Abstract
The discovery of disorders that are associated with antibodies to neuronal cell-surface proteins has led to a paradigm shift in our understanding of CNS autoimmunity. These disorders can occur in patients with or without cancer—often children or young adults who develop psychosis, catatonic or autistic features, memory problems, abnormal movements, or seizures that were previously considered idiopathic. The autoantigens in such cases have crucial roles in synaptic transmission, plasticity and peripheral nerve excitability. Patients can be comatose or encephalopathic for months and yet fully recover with supportive care and immunotherapy. By contrast, disorders in which the antibodies target intracellular antigens, and in which T-cell-mediated irreversible neuronal degeneration occurs, show a considerably poorer response to treatment. In this article, we review the various targets of neuronal antibodies, focusing predominantly on autoantigens located on the cell surface or synapses—namely, N-methyl-D-aspartate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, γ-aminobutyric acid receptors, leucine-rich glioma-inactivated protein 1, contactin-associated protein-like 2, and metabotropic glutamate receptors. We also provide an algorithm to identify and assess antibodies that bind to cell-surface and synaptic antigens.
Key Points
-
Antibodies that target neuronal antigens are becoming increasingly recognized
-
Antibodies to intracellular neuronal antigens may mark a T-cell response that targets neurons
-
Antibodies to cell-surface and synaptic antigens are associated with seizures and psychosis, as well as disorders of memory, behaviour, cognition and movement; such antibodies may be directly pathogenic
-
Many patients with antibodies to cell-surface antigens respond to treatment
-
Assessment of clinical phenotype and analysis of serum and cerebrospinal fluid are crucial for identification of known and novel autoantibodies
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dalmau, J. et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25–36 (2007).
Lai, M. et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann. Neurol. 65, 424–434 (2009).
Lancaster, E. et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 9, 67–76 (2010).
Lai, M. et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 9, 776–785 (2010).
Lancaster, E. et al. Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia. Ann. Neurol. 69, 303–311 (2011).
Irani, S. R. et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 133, 2734–2748 (2010).
Hutchinson, M. et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 71, 1291–1292 (2008).
Lancaster, E. et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 77, 1698–1701 (2011).
Dalmau, J., Furneaux, H. M., Rosenblum, M. K., Graus, F. & Posner, J. B. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology 41, 1757–1764 (1991).
Sillevis Smitt, P. A., Manley, G. T. & Posner, J. B. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 45, 1873–1878 (1995).
Sillevis Smitt, P., Manley, G., Dalmau, J. & Posner, J. The HuD paraneoplastic protein shares immunogenic regions between PEM/PSN patients and several strains and species of experimental animals. J. Neuroimmunol. 71, 199–206 (1996).
Carpentier, A. F. et al. DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. Clin. Cancer Res. 4, 2819–2824 (1998).
Darnell, R. B. & Posner, J. B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).
Rousseau, A. et al. T cell response to Hu-D peptides in patients with anti-Hu syndrome. J. Neurooncol. 71, 231–236 (2005).
Voltz, R., Dalmau, J., Posner, J. B. & Rosenfeld, M. R. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 51, 1146–1150 (1998).
Plonquet, A. et al. Oligoclonal T-cells in blood and target tissues of patients with anti-Hu syndrome. J. Neuroimmunol. 122, 100–105 (2002).
Plonquet, A. et al. Peptides derived from the onconeural HuD protein can elicit cytotoxic responses in HHD mouse and human. J. Neuroimmunol. 142, 93–100 (2003).
Kazarian, M. et al. Immune response in lung cancer mouse model mimics human anti-Hu reactivity. J. Neuroimmunol. 217, 38–45 (2009).
DeLuca, I., Blachere, N. E., Santomasso, B. & Darnell, R. B. Tolerance to the neuron-specific paraneoplastic HuD antigen. PLoS ONE 4, e5739 (2009).
Roberts, W. K. et al. Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells. J. Clin. Invest. 119, 2042–2051 (2009).
Pellkofer, H. et al. Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 127, 1822–1830 (2004).
Cross, S. A. et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann. Neurol. 54, 38–50 (2003).
