AUTOIMMUNE PARANEOPLASTIC SYNDROMES

Project: Research project

Project Details

Description

This project's objective is to identify the autoantigen in
cholinergic neurons that is the target of pathogenic antibodies in
the Lambert-Eaton myasthenic syndrome (LES). The long-range
goal is to devise antigen-specific therapy for LES. Striking
features of LES include a greater than 55% incidence of a lethal
lung cancer, small cell (oat cell) carcinoma (SCC), and a high
prevelence of autoantibodies to thyroid and stomach constituents.
Weakness results from a deficient exocytosis of acethylcholine
(ACh) from motor nerve terminals in response to a nerve impulse.
Injection of IgG from serum of patients into mice causes a
neurotransmission defect similar to that of LES.

There is considerable evidence that the abnormality of cholinergic
neurons that impairs neurotransmission in LES results from an
autoimmune response that is initiated as an anti-tumor response
directed against a neuron-related differentiation antigen of SCC.
Voltage-sensitive Ca2+ channels have been implicated as the
antigen. This project aims to examine plasma membranes of SCC
for antigens reactive with LES antibodies and for molecules
related to those on cholinergic neurones that are relevant to ACh
release.

LES patients' antibodies will be tested for pathophysiologic
effects on clonal lines and primary preparations of cholinergic
neurons, using microassays to measure voltage-dependent influx
of 45Ca2+ and release of 3H-ACh. A new rapid passive transfer
model of LES in mice will facilitate analysis of the mechanisms
responsible for impaired release of ACh quanta in LES. Isolated
cholinergic nerve terminals from the electric organ of Torpedo
californica will be investigated as a potentially rich source of the
LES antigen. The omega toxin of the snail Conus geographus,
which has high affinity and specificty for voltage-sensitive Ca2+
channels of presynaptic nerve terminals, is a promising tool for
identifying the LES antigen. Monoclonal antibodies made by
hybridomas from rats immunized with SCC or cholinergic
neuronal components, and by B cell lines from LES patients, will
be used to identify and purify the LES antigen.

The aims in the next period of this grant are 1) to identify and
purify the LES antigen, 2) to develop an animal model of LES
based on active immunization for testing new modes of therapy
for LES; 3) to develop serologic tests for diagnosis of LES and/or
SCC; and 4) to identify the Link between SCC, LES and
thyrogastric autoimmunity.
StatusFinished
Effective start/end date3/1/844/30/98

ASJC

  • Medicine(all)