Elsevier

Journal of Neuroimmunology

Volumes 201–202, 15 September 2008, Pages 145-152
Journal of Neuroimmunology

Lambert–Eaton myasthenic syndrome: Search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis

https://doi.org/10.1016/j.jneuroim.2008.04.040Get rights and content

Abstract

The Lambert–Eaton myasthenic syndrome (LEMS) is a disease of neuromuscular transmission in which autoantibodies against the P/Q-type voltage-gated calcium channel (VGCC) at the presynaptic nerve terminal play a major role in decreasing quantal release of acetylcholine (ACh), resulting in skeletal muscle weakness and autonomic symptoms. It is associated with cancer, particularly small-cell lung carcinoma (SCLC), in 50–60% of LEMS patients; the nerve terminal and carcinoma cells apparently share a common antigen (VGCC), suggesting an immunological cross-reactivity that may lead to the neurological abnormality. Non-tumor LEMS has a strong association with HLA-DR3-B8. In approximately 15% of LEMS patients, no anti-P/Q-type VGCC antibodies are found, suggesting recognition of other targets(s). The VGCC-associated protein synaptotagmin could be one candidate, because it acts as an exocytotic calcium receptor, is implicated in fast ACh release; its N-terminus is exposed extracellularly during exocytosis and it is expressed in SCLC. Antibodies against synaptotagmin-1 were detected in both anti-VGCC-positive and -negative LEMS patients (20%), and it can be immunogenic, allowing induction of an animal model of LEMS. Another candidate target is the M1-type presynaptic muscarinic ACh receptor (M1 mAChR), also expressed extracellularly on motor nerve terminals; it modulates cholinergic transmission, linking to P/Q-type VGCC. In our series of 25 LEMS patients with and without SCLC, anti-M1 mAChR antibodies were prevalent in both anti-VGCC-positive and -negative LEMS patients. Autonomic symptoms seemed more frequent in the latter; serum from one of them passively transferred LEMS-type electrophysiological defects to mice.

As a compensatory mechanism, researchers in Oxford suggested a shift in the dependence of ACh release from the P/Q-type to other types of VGCC. We have also focused on G protein-coupled mAChRs and neurotrophins, which may affect both P/Q-type VGCC and clathrin-independent “kiss-and-run” synaptic vesicle recycling (fast-mode of endocytosis) via protein kinase C activation. We hypothesize that these signaling cascades help to compensate for the immune-mediated defects in calcium entry in LEMS, compensation that may frequently be restricted by the coincident anti-M1 mAChR antibodies in this disease.

Section snippets

Voltage-gated calcium channels

As Professor Newsom-Davis stated in his posthumous review (Newsom-Davis, 2007), “Research advances over 30 years have shown that key transmembrane proteins at the neuromuscular junction are vulnerable to antibody-mediated autoimmune attack”. One example is the voltage-gated calcium channel (VGCC) in the Lambert–Eaton myasthenic syndrome (LEMS). The story of research on LEMS began in 1953, when Anderson et al. (1953) first reported a 47-year-old man with lung carcinoma who showed prolonged apnea

Synaptotagmin

Since the discovery that calcium entry into nerve terminals triggers rapid neurotransmitter release, the search for calcium sensors has intensified. It is now generally agreed that the synaptic vesicle-associated calcium binding protein, synaptotagmin, is required for the tight temporal coupling between calcium influx and synaptic vesicle exocytosis, which is due to intimate apposition between the phospholipid membrane and the SNARE complex (synaptobrevin, syntaxin and SNAP-25), followed by

Presynaptic muscarinic acetylcholine receptor

In the Symposium on myasthenia gravis and myasthenic syndrome in the 8th International Congress of Neuroimmunology held in 2006 (at Nagoya), Professor Newsom-Davis encouraged our further searches for LEMS targets other than P/Q-type VGCC. We tested LEMS sera for antibodies against likely target antigens and compensatory mediators for the defective neuromuscular transmission in LEMS, focusing particularly on the M1-type presynaptic muscarinic acetylcholine receptor (M1 mAChR), a G

Compensatory mechanisms

Besides the M1 mAChR-related signaling we propose, the Oxford group has suggested that potential presynaptic mechanisms that compensate for the immune-mediated defect of calcium entry in LEMS could include a shift in dependence of ACh release from the P/Q-type to other types of VGCC such as L-, N-, and/or R-types (Giovannini et al., 2002, Lang et al., 2003). In addition, a switch from slow- to fast-mode synaptic vesicle recycling (“kiss-and-run”) might also contribute; this clathrin-independent

Acknowledgments

We dedicate this paper with sincere gratitude to Professor Newsom-Davis who lit beacons for our ongoing research. We gratefully acknowledge the helpful contributions from the Oxford research group to the preparation of the manuscript.

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