Selected IgG rapidly induces Lambert–Eaton myasthenic syndrome in mice: Complement independence and EMG abnormalities

Abstract

Antibodies in individual patients with the Lambert-Eaton myasthenic syndrome (LES) differ in their reactivity with mouse motor nerve terminals. Of 26 LES patients' sera injected a single time into mice, 3 caused a highly significant reduction in stimulus-dependent quantal release (m) of acetylcholine (ACh) (to 6, 33, and 42 quanta per impulse at 1 Hz, respectively; mean for 10 control sera, 100 quanta at 1 Hz). The most potent serum (LES-A) was fully effective in mice deficient in complement component C5 and in mice depleted of complement components C3----C9 by cobra venom factor. A single i.v. injection of serum reduced m in direct proportion to log dose. Responses to K+ depolarization and increasing concentrations of Ca2+ were like those observed in human LES. With LES-A serum, or its IgG, m was reduced near maximally in 1 day and plateaued in 3-4 days. Recovery began after day 8; m was in the normal range by day 20-30. Electromyographic (EMG) abnormalities were not seen until m fell below 40 quanta per impulse at 1 Hz. Below 10 quanta, clinical signs of weakness appeared, and the EMG abnormalities were those classically associated with LES: a marked reduction of compound muscle action potential to a single nerve stimulus in rested muscle, a further decrement during stimulation at slow rates, but marked facilitation during rapid repetitive stimulation.

Passive Transfer of Autoimmune Autonomic Neuropathy to Mice

“…Polyclonal human autoantibodies reactive with synaptic ion channels may have limited reactivity with mouse antigens and may require multiple injections over days or weeks to cause objectively measurable deficits of synaptic transmission (Toyka et al, 1977;Lang et al, 1981;Lambert and Lennon, 1988;Lennon and Griesmann, 1989). We anticipate that future protocols using multiple injections and the screening of IgG from a larger number of patients will demonstrate more severe dysautonomia in mice (Lambert and Lennon, 1988). The data we present here support the concept that IgG is the cause of dysautonomia in at least some human cases of AAN.…”

Antibody testing as a diagnostic tool in autonomic disorders

“…For some disorders, there is convincing evidence of an antibody-mediated pathophysiology. Patients may improve clinically after plasma exchange or other immunotherapies, and the conditions can be transferred to experimental animals by injection of patients' IgG [14,31,39]. Also, the level of the antibody often correlates with the severity of disease; improvement in symptoms may be associated with a decrease in antibody level.…”

“…Antibodies against P/Q-type voltage-gated calcium channels cause impairment in presynaptic calcium influx and a reduction in the release of acetylcholine [14,40]. Calcium channel antibodies are found in nearly 100% of patients with LEMS, but these antibodies can also be associated with other autoimmune neurological disorders (notably paraneoplastic cerebellar ataxia) [6,41].…”

Autoimmune and Paraneoplastic Channelopathies

“…Passive transfer of antibodies to mice produces typical neuromuscular transmission deficits 27 and autonomic changes. 28 Binding of antibodies reduces the number of functional VGCC on the motor nerve terminal.…”