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Autoimmune thyroid disease is characterized by the tendency to cluster in families and by IgG class autoantibodies to antigens such as thyroid peroxidase (TPO). The epitopes recognized by polyclonal serum autoantibodies can be quantitatively fingerprinted using four recombinant human TPO autoantibodies (expressed as Fab) that define A and B domain epitopes in an immunodominant region. To determine whether these fingerprints are genetically transmitted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amish families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibition of serum autoantibody binding to [125I]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combined) and recognition of domain A or B (individual Fab). Complex segregation analysis was performed using a unified model (POINTER). For the 4 Fab combined inhibition phenotype, the no transmission model was rejected (chi2(4) = 20.67; P < 0.0032), and the most parsimonious model includes a major gene effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B2. Thus, for this ratio (reflecting recognition of the B domain), the no transmission model was rejected chi2(4) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypothesis, suggesting that major genes might be involved in familial transmission of this trait. In conclusion, our findings suggest that autoantibody recognition of the TPO immunodominant region and the TPO B domain is genetically transmitted. These data may open the way to the identification by candidate analysis or positional cloning of at least one gene responsible for the development of Hashimoto's thyroiditis.

Ectopic intrathyroidal thymus tissue that forms mass lesions as a consequence of aberrant thymic migration during embryogenesis is rarely reported in the literature.We present the case of a 6-year-old boy with a right thyroid nodule and bilateral cervical lymph nodes. Thyroid hormone, antibodies, and routine chemistry tests were normal. Real-time thyroid ultrasound showed a right calcified nodule measuring 8 x 5 x 7 mm and multiple bilateral cervical lymph nodes. I131 scan showed mild decreased uptake in the right upper lobe. On fine-needle aspiration biopsy we discovered an atypical lymphoid proliferation that was suspicious, although not diagnostic, of a lymphoma. Immunostain for calcitonin was negative. Flow cytometry of the thyroid nodule aspirate demonstrated an abnormal polyclonal T cell population with dual expression of CD4 and CD8, and a subpopulation of cells that expressed TdT suggesting the possibility of lymphoblastic lymphoma. DNA analysis, as well as polymerase chain reaction for T cell and B cell gene rearrangement, did not demonstrate changes in the gene for the heavy chain of immunoglobulin of B cells and gamma chain of the T cell receptor. Lymph node aspirate showed unremarkable T and B lymphoid cells.The diagnosis of ectopic intrathyroidal thymus was made after the operation.Ectopic thymus tissue should be considered in the differential diagnosis of thyroid masses, especially in children.

We reported a patient who gave birth to 3 children with transient neonatal hypothyroidism. She had 3 different antibodies (Ab) to the thyrotropin receptor (TSHR) in her serum, viz., TSH binding-inhibiting (TBIAb), thyroid-stimulating (TSAb) and an additional stimulating Ab (SAb). The SAb differed from TSAb in that its in vitro stimulating effect in human thyroid and FRTL5 cells was not inhibited by TBIAb [similar data now obtained with Chinese hamster ovary (CHO) cells transfected with cloned human TSHR]. Because of symptomatic goiter enlargement the patient underwent subtotal thyroidectomy. About 50% of the gland was infiltrated with lymphocytes; thyroid follicles had columnar epithelium, despite suppression of TSH by thyroxine and the presence of the potent TBIAb. Fifteen months later, when all 3 Ab showed a decline of approximately 3 fold, she gave birth to hypothyroid twins. These data support the following conclusions: 1) thyroidectomy and immunosuppression of pregnancy do not prevent neonatal thyroid disease if TSHR Ab (TRAb) are of high titer; 2) the thyroid is not a major site of TRAb production; 3) SAb is a thyroid stimulator, distinct from TSAb in that it does not share binding epitopes on the TSHR with either TSH or TBIAb; 4) SAb was the probable cause of thyroid growth in this patient.

The zoological specificity of human thyroid-stimulating antibody (TSAb) that occurs in the blood in Graves' disease was examined by assessing its effect on the thyroid of the dog, guinea pig, calf, and mouse as well as that of man. With all but murine glands, thyroid stimulation was assayed by measuring the increase in the concentration of cAMP in the thyroid slices or fragments after 2 h of incubation in buffer containing TSAb. Effects on the thyroid of the mouse were monitored by the in vivo bioassay for LATS. Sera from 33 patients with Graves' disease were obtained and concentrates of TSAb were prepared by precipitation of IgG with 1.64 M (NH4)2SO4. These all stimulated the human thyroid, 13 were LATS-positive, and they variably affected the tissues of other species; of 27 tested, 14 stimulated the thyroid of the dog, 8 out of 23 stimulated the thyroid of the guinea pig, and 12 out of 16 stimulated the gland of the calf. The more potent the TSAb as assayed with human tissue, the more likely was it to stimulate other species of thyroid; however, frequent exceptions occurred. In a separate analysis of 35 LATS-positive preparations of TSAb, correlation between the responses in the LATS and human thyroid slice assays was statistically significant (P less than 0.001). The data are compatible with the view that stimulation by TSAb of nonhuman thyroids, including the murine as in the LATS bioassay, reflects cross-reaction of this immunoglobulin with an antigen that has sufficient similarity to the human molecule to be recognized by the human antibody.

