Genetics of childhood disorders : XXX. Autoimmune disorders, Part 3 : Myasthenia gravis and rasmussen's encephalitis

How can autoimmunity cause illness? Over the years, immunologists have debated this issue regarding many different diseases. The consensus today is that several criteria must be fulfilled to demonstrate an autoimmune etiology. For those disorders in which a humoral etiology is proposed, autoantibodies should be found in the sera of affected individuals. In addition, removal of these autoantibodies should lead to an improvement of symptoms. Finally, transfer of the autoantibodies to an experimental animal should reproduce some of the clinical symptoms of the disorder. In this column, we review the evidence that myasthenia gravis and Rasmussen’s encephalitis are autoimmune disorders. Similar strategies will need to be used by investigators attempting to demonstrate that illnesses such as Tourette’s syndrome and obsessivecompulsive disorder are caused by an autoimmune mechanism. Myasthenia gravis is a relatively rare neurological illness that affects approximately 1 of every 200,000 individuals. A key clinical finding is muscle weakness, especially after repeated activity. Although the course of the illness is highly variable, the disease typically affects eye and eyelid muscles leading to double vision and ptosis. In more severe cases, muscles controlling swallowing, speaking, and breathing become affected. The typical treatment is to administer inhibitors of acetylcholinesterase. Acetylcholine is a neurotransmitter normally found at the neuromuscular junction. To initiate a muscle contraction, the nerve terminal releases the neurotransmitter acetylcholine into the synaptic cleft. The neurotransmitter rapidly diffuses across and binds to acetylcholine receptors on the surface of the muscle cell. The binding of neurotransmitter to its receptor leads to a rapid change in ion flow across the membrane, which in turn propagates a muscle contraction. Acetylcholine must be rapidly removed from the synaptic cleft to allow for multiple signals to arrive at the muscle and to allow for repeated contractions in sustained muscle activity. The rapid removal is accomplished in part by the action of acetylcholinesterase that degrades the neurotransmitter. The finding that drugs that inhibit this enzyme improved the muscle weakness in patients with myasthenia gravis suggested that the illness was caused by a disturbance in some component of the acetylcholine signaling pathway. Little progress was made, however, until the chance observations of two investigators at the Salk Institute in 1973. Jim Patrick and Jon Lindstrom were interested in determining the location of the nicotinic acetylcholine receptor within the CNS. In order to do this, they wanted to generate antibodies against the receptor that could be used in immunocytochemical localization studies. Generating antibodies is a time-honored procedure by which investigators produce a probe that will bind to and help visualize a specific protein under investigation. Typically, rabbits are used to produce such antibodies. When a protein or a portion of the protein is injected into a rabbit, the animal will mount a humoral response against the foreign