The Lambert-Eaton myasthenic syndrome (LES) is an IgG-mediated paraneoplastic autoimmune disorder of peripheral cholinergic synaptic transmission that causes muscle weakness and autonomic dysfunction, and is highly associated with small cell lung carcinoma (SCLC). Autoimmunity in LES appears to be the byproduct of a polyclonal IgG anti-tumor response directed against neuronal-type voltage-gated Ca2+ channels (VGCC) expressed in SCLC. The anti-VGCC antibodies produced in patients with LES have diverse specificities. Some are reactive with (omega-CgTx)-binding molecules (presumptive VGCC) expressed in human brain neurons and SCLC. IgGs of this specificity are also found in some patients who have SCLC without LES. The long-term objectives of this research are to improve the diagnosis and treatment of both LES and SCLC. Tools for the proposed studies include: frozen characterized sera from 200 LES patients: cryopreserved lymphocytes from 48 LES patients and numerous control patients; fresh specimens of human brain; omega-CgTx-GVIA (a high affinity ligand for some of the neuronal VGCC antigens that are immunoprecipitable by LES IgG); defined SCLC lines binding components of SCLC and neuronal membranes; CDNA probes and oligonucleotide primers and probes encoding a prototypic rat neuronal omega-CgTx-binding (N-type) VGCC; CDNA libraries (lambda gt11) made from RNAs of an omega-CgTx-binding SCLC lineand from human brain neurons.
The Specific Aims are 1) to characterize and sequence the VGCC-like antigen of SCLC to which LES IgG binds, and the neuronal VGCC antigens that are targets for pathogenic IgG; ii) to use purified, recombinant and synthetic peptide VGCC antigens, and monoclonal antibodies (Mabs), to define immunologically the VGCC molecules (and epitopes) relevant to the pathogenesis of LES; iii) to develop new animal models to investigate the pathophysiological basis of neuromuscular and autonomic synaptic defects of LES.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA037343-07
Application #
3175162
Study Section
Neurology C Study Section (NEUC)
Project Start
1984-03-01
Project End
1997-04-30
Budget Start
1992-07-01
Budget End
1993-04-30
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Lennon, Vanda A; Ermilov, Leonid G; Szurszewski, Joseph H et al. (2003) Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J Clin Invest 111:907-13
Ermilov, L G; Miller, S M; Schmalz, P F et al. (2003) Morphological characteristics and immunohistochemical detection of nicotinic acetylcholine receptors on intestinofugal afferent neurones in guinea-pig colon. Neurogastroenterol Motil 15:289-98
Pardi, Darrell S; Miller, Steven M; Miller, Daniel L et al. (2002) Paraneoplastic dysmotility: loss of interstitial cells of Cajal. Am J Gastroenterol 97:1828-33
Dong, Haidong; Strome, Scott E; Salomao, Diva R et al. (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793-800
Manley, H A; Lennon, V A (2001) Endoplasmic reticulum membrane-sorting protein of lymphocytes (BAP31) is highly expressed in neurons and discrete endocrine cells. J Histochem Cytochem 49:1235-43
Thambisetty, M R; Scherzer, C R; Yu, Z et al. (2001) Paraneoplastic optic neuropathy and cerebellar ataxia with small cell carcinoma of the lung. J Neuroophthalmol 21:164-7
Chan, K H; Vernino, S; Lennon, V A (2001) ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol 50:301-11
Lee, H R; Lennon, V A; Camilleri, M et al. (2001) Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am J Gastroenterol 96:373-9
Yu, Z; Kryzer, T J; Griesmann, G E et al. (2001) CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49:146-54
Vernino, S; Lennon, V A (2000) New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol 47:297-305

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