Verschuren, M. C., van Bergen, C. J., van Gastel-Mol, E. J., Bogers, A. J. & van Dongen, J. J. A DNA binding protein in human thymocytes recognizes the T cell receptor-δ-deleting element ψJα. J. Immunol. 156, 3806–3814 (1996).
Giometto, B. et al. Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system. Neuropathol. Appl. Neurobiol. 23, 468–474 (1997).
Storstein, A., Krossnes, B. K. & Vedeler, C. A. Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies. Acta Neurol. Scand. 120, 64–67 (2009).
Albert, M. L. et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat. Med. 4, 1321–1324 (1998).
Albert, M. L., Austin, L. M. & Darnell, R. B. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann. Neurol. 47, 9–17 (2000).
Sutton, I. J., Steele, J., Savage, C. O., Winer, J. B. & Young, L. S. An interferon-γ ELISPOT and immunohistochemical investigation of cytotoxic T lymphocyte-mediated tumour immunity in patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies. J. Neuroimmunol. 150, 98–106 (2004).
Greenlee, J. E. et al. Purkinje cell death after uptake of anti-Yo antibodies in cerebellar slice cultures. J. Neuropathol. Exp. Neurol. 69, 997–1007 (2010).
Graus, F. et al. Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model. J. Neurol. Sci. 106, 82–87 (1991).
Greenlee, J. E., Burns, J. B., Rose, J. W., Jaeckle, K. A. & Clawson, S. Uptake of systemically administered human anticerebellar antibody by rat Purkinje cells following blood–brain barrier disruption. Acta Neuropathol. 89, 341–345 (1995).
Soghomonian, J. J. & Martin, D. L. Two isoforms of glutamate decarboxylase: why? Trends Pharmacol. Sci. 19, 500–505 (1998).
Wu, Y., Matsui, H. & Tomizawa, K. Amphiphysin I and regulation of synaptic vesicle endocytosis. Acta Med. Okayama 63, 305–323 (2009).
Pittock, S. J. et al. Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin. Proc. 81, 1207–1214 (2006).
Saiz, A. et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 131, 2553–2563 (2008).
Malter, M. P., Helmstaedter, C., Urbach, H., Vincent, A. & Bien, C. G. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470–478 (2010).
Murinson, B. B. & Guarnaccia, J. B. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71, 1955–1958 (2008).
Pittock, S. J. et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann. Neurol. 58, 96–107 (2005).
Ishida, K., Mitoma, H. & Mizusawa, H. Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies. J. Neurol. Sci. 271, 186–190 (2008).
Manto, M. U., Hampe, C. S., Rogemond, V. & Honnorat, J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J. Rare Dis. 6, 3 (2011).
Burton, A. R. et al. On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes 57, 1321–1330 (2008).
Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863–4870 (2010).
Sommer, C. et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 365, 1406–1411 (2005).
Geis, C. et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 133, 3166–3180 (2010).
Geis, C. et al. Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [Ca2+]i rise in embryonic motoneurons. Neurobiol. Dis. 36, 191–199 (2009).
Florance, N. R. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann. Neurol. 66, 11–18 (2009).
Dalmau, J., Lancaster, E., Martinez-Hernandez, E., Rosenfeld, M. R. & Balice-Gordon, R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 10, 63–74 (2011).
Gable, M. S., Sheriff, H., Dalmau, J., Tilley, D. H. & Glaser, C. A. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the california encephalitis project. Clin. Infect. Dis. 54, 899–904 (2012).
Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
Tuzun, E. et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 118, 737–743 (2009).
Belforte, J. E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat. Neurosci. 13, 76–83 (2010).
Hughes, E. G. et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30, 5866–5875 (2010).
Iizuka, T. et al. Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal. Neurology 70, 504–511 (2008).
Manto, M., Dalmau, J., Didelot, A., Rogemond, V. & Honnorat, J. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J. Rare Dis. 5, 31 (2010).
