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Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes
V A Lennon1, T J Kryzer, G E Griesmann
1Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Background:
Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known.
Methods:
We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex.
Results:
P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma.
Conclusions:
The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.
Insights
Autoimmunity in Lambert-Eaton syndrome is linked to P/Q-type calcium channels. This study identifies P/Q-type calcium-channel antibodies as key players in the presynaptic pathophysiology of this neuromuscular disorder.
Area of Science:
- Neuroimmunology
- Molecular Medicine
- Oncology
Background:
- Small-cell lung carcinoma can trigger autoimmune responses leading to paraneoplastic neuromuscular disorders like Lambert-Eaton syndrome.
- The specific subtype of voltage-gated calcium channels responsible for this autoimmune reaction remains unidentified.
Purpose of the Study:
- To determine the specific subtype of neuronal voltage-gated calcium channels involved in Lambert-Eaton syndrome.
- To investigate the presence and significance of antibodies targeting different calcium channel subtypes in patients with Lambert-Eaton syndrome and related conditions.
Main Methods:
- Compared the efficacy of L-type, N-type, and P/Q-type calcium channel antagonists on 45Ca influx in cultured small-cell carcinoma cells.
- Screened patient serum samples for antibodies against P/Q-type and N-type calcium channels.
Main Results:
- P/Q-type calcium channel antagonists most effectively inhibited 45Ca influx in small-cell carcinoma cell lines.
- Anti-P/Q-type calcium channel antibodies were detected in all Lambert-Eaton syndrome patients with cancer (32/32) and 91% without cancer (33 patients).
- Anti-N-type antibodies were found in 49% of Lambert-Eaton syndrome patients, with lower titers of both antibody types observed in patients with other paraneoplastic or neurological conditions.
Conclusions:
- The high prevalence of anti-P/Q-type calcium channel antibodies in Lambert-Eaton syndrome patients strongly suggests their involvement in the presynaptic pathophysiology.
- These findings implicate P/Q-type calcium channels as critical targets in the autoimmune process underlying Lambert-Eaton syndrome.