Significance of antibodies reactive with a 64 kDa eye muscle membrane antigen in patients with thyroid autoimmunity.

SDS-polyacrylamide gel electrophoresis and Western blotting for antibodies reactive with a 64 kDa protein in pig eye muscle membrane was carried out in patients with lid lag and retraction, but no other signs of ophthalmopathy, associated with thyroid disease or nonimmunologic goiter and in patients with Graves' hyperthyroidism without ophthalmopathy who were studied prospectively to determine the relationship of eye muscle antibodies to clinical features of the ophthalmopathy as they appeared in this group of predisposed patients. Seventy-one percent of euthyroid patients with lid lag and retraction but no established ophthalmopathy had detectable serum antibodies to a 64 kDa eye muscle membrane protein. Much smaller proportions had antibodies to proteins of other MW. In normal subjects with previously detectable antibodies to a 64 kDa protein, serum titers, determined by carrying out immunoblotting at serum dilutions of 1:25-1:6400, were low (less-than-or-equal-to 1:100) in all cases tested. On the other hand, titers were higher (1:200-1:6400) in 16 of 22 patients with established ophthalmopathy and in 5 of 7 patients with lid lag and retraction tested. Titers tended to be lower in patients with ophthalmopathy of greater-than-or-equal-to 3 years duration than in those of less-than-or-equal-to 1 year duration. Antibody titers were low (1:25) in 6 of 7 patients with Graves' hyperthyroidism without evident eye disease tested. Antibodies to a 64 kDa eye muscle membrane protein were predictive of the development of ophthalmopathy in patients with Graves' hyperthyroidism studied prospectively for periods of 8-42 months. All 7 patients who developed ophthalmopathy (6 patients) or lid lag (1 patient) had detectable serum antibodies to the 64 kDa antigen from 2 to 4 months before the onset of eye signs and symptoms, although in 2 of these patients, both the detection of antibody and the clinical features were transient. Appearance of serum antibodies to a 64 kDa eye muscle membrane protein as detected in immunoblotting is an early event in the natural history of ophthalmopathy and may be predictive of the development of the eye disease in patients with Graves' hyperthyroidism. Lid lag and retraction, as the unique signs of an eye muscle inflammatory disorder, may represent an early phase of ophthalmopathy, perhaps caused by an immunologic reaction against a 64 kDa protein in the eye lid levator muscle, although this needs to be proven. Further studies of patients with Graves' hyperthyroidism without evident eye disease and those with thyroid autoimmunity associated with lid lag and retraction are warranted. Although antibodies to a 64 kDa protein are early and important diagnostic markers of eye disease in the autoimmune thyroid population, it is not yet proven that these antibodies are cytotoxic to human eye muscle cells and thus of pathogenetic significance.