Myasthenia gravis is an organ-specific autoimmune disorder generally thought to be caused by an antibody-mediated attack against the skeletal muscle nicotinic
acetylcholine (
Ach) receptor (AchR) at the neuromuscular junction. Extraocular muscle weakness and
double vision are present in about 90% of patients with
myasthenia gravis and are the predominant complaints in about 20% of patients, when the condition is called
ocular myasthenia gravis (OMG). While serum
antibodies against the AchR are detected in most patients with
generalized myasthenia gravis (
GMG), they are not found in about one-third of patients with the ocular variety, and epidemiological, clinical, and serological studies suggest that OMG and
GMG are two separate diseases. Both forms of
myasthenia gravis are sometimes associated with thyroid autoimmunity or
thyroid-associated ophthalmopathy (
TAO). We have therefore tested the sera of patients with
GMG and OMG by Western blotting for
antibodies against porcine eye muscle
membrane proteins in general, and by
enzyme-linked
immunosorbent assays (ELISA) specifically for reaction with two skeletal muscle
antigens which are prominent
marker antigens for
TAO, namely, the
calcium-binding protein calsequestrin and the so-called "64-kDa
protein." The 64-kDa
protein has recently been identified as the
flavoprotein subunit of mitochondrial
succinate dehydrogenase. Patients with ophthalmopathy and myasthenia were excluded. Nine of the patients had associated Graves'
hyperthyroidism without evident ophthalmopathy and one had Hashimoto's
thyroiditis.
Antibodies against porcine eye muscle membrane
antigens of M(r) 15-110 kDa were detected in patients with
GMG or OMG, one or more
antibodies being detected in 100% of patients with
GMG and in 88% of those with OMG. The most frequently found
antibodies were those targeting eye muscle
membrane proteins of 15, 67, and 110 kDa.
Antibodies reactive with purified
calsequestrin (63 kDa) were detected in 21% of patients with OMG but in no patient with
GMG.
Antibodies recognizing purified
succinate dehydrogenase (67 kDa) were found in 42% of patients with OMG, in 100% (5 of 5) of patients with
GMG, and in 48% of all patients with
myasthenia gravis not associated with Graves'
hyperthyroidism. There was no close correlation between any eye muscle-reactive antibody and
antibodies against the AchR in either group of myasthenic patients. The findings support the notion that immunoreactivity against skeletal muscle
proteins other than the AchR may play a role in the development of the
muscle weakness in AchR antibody-negative patients with OMG and
GMG, although it is unlikely that any of the
antibodies demonstrated in this study are directly implicated. Similarly, while the demonstration of
antibodies reactive with eye muscle
antigens associated with
TAO in patients with OMG raises the possibility that the link between the ocular lesions of
myasthenia gravis and
Graves' disease may be autoimmunity against a common
antigen(s), it is more likely that both disorders are mediated by cytotoxic T cells recognizing another cell membrane
antigen, such as the novel thyroid and eye muscle shared
protein G2s, and that serum
antibodies reactive with
succinate dehydrogenase Fp subunit and
calsequestrin are markers of an immune-mediated eye muscle reaction.