Manto, M., Dalmau, J., Didelot, A., Rogemond, V. & Honnorat, J. Afferent facilitation of corticomotor responses is increased by IgGs of patients with NMDA-receptor antibodies. J. Neurol. 258, 27–33 (2011).
Hart, I. K. et al. Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia. Ann. Neurol. 41, 238–246 (1997).
Tan, K. M., Lennon, V. A., Klein, C. J., Boeve, B. F. & Pittock, S. J. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology 70, 1883–1890 (2008).
Kleopa, K. A., Elman, L. B., Lang, B., Vincent, A. & Scherer, S. S. Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations. Brain 129, 1570–1584 (2006).
Boronat, A. et al. Analysis of antibodies to surface epitopes of contactin-2 in multiple sclerosis. J. Neuroimmunol. 244, 103–106 (2012).
Fukata, Y. et al. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc. Natl Acad. Sci. USA 107, 3799–3804 (2010).
Morante-Redolat, J. M. et al. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum. Mol. Genet. 11, 1119–1128 (2002).
Chatzopoulou, E. et al. Structural requirement of TAG-1 for retinal ganglion cell axons and myelin in the mouse optic nerve. J. Neurosci. 28, 7624–7636 (2008).
Gu, C. & Gu, Y. Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons. J. Biol. Chem. 286, 25835–25847 (2011).
Zhou, L., Messing, A. & Chiu, S. Y. Determinants of excitability at transition zones in Kv1.1-deficient myelinated nerves. J. Neurosci. 19, 5768–5781 (1999).
Geschwind, M. D. et al. Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt–Jakob disease. Arch. Neurol. 65, 1341–1346 (2008).
Irani, S. R. et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann. Neurol. 69, 892–900 (2011).
Andrade, D. M., Tai, P., Dalmau, J. & Wennberg, R. Tonic seizures: a diagnostic clue of anti-LGI1 encephalitis? Neurology 76, 1355–1357 (2011).
Chabrol, E. et al. Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice. Brain 133, 2749–2762 (2010).
Lalic, T., Pettingill, P., Vincent, A. & Capogna, M. Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 52, 121–131 (2011).
Irani, S. R. et al. Morvan's syndrome: clinical and serological observations in 29 cases. Ann. Neurol. http://dx.doi.org/10.1002/ana.23577.
Verkerk, A. J. et al. CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82, 1–9 (2003).
Strauss, K. A. et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N. Engl. J. Med. 354, 1370–1377 (2006).
Gregor, A. et al. Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC Med. Genet. 12, 106 (2011).
Penagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).
Whalley, H. C. et al. Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 941–948 (2011).
Bataller, L. et al. Reversible paraneoplastic limbic encephalitis associated with antibodies to the AMPA receptor. Neurology 74, 265–267 (2010).
Graus, F. et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 74, 857–859 (2010).
Granger, A. J., Gray, J. A., Lu, W. & Nicoll, R. A. Genetic analysis of neuronal ionotropic glutamate receptor subunits. J. Physiol. 589, 4095–4101 (2011).
Boronat, A., Sabater, L., Saiz, A., Dalmau, J. & Graus, F. GABAB receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 76, 795–800 (2011).
Bettler, B., Kaupmann, K., Mosbacher, J. & Gassmann, M. Molecular structure and physiological functions of GABAB receptors. Physiol. Rev. 84, 835–867 (2004).
Titulaer, M. J., Lang, B. & Verschuuren, J. J. Lambert–Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 10, 1098–1107 (2011).
Clouston, P. D. et al. Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert–Eaton myasthenic syndrome. Neurology 42, 1944–1950 (1992).
Lennon, V. A. et al. Calcium-channel antibodies in the Lambert–Eaton syndrome and other paraneoplastic syndromes. N. Engl. J. Med. 332, 1467–1474 (1995).
Burk, K., Wick, M., Roth, G., Decker, P. & Voltz, R. Antineuronal antibodies in sporadic late-onset cerebellar ataxia. J. Neurol. 257, 59–62 (2010).
Pinto, A., Iwasa, K., Newland, C., Newsom-Davis, J. & Lang, B. The action of Lambert–Eaton myasthenic syndrome immunoglobulin G on cloned human voltage-gated calcium channels. Muscle Nerve 25, 715–724 (2002).
