

Abstract

Paraneoplastic neurological disorders (PNDs) are syndromes that develop in cancer patients when an efficient antitumor immune response, directed against antigens expressed by both malignant cells and healthy neurons, damages the nervous system. Herein, we analyze existing data on the mechanisms of loss of self tolerance and nervous tissue damage that underpin one of the most frequent PNDs, the anti-Hu syndrome. In addition, we discuss future directions and propose potential strategies aimed at blocking deleterious encephalitogenic immune responses while preserving the antineoplastic potential of treatment.

Keywords
anti-Hu syndrome autoimmunity cancer central nervous system paraneoplastic neurological disorder
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Pignolet Béatrice Sl
INSERM-UMR1043; Toulouse, France ; CNRS, U5282; Toulouse, France ; Universite de Toulouse; UPS; Centre de Physiopathologie Toulouse Purpan (CPTP); Toulouse, France ; CHU Toulouse Purpan; Toulouse, France.
Gebauer Christina Mt
INSERM-UMR1043; Toulouse, France ; CNRS, U5282; Toulouse, France ; Universite de Toulouse; UPS; Centre de Physiopathologie Toulouse Purpan (CPTP); Toulouse, France.
Liblau Roland S
INSERM-UMR1043; Toulouse, France ; CNRS, U5282; Toulouse, France ; Universite de Toulouse; UPS; Centre de Physiopathologie Toulouse Purpan (CPTP); Toulouse, France ; CHU Toulouse Purpan; Toulouse, France.
References (96)
96 references, click to expand
  1. RNA-protein interactions and control of mRNA stability in neurons.
    J Neurosci Res. 2008 Feb 15;86(3):481-9 PMID: 17853436
  2. Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients.
    Medicine (Baltimore). 1992 Mar;71(2):59-72 PMID: 1312211
  3. Molecular analysis of the HuD gene in neuroendocrine lung cancers.
    Lung Cancer. 2010 Jan;67(1):69-75 PMID: 19410329
  4. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies.
    Lancet. 1993 Jan 2;341(8836):21-2 PMID: 8093269
  5. Do MHCII-presented neoantigens drive type 1 diabetes and other autoimmune diseases?
    Cold Spring Harb Perspect Med. 2012 Sep 01;2(9):a007765 PMID: 22951444
  6. Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome.
    J Neurol Neurosurg Psychiatry. 1999 Jan;66(1):97-9 PMID: 9886463
  7. Hu antigens: reactivity with Hu antibodies, tumor expression, and major immunogenic sites.
    Ann Neurol. 1995 Jul;38(1):102-10 PMID: 7541976
  8. Three sensitive assays do not provide evidence for circulating HuD-specific T cells in the blood of patients with paraneoplastic neurological syndromes with anti-Hu antibodies.
    Neuro Oncol. 2012 Jul;14(7):841-8 PMID: 22591661
  9. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome.
    Ann Neurol. 2004 Nov;56(5):715-9 PMID: 15468074
  10. Characterization and spatial distribution of the ELAV protein during Drosophila melanogaster development.
    J Neurobiol. 1991 Jul;22(5):443-61 PMID: 1716300
  11. Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis.
    Acta Neuropathol. 2002 May;103(5):509-15 PMID: 11935268
  12. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs.
    Science. 1988 Dec 16;242(4885):1570-2 PMID: 3144044
  13. Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells.
    J Clin Invest. 2009 Jul;119(7):2042-51 PMID: 19509467
  14. Anti-Hu antibody titre and brain metastases before and after treatment for small cell lung cancer.
    J Neurol Neurosurg Psychiatry. 1999 Sep;67(3):353-7 PMID: 10449558
  15. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice.
