EYE MUSCLE ANTIBODIES IN PATIENTS WITH OCULAR MYASTHENIA-GRAVIS - POSSIBLE MECHANISM FOR EYE MUSCLE INFLAMMATION IN ACETYLCHOLINE-RECEPTOR ANTIBODY-NEGATIVE PATIENTS

Myasthenia gravis is an organ-specific autoimmune disorder generally t hought to be caused by an antibody-mediated attack against the skeleta l muscle nicotinic acetylcholine (Ach) receptor (AchR) at the neuromus cular junction. Extraocular muscle weakness and double vision are pres ent in about 90% of patients with myasthenia gravis and are the predom inant complaints in about 20% of patients, when the condition is calle d ocular myasthenia gravis (OMG). While serum antibodies against the A chR are detected in most patients with generalized myasthenia gravis ( GMG), they are not found in about one-third of patients with the ocula r variety, and epidemiological, clinical, and serological studies sugg est that OMG and GMG are two separate diseases. Both forms of myasthen ia gravis are sometimes associated with thyroid autoimmunity or thyroi d-associated ophthalmopathy (TAO). We have therefore tested the sera o f 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 skele tal muscle antigens which are prominent marker antigens for TAO, namel y, the calcium-binding protein calsequestrin and the so-called ''64-kD a protein.'' The 64-kDa protein has recently been identified as the fl avoprotein 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 m uscle membrane antigens of M-r 15-110 kDa were detected in patients wi th GMG or OMG, one or-more antibodies being detected in 100% of patien ts with GMG and in 88% of those with OMG. The most frequently found an tibodies 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 G MG, and in 48% of all patients with myasthenia gravis not associated w ith Graves' hyperthyroidism. There was no close correlation between an y eye muscle-reactive antibody and antibodies against the AchR in eith er 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 anti body-negative patients with OMG and GMG, although it is unlikely that any of the antibodies demonstrated in this study are directly implicat ed. Similarly, while the demonstration of antibodies reactive with eye muscle antigens associated with TAO in patients with OMG raises the p ossibility that the link between the ocular lesions of myasthenia grav is and Graves' disease may be autoimmunity against a common antigen(s) , it is more likely that both disorders are mediated by cytotoxic T ce lls recognizing another cell membrane antigen, such as the novel thyro id and eye muscle shared protein G2s, and that serum antibodies reacti ve with succinate dehydrogenase Fp subunit and calsequestrin are marke rs of an immune-mediated eye muscle reaction. (C) 1998 Academic Press.