Nine patients with severe Graves' ophthalmopathy were treated by intensive plasma exchange, followed by immunosuppression. Severity of ocular involvement and response to therapy were evaluated clinically by numerical scoring (ophthalmopathy index). Serum thyroid stimulating immunoglobulins (TSI) and urinary excretion of glycosaminoglycans (GAG) were measured immediately before and immediately after plasmapheresis.Plasma exchange was rapidly accompanied by marked clinical improvement in 8/9 patients. The most marked effects were on soft tissue involvement, proptosis, intraocular pressure, and visual acuity. The ophthalmopathy index decreased from 9.7 \ m=+-\ 4.1 to 5.7 \ m=+-\ 2.2 (P <0.001) after plasmapheresis. Serum TSI levels were initially elevated in 6 patients and remained positive in 3 patients after treatment. Urinary GAG excretion was initially 2-to 12-fold normal levels and was decreased by 60%. After plasmapheresis, patients received immunosuppressive drugs for 3\p=n-\6months. The follow-up period, after withdrawal of drugs, ranged from 5 to 38 months with a median of 17 months. The ocular condition remained stable in 6 patients. Three patients had a relapse 1 year after plasmapheresis: they were treated a second time by plasma exchange with subsequent improvement. In conclusion, intensive plasma exchange provided prompt and effective improvement in patients with severe progressive Graves' ophthalmopathy. This therapeutic procedure, followed by immunosuppression, gave long lasting results.

Abstract. The titres of anti-α-galactosyl antibodies were measured by passive haemagglutination in 50 control subjects and in 128 patients presenting with various thyroid disorders. Titres of control subjects ranged from 1/10 to 1/80, regardless of age and blood group. Elevated titres (> 1/80) were constantly noted in 6/6 patients with progressive exophthalmos, in 5/5 patients with untreated Graves' disease, and in 11/12 patients with progressive nontoxic goitre. By contrast, the titres were within the normal range in primary myxoedema (17 patients) and in residual exophthalmos (11 patients), whereas they were only erratically increased in 1/31 patients with treated or cured Graves' disease and in 5/36 patients with nonprogressive nontoxic goitre. Finally, elevated titres were also found in 3/7 patients presenting with autoimmune thyroiditis. No correlations could be established between elevated titres and the thyrotropin binding inhibiting immunoglobulin activity, the antithyroglobulin antibody titres or the antimicrosomal antibody titres. As in the control subjects, the anti-α-galactosyl antibodies mainly belonged to the IgG class. Affinity purified anti-α-galactosyl antibodies were capable of binding to trypsinized human and porcine thyroid cells in culture, as shown by indirect immunofluorescence. On the other hand, they were not able to react with untreated thyroid cells. The data show that the measurement of anti-α-galactosyl antibody titres could represent an easy and useful tool to determine whether an autoimmune thyroid disorder is in progression. Besides, they suggest that some of the antigenic determinants implicated in the enhanced production of anti-α-galactosyl antibodies are present, but normally hidden, within the cell surface of thyroid cells.

Abstract. Studies on the distribution of α-galactosyl epitopes with the structure Galα1→3Galβ1→4GlcNac-R on mammalian thyroid cell membranes are of interest, since a natural antibody interacting with this carbohydrate antigen (i.e. the natural anti α-galactosyl IgG antibody) was found to increase in its titre in patients with autoimmune thyroid disorders. By using a radioimmunoassay for quantification of the α-galactosyl epitope, we found variable concentrations of this epitope on thyroid cell membranes of all nonprimate mammals and New World monkeys studied, but not in Old World monkeys and human thyroid. The absence of the identifiable α-galactosyl epitopes on human and Old World monkey thyroid cells correlates with diminished activity of the enzyme, α1-3 galactosyltransferase, which, in other species, synthesizes the α-galactosyl epitopes within the Golgi apparatus. It is argued that a proportion of anti-thyroid reactivity in human normal and pathologic sera, when assayed with mammalian thyroid cells, may be attributed to natural anti α-galactosyl IgG antibody, which interacts with α-galactosyl epitopes on thyroid tissues used for the bioassay.

A new sensitive and reproducible technique for the determination of thyroid stimulating immunoglobulins is described. This procedure employs cells obtained from primary culture of human thyroid gland. We measured the increase of cyclic AMP after addition of patient sera. The major advantages of this procedure are the improved sampling throughout with the ability to measure eighty samples simultaneously without fractionation of serum. This large sample allows us to test forty sera together and to assay in duplicate, thus increasing the validity of the results. The TSI activity is associated with the immunoglobulins G (IgG) fraction and we obtained a linear dose response curve with IgG as well as with whole serum. The results obtained in various thyroid diseases are discussed.

As much as 1% of circulating IgG in man (the natural anti-Gal antibody) is directed against the alpha-galactosyl epitope, with the structure Gal alpha 1----3Gal beta 1----4GlcNAc-R. The alpha-galactosyl epitope is abundantly expressed on cells of nonprimate mammals, prosimians, and New World monkeys. Its expression is diminished in Old World monkeys, apes, and humans. It has been previously suggested that interaction between anti-Gal and aberrantly expressed alpha-galactosyl epitopes on thyroid cells may contribute to the initiation of autoimmune thyroid disorders. To study this possibility, alpha-galactosyl epitope expression on thyroid cell membranes of normal individuals and patients with Graves' disease was assessed by a sensitive radioimmunoassay. alpha-Gal-actosyl epitopes were found both on normal and diseased thyroid cells. Whereas the concentration of these epitopes on Graves' disease thyroid membranes was somewhat higher than that observed in normal glands, the difference was not significant. The activity of the enzyme, alpha 1-3-galactosyltransferase, which synthesizes the alpha-galactosyl epitope, was higher in microsomal fractions obtained from some patients as compared with healthy controls, but not significantly different. In view of the abundance of anti-Gal antibody in the circulation, it is argued that, under physiologic conditions, the interaction of this antibody with alpha-galactosyl epitopes does not elicit pathologic effects. However, aberrant expression of the alpha-galactosyl epitope may result in effective anti-Gal binding to thyroid cells (e.g., rearrangement of this structure on the cell membrane or its increased expression).(ABSTRACT TRUNCATED AT 250 WORDS)