    Neurology. 1995 Oct;45(10):1873-8 PMID: 7477985
  16. Cross-reactive T-cell receptors in tumor and paraneoplastic target tissue.
    Arch Neurol. 2009 May;66(5):655-8 PMID: 19433667
  17. Cytoplasmic localization is required for the mammalian ELAV-like protein HuD to induce neuronal differentiation.
    Genes Cells. 1999 Nov;4(11):667-83 PMID: 10620013
  18. Regulatory T cells in paraneoplastic neurological syndromes.
    J Neuroimmunol. 2008 May 30;196(1-2):166-9 PMID: 18455243
  19. IgG-mediated cytotoxicity to myenteric plexus cultures in patients with paraneoplastic neurological syndromes.
    J Autoimmun. 2000 Dec;15(4):479-84 PMID: 11090247
  20. Functional and direct interaction between the RNA binding protein HuD and active Akt1.
    Nucleic Acids Res. 2012 Mar;40(5):1944-53 PMID: 22075994
  21. Effects of antineuronal antibodies from patients with paraneoplastic neurological syndrome on primary-cultured neurons.
    J Neurol Sci. 2004 Jan 15;217(1):25-30 PMID: 14675605
  22. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer.
    Neurology. 1985 Apr;35(4):538-43 PMID: 2984600
  23. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival.
    J Clin Oncol. 1997 Aug;15(8):2866-72 PMID: 9256130
  24. Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides.
    Nat Med. 2012 May;18(5):824-8 PMID: 22484809
  25. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies.
    J Neurol Neurosurg Psychiatry. 1996 Apr;60(4):388-92 PMID: 8774401
  26. Neurons as targets for T cells in the nervous system.
    Trends Neurosci. 2013 Jun;36(6):315-24 PMID: 23478065
  27. Lack of association between human leukocyte antigens and the anti-Hu syndrome in patients with small-cell lung cancer.
    Neurology. 1998 Feb;50(2):565-6 PMID: 9484403
  28. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy.
    J Neurol. 2002 Jun;249(6):745-53 PMID: 12111309
  29. Oligoclonal T-cells in blood and target tissues of patients with anti-Hu syndrome.
    J Neuroimmunol. 2002 Jan;122(1-2):100-5 PMID: 11777548
  30. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy.
    Neurology. 1991 Nov;41(11):1757-64 PMID: 1944905
  31. Ganglionitis in paraneoplastic subacute sensory neuronopathy: a morphologic study.
    Neurology. 1997 Oct;49(4):1156-9 PMID: 9339709
  32. Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus.
    J Immunol. 2012 May 15;188(10):4731-5 PMID: 22504649
  33. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies.
    Ann Neurol. 1999 Feb;45(2):162-7 PMID: 9989617
  34. Observing the invisible: successful tumor immunity in humans.
    Nat Immunol. 2003 Mar;4(3):201 PMID: 12605223
  35. Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
    J Exp Med. 2013 Sep 23;210(10):2087-103 PMID: 23999498
  36. Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer.
    J Clin Oncol. 2004 Mar 1;22(5):795-800 PMID: 14990634
  37. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.
    Nat Rev Drug Discov. 2010 Nov;9(11):883-97 PMID: 21031003
  38. Disturbance in the serum IgG subclass distribution in patients with anti-Hu positive paraneoplastic neurological syndromes.
    Eur J Neurol. 2002 Jul;9(4):369-72 PMID: 12099920
  39. Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu-associated paraneoplastic encephalomyelitis.
    Neurology. 1994 Jan;44(1):140-7 PMID: 8290049
  40. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis.
    Brain. 2012 May;135(Pt 5):1622-38 PMID: 22539258
  41. Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes.
    Neurology. 1990 Jul;40(7):1085-91 PMID: 2356009
  42. Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility.
    Gastroenterology. 2003 Jul;125(1):70-9 PMID: 12851872
  43. Intrathecal synthesis of the anti-Hu antibody in patients with paraneoplastic encephalomyelitis or sensory neuronopathy: clinical-immunologic correlation.
    Neurology. 1994 Nov;44(11):2145-7 PMID: 7969974
  44. Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin.