Lang, B., Pinto, A., Giovannini, F., Newsom-Davis, J. & Vincent, A. Pathogenic autoantibodies in the Lambert–Eaton myasthenic syndrome. Ann. NY Acad. Sci. 998, 187–195 (2003).
Liao, Y. J. et al. Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo. Proc. Natl Acad. Sci. USA 105, 2705–2710 (2008).
Fukuda, T. et al. Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert–Eaton myasthenic syndrome. Ann. Neurol. 53, 21–28 (2003).
Piotrowicz, A., Thumen, A., Leite, M. I., Vincent, A. & Moser, A. A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings. J. Neurol. 258, 2268–2270 (2011).
Mas, N. et al. Antiglycine-receptor encephalomyelitis with rigidity. J. Neurol. Neurosurg. Psychiatry 82, 1399–1401 (2011).
Hernandes, M. S. & Troncone, L. R. Glycine as a neurotransmitter in the forebrain: a short review. J. Neural Transm. 116, 1551–1560 (2009).
Shiang, R. et al. Mutations in the α1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat. Genet. 5, 351–358 (1993).
Harvey, R. J., Topf, M., Harvey, K. & Rees, M. I. The genetics of hyperekplexia: more than startle! Trends Genet. 24, 439–447 (2008).
Makarovsky, I. et al. Strychnine—a killer from the past. Isr. Med. Assoc. J. 10, 142–145 (2008).
Sillevis Smitt, P. et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N. Engl. J. Med. 342, 21–27 (2000).
Marignier, R. et al. Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease? Arch. Neurol. 67, 627–630 (2010).
Carr, I. The Ophelia syndrome: memory loss in Hodgkin's disease. Lancet 1, 844–845 (1982).
Nicoletti, F. et al. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60, 1017–1041 (2011).
Simonyi, A., Schachtman, T. R. & Christoffersen, G. R. Metabotropic glutamate receptor subtype 5 antagonism in learning and memory. Eur. J. Pharmacol. 639, 17–25 (2010).
Hildebrand, M. E. et al. Functional coupling between mGluR1 and Cav3.1 T-type calcium channels contributes to parallel fiber-induced fast calcium signaling within Purkinje cell dendritic spines. J. Neurosci. 29, 9668–9682 (2009).
Coesmans, M. et al. Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann. Neurol. 53, 325–336 (2003).
Ichise, T. et al. mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288, 1832–1835 (2000).
Masdeu, J. C. et al. Serum IgG antibodies against the NMDA receptor not detected in schizophrenia. Biol. Psychiatry 71, 53S (2012).
Zuliani, L., Graus, F., Giometto, B., Bien, C. & Vincent, A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J. Neurol. Neurosurg. Psychiatry 83, 638–645 (2012).
Hajj-Ali, R. A., Singhal, A. B., Benseler, S., Molloy, E. & Calabrese, L. H. Primary angiitis of the CNS. Lancet Neurol. 10, 561–572 (2011).
Ances, B. M. et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128, 1764–1777 (2005).
Lancaster, E., Martinez-Hernandez, E. & Dalmau, J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189 (2011).
Becker, E. B. et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J. Neurol. Neurosurg. Psychiatry 83, 437–440 (2012).
Pruss, H. et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology http://dx.doi.org/10.1212/WNL.0b013e318258300d.
Martinez-Hernandez, E. et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77, 589–593 (2011).
Titulaer, M. et al. Clinical features, treatment, and outcome of 500 patients with anti-NMDA receptor encephalitis [abstract]. Neurology 78 (Meeting abstracts 1), PL01.001 (2012).
Dalmau, J., Furneaux, H. M., Gralla, R. J., Kris, M. G. & Posner, J. B. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative western blot analysis. Ann. Neurol. 27, 544–552 (1990).
Hubers, L. et al. HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. Hum. Mol. Genet. 20, 553–579 (2011).
Okano, H. J. & Darnell, R. B. A hierarchy of Hu RNA binding proteins in developing and adult neurons. J. Neurosci. 17, 3024–3037 (1997).
