Cell-mediated lysis of lipid vesicles containing eye muscle protein: Implications regarding pathogenesis of Graves ophthalmopathy

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Abstract
Artificial vesicles were lysed upon cell-mediated immunological attack by human lymphocytes. These vesicles are made from a mixture of dimyristoyl lecithin, dipalmitoyl lecithin and cholesterol, and have eye muscle membrane protein (EMP) inserted into the bilayer wall and contain intravesicular 99mTc marker. Injury to the vesicular membrane was assessed by measurement of 99mTc release. Thyroglobulin (Tg) and Tg-anti-Tg complex (TgA) bind to EMP-vesicles to an extent equal to or greater than to native eye muscle membranes in vitro; this binding requires the presence of normal human Ig[immunoglobulin]G. The role of Tg, TgA, IgG, and peripheral blood lymphocytes in altering membrane permeability was analyzed. Incubation of vesicles for up to 3 h alone, with added IgG alone or with further addition of Tg or TgA did not result in 99mTc release. Addition of lymphocytes from normal donors to the above 4 preparations showed release in the presence of TgA. Lymphocytes from each of 8 patients with Graves ophthalmopathy caused release in the presence of TgA and in the presence of Tg. Separation of a patient''s lymphocytes into high- and low-affinity rosette-formers (T[thymus-derived]- and K[antibody-dependent killer]-cells, respectively) showed that cell-mediated vesicle lysis in the presence of TgA was greater with K-cells than with T-cells, while vesicle lysis in the presence of Tg was greater with T-cells than with K-cells. Vesicles made with inserted Tg but lacking EMP were not lysed by such T-cells. Lymphocytes failed to induce permeability changes in vesicles containing other inserted proteins obtained from human nonextraocular muscle, liver, spleen or adrenal, even if Tg or TgA were present. Muscle cell damage in Graves ophthalmopathy may be immunological, cell-mediated and of 2 types: K-lymphocytes reacting to immune complex, TgA, on the eye muscle cell surface (i.e., antibody-dependent cytotoxicity) and sensitized T-lymphocytes reacting to Tg on the eye muscle cell surface. An antigenic role for EMP is possible.