    Brain. 2011 Dec;134(Pt 12):3560-77 PMID: 22058139
  45. No evidence for circulating HuD-specific CD8+ T cells in patients with paraneoplastic neurological syndromes and Hu antibodies.
    Cancer Immunol Immunother. 2007 Sep;56(9):1501-6 PMID: 17597332
  46. Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines.
    Cancer Res. 1994 Sep 15;54(18):4988-92 PMID: 8069866
  47. Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat.
    Brain. 2004 Aug;127(Pt 8):1822-30 PMID: 15201193
  48. Type IIa ('anti-Hu') antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro.
    Neurology. 1993 Oct;43(10):2049-54 PMID: 8413965
  49. Tolerance to the neuron-specific paraneoplastic HuD antigen.
    PLoS One. 2009 Jun 03;4(6):e5739 PMID: 19492067
  50. Celiac disease: an immunological jigsaw.
    Immunity. 2012 Jun 29;36(6):907-19 PMID: 22749351
  51. Antibody types and IgG subclasses in paraneoplastic neurological syndromes.
    J Neurol Sci. 2001 Mar 1;184(2):131-7 PMID: 11239946
  52. A T-cell receptor associated with naturally occurring human tumor immunity.
    Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19073-8 PMID: 18045792
  53. Anti-Hu-associated paraneoplastic sensory neuropathy responding to early aggressive immunotherapy: report of two cases and review of literature.
    Muscle Nerve. 1997 Dec;20(12):1576-82 PMID: 9390671
  54. Expression of HuD (a paraneoplastic encephalomyelitis antigen) mRNA in lung cancer.
    J Korean Med Sci. 1997 Aug;12(4):305-10 PMID: 9288629
  55. Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.
    Neurology. 2013 Jun 11;80(24):2226-32 PMID: 23658383
  56. Demonstration of anti-HuD specific oligoclonal bands in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes. Qualitative evidence of anti-HuD specific IgG-synthesis in the central nervous system.
    J Neuroimmunol. 2000 Nov 1;111(1-2):241-4 PMID: 11063845
  57. Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein.
    J Biol Chem. 1996 Apr 5;271(14):8144-51 PMID: 8626503
  58. DNA vaccination with HuD inhibits growth of a neuroblastoma in mice.
    Clin Cancer Res. 1998 Nov;4(11):2819-24 PMID: 9829748
  59. 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
  60. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.
    Brain. 2001 Jun;124(Pt 6):1138-48 PMID: 11353730
  61. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor.
    Neurology. 1999 Nov 10;53(8):1719-23 PMID: 10563618
  62. Cerebrospinal fluid study in paraneoplastic syndromes.
    J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):42-5 PMID: 19324868
  63. 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
  64. A hierarchy of Hu RNA binding proteins in developing and adult neurons.
    J Neurosci. 1997 May 1;17(9):3024-37 PMID: 9096138
  65. 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
  66. Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability.
    Neuron. 2012 Sep 20;75(6):1067-80 PMID: 22998874
  67. T cell response to Hu-D peptides in patients with anti-Hu syndrome.
    J Neurooncol. 2005 Feb;71(3):231-6 PMID: 15735910
  68. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders.
    Curr Opin Immunol. 2011 Dec;23(6):732-8 PMID: 21917438
  69. Expression of peptide and other markers in lung cancer cell lines.
    Recent Results Cancer Res. 1985;99:167-74 PMID: 2999915
  70. Neurologic disorders in 432 consecutive patients with small cell lung carcinoma.
    Cancer. 2004 Feb 15;100(4):801-6 PMID: 14770437
  71. Elevated numbers of regulatory T cells, central memory T cells and class-switched B cells in cerebrospinal fluid of patients with anti-Hu antibody associated paraneoplastic neurological syndromes.
    J Neuroimmunol. 2013 May 15;258(1-2):85-90 PMID: 23566401
  72. Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies.
