The pathophysiological significance of a thyroglobulin-acetylcholinesterase shared epitope in patients with Graves' ophthalmopathy

Theoretical considerations suggest that thyroglobulin and acetylcholinesterase may share common epitopes and thus provide an autoantigenic link between the thyroid gland and eye orbit and consequently an explanation for the association of Graves' ophthalmopathy with autoimmune thyroid disease. We have demonstrated that the two proteins share epitopes by screening a λgt 11 human thyroid cDNA library with a rabbit antibody to Torpedo-acetylcholinesterase and isolating two virtually identical clones. These contain cDNAs encoding fragments of thyroglobulin between residues 2376 and 2464, corresponding to acetylcholinesterase residues 206 to 294. This thyroglobulin peptide has been produced as a recombinant fusion protein and used to establish an enzyme-linked immunosorbent assay to measure antibodies in patients with autoimmune thyroid disease in which antibodies to biochemically prepared intact thyroglobulin have also been assayed. 64 percent of patients with Graves' disease (both with and without ophthalmopathy) and 36% of patients with Hashimoto's thyroiditis have antibodies to the thyroglobulin peptides, antibodies to intact thyroglobulin being detected in 20% and 95%, respectively. Levels of antibodies to the thyroglobulin peptide did not correlate closely with the presence of eye disease, but were more prevalent and of higher titres in patients having active severe disease. We have shown by in situ immunolocalization that immunoglobulins from patients with Graves' ophthalmopathy bind to end plate regions of muscle concurrently shown to be rich in acetylcholinesterase. In conclusion, we have characterized an epitope shared between thyroglobulin and acetylcholinesterase which is an autoepitope recognized by a higher proportion of patients with Graves' disease than with Hashimoto's thyroiditis.