RATS were chronically fed low-iodine diet or purina chow with propylthiouracil; after 30–40 days the thyroid concentration of cyclic AMP was increased only about 2-fold. The affinity (Ka) of protein in the thyroid (30,000 x g supernatant solution of an homogenate) for cyclic AMP was 3.6 × 10−8 M and this was little affected (increase to 4.5 × 10−8M) by goitrogenesis. y in vitro labelling with tritiated cyclic AMP less than 20% of endogenous cyclic AMP was found to be protein-bound. From these studies the importance of the free nucleotide and of phosphodiesterase becomes apparent.

Dispersed anterior pituitary cells were prepared by treatment of hog pituitaries with collagenase. The cell yield based on DNA recovered in intact cells after collagenase treatment was 5–10%. Ninety percent of the cells appeared intact by phase contrast microscopy. The three major cell types were identifiable by Mallory-Heidenhain staining. The dispersed cells incorporated glucose carbon into CO2 and leucine into protein more rapidly than corresponding slices. Increasing the glucose concentration of the medium caused a progressive rise in cellular growth hormone (GH) content and in leucine incorporation into protein. The dispersed cells were capable of releasing immunoreactive GH and bioassayable thyroid-stimulating hormone (TSH). Crude acid extracts of stalk-median eminence had variable effects on the release of these hormones. Some extracts enhanced GH release while having a minimal effect on TSH release; others had the reverse effect. Stimulation of adenyl cyclase activity paralleled TSH release, but not GH release. In addition, during short incubations dibutyryl cyclic AMP and inhibitors of phosphodiesterase activity had no effect on GH release, but enhanced TSH release. Other cyclic nucleotides did not stimulate the release of either hormone. Prostaglandin E1 stimulated GH and TSH release as well as adenyl cyclase activity. These results suggest that the mechanisms controlling GH and TSH release differ, and that cyclic AMP may not be involved in GH release.

This review will be divided into the following segments: 1. Overview of what is known regarding the effects on the fetus of the transplacental passage of circulating antibodies that occur in autoimmune thyroid disease. 2. Description of what is known about the progression of development of the fetal thyroid-pituitary axis; relevant comparison will be made of the time frame for fetal and maternal contributions to the concentration of IgG in the fetal circulation. 3. Descriptions, with references to the above reviews, of fetal and neonatal thyroid disorders based on maternal autoimmune thyroid disease, collating published reports with experience garnered in this laboratory.

Publisher Summary This chapter discusses hyperkinetic features of Graves' disease. It describes two categories of assays for thyroid-stimulating antibody (TSAb)—(1) the assay in which there is a more or less direct measure of thyroid stimulation; and (2) the assay in which TSAb interferes with binding of radioactive thyrotropin to its receptor in a preparation of human thyroid membranes. Although it has not been directly proven beyond doubt, it should be accepted that TSAb inhibits the binding of thyrotropin to its receptor and should be positive in a thyrotropin-binding inhibition (TBI) assay. It seems likely that the combination of an antibody with an antigen on the plasma membrane, at a site remote from the receptor for thyrotropin, may perturb the entire membrane so that the binding of thyrotropin is affected. The chapter also presents the results of studies regarding the clinical significance of TSAb.

We correlated thyroid-stimulating antibody (direct thyroid stimulation method) with the clinical course of 187 patients with Graves' disease. Of 64 patients with newly diagnosed hyperthyroidism, 59 were positive; 36 of 38 patients tested early in therapy were positive. Twenty-eight patients received antithyroid drug therapy, and thyroid-stimulating antibody was measured at cessation of therapy; 13 patients, negative in the assay, remained in remission, and of 15 relapsed cases 12 were positive. Of 57 patients previously treated by various means for hyperthyroidism, 34 were positive, and they primarily had had relapse after initial treatment, then ablative therapy causing hypothyroidism. Six of 10 patients with euthyroid ophthalmopathy had a positive assay and an abnormal thyrotropin-releasing hormone (TRH) test or thyroid suppression test; the four negative patients had a normal TRH test. Thus measurement of thyroid-stimulating antibody appears effectively to reflect activity of the underlying disturbance in Graves' disease.

Long-acting thyroid stimulator (LATS) is a 7S (IgG) γ-globulin of unknown origin found in a large number of patients with pretibial myxedema. In this study, statistically positive responses for serum LATS activity were demonstrated in 18 (94%) of 19 patients. There was, however, a poor correlation between the severity of the skin lesions and the level of serum LATS. In all patients tested, serum immunoglobulins IgG, IgA, and IgM were within normal limits. With immunofluorescent techniques, attempts were made to demonstrate IgG, IgA, IgM, fibrinogen, and complement C'3 in affected tissues, but results were uniformly negative. No LATS response could be demonstrated from tissue extracts from areas of pretibial myxedema. These latter two findings do not support the concept of the production of pretibial myxedema as a result of a local antigenantibody tissue reaction.