The identification of immune responses against neuronal proteins in patients with cancer and neurologic disorders, known as paraneoplastic neurologic disorders (PNDs), has uncovered the existence of antigens shared by some cancers and the nervous system. As part of the immune response patients develop characteristic serum and cerebrospinal antibodies. Detection of these antibodies in a patient with neurologic disease of unknown etiology establishes the diagnosis of PND and focuses the search of the tumor to a few organs. This is important because, 1) in most patients the presence of a cancer is unknown at the time the PND develops, and 2) prompt diagnosis and treatment of the tumor is critical for improving the neurologic outcome. Of all patients suspected of having a PND, only 60% harbor antibodies to known target antigens. The hypothesis of this proposal is that antibody-associated PND are more frequent than believed. We postulate that the current techniques of antibody detection underestimate the true incidence of antibody-associated PND. Moreover, we postulate that some antibody-associated neurological syndromes may occur with or without cancer. To support our hypothesis we developed and validated a highly sensitive strategy for the rapid identification of antibodies in patients previously considered antibody-negative. This resulted in the isolation of 10 novel antibody associated disorders, targeting intracellular proteins and cell surface ion channels or receptors (AMPA, NMDA, GABAB receptors) with critical synaptic functions. While the intracellular antigens are important as surrogate diagnostic markers of PND and specific tumors, the cell surface antigens are notable for 4 reasons: 1) the associated disorders can occur with or without cancer and affect young individuals and children, 2) they are treatment-responsive, 3) the antibodies have direct effects on the target antigens, suggesting they are pathogenic, and 4) some antibodies define new syndromes. These novel antibody/antigen associations not only provide diagnostic tests but also direct the treatment approach. This proposal is an extension of this work and focuses on the comprehensive identification of autoantigens in four disorders: 1) rapidly progressive dementia with CSF inflammatory/autoimmune features, 2) opsoclonus-myoclonus-ataxia, 3) acute encephalitis with dyskinesias, and 4) encephalitis with refractory-relapsing seizures. The long-range goal is to develop autoantigen arrays to facilitate diagnosis and guide therapy. The two specific aims are: 1) To identify autoantigens of PND and similar syndromes using modified highly sensitive methods for the presence of antibodies to intracellular and neuronal cell surface antigens, and 2) To characterize the target synaptic antigens and determine the effects of patients'antibodies on the antigens and synapses in neuronal cultures.

Public Health Relevance

We have and propose to continue to identify new disorders of the nervous system that are due to the dysfunction of the patient's immunological system. This research has led to the development of blood tests to diagnose these disorders and the determination of appropriate treatments. Some of these disorders can be fatal if not diagnosed or properly treated and therefore, this work has resulted in improved outcomes for these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS077851-06
Application #
8337725
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2004-04-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$454,000
Indirect Cost
$170,250
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Kayser, Matthew S; Dalmau, Josep (2014) Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res :
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Armangue, Thais; Leypoldt, Frank; Malaga, Ignacio et al. (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75:317-23
Petit-Pedrol, Mar; Armangue, Thaís; Peng, Xiaoyu et al. (2014) Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 13:276-86
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Armangue, Thaís; Leypoldt, Frank; Dalmau, Josep (2014) Autoimmune encephalitis as differential diagnosis of infectious encephalitis. Curr Opin Neurol 27:361-8
Armangue, Thais; Titulaer, Maarten J; Sabater, Lidia et al. (2014) A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann Neurol 75:435-41
Gresa-Arribas, Nuria; Titulaer, Maarten J; Torrents, Abiguei et al. (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13:167-77

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