    Neurology. 1992 Mar;42(3 Pt 1):536-40 PMID: 1312683
  73. Absence of HuD gene mutations in paraneoplastic small cell lung cancer tissue.
    Neurology. 1998 Jun;50(6):1919 PMID: 9633765
  74. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures.
    Immunity. 2013 Jul 25;39(1):11-26 PMID: 23890060
  75. Pathogenesis and treatment of paraneoplastic neurologic syndrome.
    Expert Rev Neurother. 2002 Nov;2(6):901-9 PMID: 19810923
  76. 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
  77. New perspectives on the role of vitiligo in immune responses to melanoma.
    Oncotarget. 2011 Sep;2(9):684-94 PMID: 21911918
  78. Expression of lymphocyte, macrophage and class I and II major histocompatibility complex antigens in normal human dorsal root ganglia.
    J Neurol Sci. 1990 Sep;98(2-3):203-11 PMID: 1700807
  79. Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity.
    J Neuroimmunol. 1994 Dec;55(2):205-12 PMID: 7829670
  80. Purification and properties of HuD, a neuronal RNA-binding protein.
    J Biol Chem. 1996 May 10;271(19):11518-24 PMID: 8626712
  81. Onconeural antibodies in sera from patients with various types of tumours.
    Cancer Immunol Immunother. 2009 Nov;58(11):1795-800 PMID: 19294382
  82. HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes.
    J Neuroimmunol. 2010 Sep 14;226(1-2):147-9 PMID: 20547426
  83. Role of HuD and other RNA-binding proteins in neural development and plasticity.
    J Neurosci Res. 2002 Apr 15;68(2):121-6 PMID: 11948657
  84. Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: clinicopathological study of an autopsy case.
    Muscle Nerve. 1998 Jul;21(7):850-7 PMID: 9626244
  85. Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration.
    Exp Neurol. 2003 Sep;183(1):100-8 PMID: 12957493
  86. Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis.
    Eur J Immunol. 2012 Mar;42(3):790-8 PMID: 22144343
  87. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis.
    Neurology. 1998 Oct;51(4):1146-50 PMID: 9781545
  88. Tumor-specific killer cells in paraneoplastic cerebellar degeneration.
    Nat Med. 1998 Nov;4(11):1321-4 PMID: 9809559
  89. 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
  90. Imbalances in circulating lymphocyte subsets in Hu antibody associated paraneoplastic neurological syndromes.
    Eur J Neurol. 2007 Dec;14(12):1383-91 PMID: 18028190
  91. Combination checkpoint blockade--taking melanoma immunotherapy to the next level.
    N Engl J Med. 2013 Jul 11;369(2):187-9 PMID: 23724866
  92. Cell surface expression of paraneoplastic encephalomyelitis/sensory neuronopathy-associated Hu antigens in small-cell lung cancers and neuroblastomas.
    Neurology. 1997 Mar;48(3):735-41 PMID: 9065557
  93. Immune response in lung cancer mouse model mimics human anti-Hu reactivity.
    J Neuroimmunol. 2009 Dec 10;217(1-2):38-45 PMID: 19765830
  94. Peptides derived from the onconeural HuD protein can elicit cytotoxic responses in HHD mouse and human.
    J Neuroimmunol. 2003 Sep;142(1-2):93-100 PMID: 14512168
  95. HuD promotes BDNF expression in brain neurons via selective stabilization of the BDNF long 3'UTR mRNA.
    PLoS One. 2013;8(1):e55718 PMID: 23383270
  96. Paraneoplasia and autoimmunologic injury of the nervous system: the anti-Hu syndrome.
    Brain Pathol. 1993 Jul;3(3):199-212 PMID: 8293180
Article Info
Journal
Oncoimmunology
Abbr.
Oncoimmunology
ISSN
2162-4011
DOI
10.4161/onci.27384
Published
2013-12-01
Epub
2013-00-10
Pages
e27384
Language
English
Region
United States
NLM ID
101570526
PMCID
PMC3913668
External Links
PubMed source DOI: 10.4161/onci.27384 PMC Full Text
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