Long-term neuromuscular dysfunction produced by passive transfer of amyotrophic lateral sclerosis immunoglobulins

We investigated the role of the immune system in the pathogenesis of amyotrophic lateral sclerosis (ALS) by studying the long-term consequences of ALS immunoglobulin (Ig) application on the levator auris muscle of the mouse. We applied Ig from seven ALS patients, four disease controls, and a pool of normal Ig (6 mg of Ig in 2 weeks) by subcutaneous injection; removed the muscles 4 to 12 weeks after the beginning of treatment; and recorded both spontaneous and evoked release of transmitter. None of the control Ig induced changes in transmitter, whereas five of seven ALS Ig induced a significant increase in the rate of spontaneous release, and all ALS Ig produced significant changes in the quantal content of evoked release. In muscles treated with one of the ALS Igs, synaptic activity was completely absent. Cholinesterase and silver staining demonstrated intact neuromuscular junctions in the control Ig-treated muscles and also in many areas of ALS Ig-treated muscles. Axonal degeneration and denervation were present in most muscles treated with ALS Ig. There was complete denervation when no synaptic activity could be recorded. Thus, ALS Ig appears to lead to long-lasting effects at the neuromuscular junction, and such effects may be an early stage in the immune-mediated pathogenesis of ALS.