Studies of cytotoxic antibodies against eye muscle antigens in patients with thyroid-associated ophthalmopathy

Z. G. Zhang, G. Medeiros-Neto, A. Iacona, N. Lima, Y. Hiromatsu, M. Salvi, H. Triller, N. Bernard, J. R. Wall

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Abstract

We have studied the prevalence and significance of cytotoxic antibodies against human eye muscle cells, as detected in antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated antibody-dependent cytotoxicity (CMAC) in 51Cr release assays, in patients with Graves' ophthalmopathy or Hashimoto's thyroiditis. A high prevalence of positive ADCC tests was found in all groups of patients with ophthalmopathy tested. Tests were positive in 64% of patients with Graves' ophthalmopathy from an area of severe iodine deficiency (Sao Paulo) and in 64% of such patients from an iodine replete area (Montreal). In patients with so-called 'euthyroid ophthalmopathy', i.e. eye disease associated with thyroiditis, ADCC tests were positive in 75 and 38% of patients from the two areas, respectively, while tests were positive in 40 and 22%, respectively, of patients with Graves' hyperthyroidism without evident eye disease. In normal subjects, levels of 51Cr release was always at background levels. In a group of patients from the high-iodine area, levels of antibodies in ADCC correlated positively with the intraocular pressure (mmHg) in primary position as a parameter of eye muscle dysfunction. In patients with ophthalmopathy, positive ADCC tests were associated with antibodies to eye muscle membrane antigens of 55, 64 and 95 kD as detected by immunoblotting, although the correlation was not close for any antigen. In contrast, CMAC tests were negative in all patients with ophthalmopathy. We also tested 9 mouse and 10 human monoclonal antibodies, reactive with orbital antigens in an enzyme-linked immunosorbent assay, for cytotoxic activity, in ADCC and CMAC, against eye muscle and thyroid cells. All monoclonal antibodies were of the IgM class and negative in ADCC assays. When tested in CMAC against eye muscle cells, one of 9 mouse and 5 of 8 human monoclonal antibodies showed significant activity while tests were positive in one of 9 and one of 10 monoclonal antibodies, respectively, against thyroid cells. These data support a role for antibodies which are cytotoxic to eye muscle cells in the pathogenesis of thyroid-associated ophthalmopathy. Moreover measurement of ADCC may provide a useful laboratory test to confirm the diagnosis of ophthalmopathy in patients with autoimmune thyroid disease. Lack of close correlation between ADCC and immunoblotting activities of ophthalmopathy patient sera suggests that antibodies which are cytotoxic, in ADCC, may not react with any of the eye muscle antigens so far identified. Availability of human and mouse monoclonal antibodies with cytotoxic activity against eye muscle cells will provide important probes for further studies of the role of cytotoxic antibodies in the pathogenesis of thyroid-associated ophthalmopathy.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalActa Endocrinologica, Supplement
Volume121
Issue number2
Publication statusPublished - 1989

ASJC Scopus subject areas

  • Endocrinology

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    Zhang, Z. G., Medeiros-Neto, G., Iacona, A., Lima, N., Hiromatsu, Y., Salvi, M., Triller, H., Bernard, N., & Wall, J. R. (1989). Studies of cytotoxic antibodies against eye muscle antigens in patients with thyroid-associated ophthalmopathy. Acta Endocrinologica, Supplement, 121(2), 23-30.