Dalmau, J., Graus, F., Rosenblum, M. K. & Posner, J. B. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 71, 59–72 (1992).
Veyrac, A. et al. CRMP5 regulates generation and survival of newborn neurons in olfactory and hippocampal neurogenic areas of the adult mouse brain. PLoS ONE 6, e23721 (2011).
Honnorat, J. et al. Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J. Neurol. Neurosurg. Psychiatry 80, 412–416 (2009).
Graus, F. et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J. Neurol. Neurosurg. Psychiatry 75, 1135–1140 (2004).
Dalmau, J. et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 127, 1831–1844 (2004).
Furneaux, H. M. et al. Characterization of a cDNA encoding a 34-kDa Purkinje neuron protein recognized by sera from patients with paraneoplastic cerebellar degeneration. Proc. Natl Acad. Sci. USA 86, 2873–2877 (1989).
O'Donovan, K. J., Diedler, J., Couture, G. C., Fak, J. J. & Darnell, R. B. The onconeural antigen cdr2 is a novel APC/C target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells. PLoS ONE 5, e10045 (2010).
Rojas, I. et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 55, 713–715 (2000).
Shams'ili, S. et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126, 1409–1418 (2003).
Pittock, S. J., Lucchinetti, C. F. & Lennon, V. A. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann. Neurol. 53, 580–587 (2003).
Yang, Y. Y., Yin, G. L. & Darnell, R. B. The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia. Proc. Natl Acad. Sci. USA 95, 13254–13259 (1998).
Buckanovich, R. J. & Darnell, R. B. The neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo. Mol. Cell Biol. 17, 3194–3201 (1997).
Drlicek, M. et al. Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J. Neurol. 244, 85–89 (1997).
Graus, F. et al. Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J. Neuroimmunol. 74, 55–61 (1997).
Bernal, F. et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology 60, 230–234 (2003).
Bataller, L., Wade, D. F., Fuller, G. N., Rosenfeld, M. R. & Dalmau, J. Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum. Neurology 59, 1985–1987 (2002).
Dalakas, M. C. Advances in the pathogenesis and treatment of patients with stiff person syndrome. Curr. Neurol. Neurosci. Rep. 8, 48–55 (2008).
Espay, A. J. & Chen, R. Rigidity and spasms from autoimmune encephalomyelopathies: stiff-person syndrome. Muscle Nerve 34, 677–690 (2006).
Acknowledgements
This work is supported in part by grants to J. Dalmau from the NIH (RO1NS077851 and RO1MH094741), the National Cancer Institute (RO1CA089054), Fundació la Marató TV3 and Fondo de Investigaciones Sanitarias (FIS, PI11/01780), and Euroimmun. This work is also supported in part by grants to E. Lancaster from the National Organization for Rare Disorders and the Dana Foundation.
Author information
Authors and Affiliations
Contributions
Both authors contributed to researching data for the article, discussion of the content, writing the article, and review and/or editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
E. Lancaster receives grant support from Lundbeck and Talecris. J. Dalmau is a patent holder of antibody tests from the University of Pennsylvania, and receives grant support from Euroimmun.
Rights and permissions
About this article
Cite this article
Lancaster, E., Dalmau, J. Neuronal autoantigens—pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8, 380–390 (2012). https://doi.org/10.1038/nrneurol.2012.99
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2012.99
This article is cited by
-
Autoimmune encephalitis: what the radiologist needs to know
Neuroradiology (2024)
-
Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis
Neurological Sciences (2024)
-
Discrimination between leucine-rich glioma-inactivated 1 antibody encephalitis and gamma-aminobutyric acid B receptor antibody encephalitis based on ResNet18
Visual Computing for Industry, Biomedicine, and Art (2023)
-
FDG–PET in patients with autoimmune encephalitis: a review of findings and new perspectives
Clinical and Translational Imaging (2023)
-
Phosphodiesterase 10A autoimmunity presenting as cerebellar ataxia responsive to plasma exchange: a case report
Journal of Neurology (2023)