The spectrum and significance of autoantibodies reacting with the thyrotropin receptor.

Autoantibodies that occur in autoimmune thyroid disease and that interact with the TSH receptor are reviewed. Current limited understanding of the nature of the TSH receptor is detailed, and available assays for the different types of antibodies are described. The incidence, clinical significance, and interactions of the various antibodies are summarized.

Relapse of Graves' disease 23 years after treatment with radioactive iodine (131I).

The use of radioactive iodine (131I) in the treatment of Graves' disease results frequently in hypothyroidism requiring thyroid hormone supplementation. Relapse of Graves' disease months after inadequate treatment with 131I is well-recognized. However, late relapse of Graves' disease in a patient rendered hypothyroid by 131I years after therapy has not been reported. The authors discuss a patient who had a relapse of his Graves' disease 23 yr after treatment with 131I. Over the interval the patient had been on 1-thyroxine replacement for hypothyroidism and had persistently high levels of long acting thyroid stimulator or thyroid stimulating antibody. The authors speculate that the immune nature of Graves' disease may play a role in the observed clinical response to 131I.

[Autoimmune thrombocytopenia and diffuse-toxic goiter]. / Autoimmunnaia trombotsitopeniia i diffuzno-toksicheskii zob.

The authors describe 10 patients with associated diffuse toxic goiter and thrombocytopenic purpura and a female patient with associated goiter and a three-shoot autoimmune peripheral cytopenia. In 8 patients thyrotoxicosis preceded the appearance of thrombocytopenia, in 3 patients, both the conditions were diagnosed at a time. In 4 patients, the measurements were taken of the IgG content on the surface of platelets according to Dixon et al. In 3 patients, the IgG content turned out to be appreciably elevated, in one patient, the content of IgG was within normal, however the latter patient was examined after prednisolone intake that had given rise to an increase in the platelet count. Two patients who received radioactive iodine and three patients treated by thyrostatic drugs were later on subjected to splenectomy. In 4 patients, thrombocytopenic purpura remitted after subtotal strumectomy. One female patient was subjected to sectoral resection of the thyroid. Two years after surgery the patient, who was in an euthyroid state, developed thrombocytopenia which required splenectomy. It is possible that in the latter case there was no direct relation between the two diseases. The relationship between the two autoimmune diseases, diffuse toxic goiter and thrombocytopenic purpura, remained unclear in other 10 cases. The relationship between the diseases under consideration and approaches to specifying the character of such a relationship are under discussion.

Comparison of LATS activity and TSH receptor antibody in Graves' disease.

TSH-receptor antibody (TRAb) activity and LATS activity of Graves' sera were compared. All of 50 LATS-positive cases were TRAb positive, although only 63% of LATS-negative cases were TRAb positive. Binding of 125I-TSH to the TSH receptors was inhibited dose-dependently by LATS-immunoglobulin. However, no correlation between TRAb activity and LATS activity was observed. TRAb was positive in 2 LATS-positive cases even when the symptoms of hyperthyroidism were controlled by treatment (antithyroid or radioisotope). The positive TRAb was not changed in 4 Graves' disease patients whose LATS activity had disappeared following antithyroid treatment. These clinical studies show that TRAb is more sensitive than LATS and suggest that LATS may be one of a heterogenous population of antibodies to the TSH receptor in Graves' disease.

Absence of allotypic variation in the autoantigen for thyroid stimulating autoantibodies.

The question of whether autoimmune reactions result from abnormality of the autoantigen or of the autoantibody is fundamental. When reaction of the thyroid stimulating autoantibodies (TSaab) of Graves' disease with their autoantigen is measured in the mouse bioassay which has a very sensitive dose-response curve this provides a favourable system for detecting any influence of allotypic variation in the autoantigen on the affinity of the corresponding autoantibodies. Seven high potency long acting thyroid stimulator (LATS) sera were tested for degree of neutralization by soluble extracts from nine thyroids, using the mouse bioassay to measure changes in LATS activity. The thyroid extracts differed in neutralizing potency and the LATS sera differed in susceptibility to neutralization, but these variations were consistent enough to enable ranking and there were no significant exceptions from especially strong or weak reactions between any individual thyroid extract and any individual LATS serum. Even autologous reactants had no greater or lesser affinity than homologous ones. Five LATS protector (LATSP) sera, tested against six thyroid extracts, including their own, again showed no evidence of allotypic variation in the autoantigen, nor did 55 LATSP sera tested with one of four thyroid extracts. Altogether we have looked at over 200 individual reactions between soluble thyroid antigen and thyroid stimulating autoantibody (LATS and LATSP). We have not found a single significant instance of any exceptionally strong or weak affinities, even with autologous antigen. The findings are in accord with Burnet's theory that autoimmune reactions are due to the emergence of forbidden clones of lymphocytes, reactive with normal self antigens.

[Myxedema tuberosum atypicum (Jadassohn-Doesserkker, 1916) in the clinical picture of the myxodermias and in the normal course of Graves-Basedow's disease]. / O myxedema tuberosum atypicum (Jadassohn-Doesserkker, 1916) no quadro das mixodermias e no ciclo formal da moléstia de Graves-Basedow.

An extraordinary case: large cutaneous tumors, intense "endocrine" exophthalmos, macroglossia, acropachie, prétibial mucinosis, diffuse myxodermia, symptoms of systemic involvement.

Graves' ophthalmopathy.

Graves' ophthalmopathy usually occurs in association with hyperthyroidism. Its occasional occurrence in the absence of thyroid disease suggests, however, that it may be a separate autoimmune disorder. While the evidence supporting an autoimmune pathogenesis is considerable for the ophthalmopathy, it is not so impressive as that for Graves' hyperthyroidism: orbital antibodies have not been convincingly demonstrated and autoantigens have not been identified. On the other hand, in patients with Graves' ophthalmopathy the orbital tissues and eye muscle membranes are infiltrated with lymphoid cells and show evidence of cell-mediated immune reactions. Although there is some evidence that binding of thyroid stimulating hormone fragments and thyroglobulin-antithyroglobulin immune complexes to eye muscle membranes may be important in the pathogenesis of the ophthalmopathy, this needs to be confirmed. The mechanism for the association of hyperthyroidism and ophthalmopathy is unknown, but the association likely reflects an influence of thyroid hormones on the immune system. In view of the autoimmune pathogenesis the logical treatment of Graves' ophthalmopathy appears to be immunosuppression.