Modern reports about molecular mechanisms of the effects of thyroid hormones and the pathogenesis of autoimmune thyroid diseases are reviewed. The significance of fundamental studies in thyroidology for deciphering the pathogenesis of the most prevalent endocrine and other than endocrine diseases is emphasized.

The significance and mechanisms of action of different antithyroid antibodies in diffuse toxic goiter (Graves' disease) and chronic lymphocytic thyroiditis (Hashimoto’s disease) arc analyzed. Antibodies immediately decreasing the level of cAMP in isolated thyrocytes were revealed in the sera of adolescents with juvenile struma, often resulting from lymphocytic thyroiditis. Complement-fixing cytotoxic antibodies are heterogeneous in patients with Graves' diseases and Hashimoto's thyroiditis. Thyrocytes from the tissue of diffuse toxic goiter are resistant to the cytolytic effect of such antibodies from patients with Graves' diseases but not from patients with Hashimoto's thyroiditis. The causes and mechanisms of development of resistance of thyrocytes from diffuse toxic goiter to antibody-dependent complement-mediated cytotoxicity of sera from patients with Graves' disease and the possibility of using this phenomenon as a differential diagnostic test are discussed.

The present paper briefly outlines the main lines of experimental endocrinological research carried out at Endocrinological Research Centre started in the first experimental laboratories and continued up to the present time.

Lymphocytes isolated from diffuse toxic goiter (Graves' disease, GD) stimulate the proliferation of "normal" thyrocytes (isolated from euthyroid goiter) in primary culture, and give them the properties of GD-thyrocytes (loss of sensitivity to the growth-promoting factors of FCS and lesser capacity of binding antibodies from GD patients' serum). The complement-free sera of GD patients (but not the sera of patients with Hashimoto's thyroiditis, HT) induce the death of "normal" thyrocytes more rarely than full-complement sera do. Both types of serum cytotoxicity are manifested on GD-thyrocytes much more rarely than on "normal" cells. The Fas-receptor on GD-thyrocytes in situ is expressed less than on "normal" and especially on HT-cells. The level of soluble Fas-ligand in the serum of some complement-free patients was found to be increased. These sera induce apoptosis in "normal" thyrocytes, but not in GD-cells nor in human skin fibroblasts. In the authors' opinion, the proliferation of GD-thyrocytes in situ is stimulated by intrathyroid lymphocytes, which directly stimulate this process and induce the loss of receptors which mediate the cytotoxic effects of serum factors.

We studied the dependence of serum cytotoxic activity on the contents of soluble apoptosis receptor and its soluble ligand in patients with autoimmune thyroid diseases.

The primary cultures of thyrocytes isolated from the paranodal tissue of euthyroid nodal goiter indicated that the sera from patients with Hashimoto ’s thyroiditis and Graves’ disease had complement-independent cytotoxicity. This effect was found in about 40% of the sera from patients at different stages of drug compensation of autoimmune thyroid diseases. The cytotoxic effect of the sera was not shown in the primary cultures of human skin fibroblasts. The detection rate of complement-independent cytotoxicity in the sera from patients with Hashimoto ’s thyroiditis and Graves’ disease coincided with that of elevated levels of soluble FAS-receptor ligand in the respective sera. Thyrocytes isolated from patients with Graves’ disease turned out to be resistant to the action of 60% of the cytotoxic sera. This resistance may be associated with the lowered FAS-receptor expression on these cells, which has been revealed in special studies.

Autoantibodies to cell surface antigens of human somatotropinoma (ASAS), human prolactinoma (ASAP) and rat adenohypophysis (ASARA) were assayed in the serum of patients with pituitary diseases associated with GH deficiency (GHD), such as pituitary dwarfism and primary empty sella syndrome (ESS), and in the serum of patients with hyperprolactinaemia of different etiologies: idiopathic hyperprolactinaemia, prolactinoma and ESS. The investigation was carried out with a cellular variant of an ELISA. Among children with GHD, the highest percentage of antibody-positive patients was found in the group with idiopathic isolated GHD (89% of ASAS(+) patients and 30% of ASARA(+) patients vs 33.3% and 0% respectively in the group with idiopathic combined pituitary hormone deficiency, and 33.3% and 9% in patients with pituitary hypoplasia associated with isolated GHD or combined pituitary hormone deficiency). Among hyperprolactinaemic patients, the highest ASAP and ASARA frequency was observed in patients with idiopathic hyperprolactinaemia (67.7% and 41.9% respectively) where it was twice as high as in the group of patients with prolactinoma. The proportion of ASAS(+) and ASARA(+) did not differ significantly between the groups of patients with ess with or without GHD. Similarly, there was no significant difference between the number of ESS ASAP(+) and ASARA(+) patients with or without hyperprolactinaemia. The data obtained suggested that autoimmune disorders may be primary, and responsible, at least in part, for pituitary dysfunction in the cases of idiopathic isolated GHD and idiopathic hyperprolactinaemia. At the same time, the autoimmune disorders in the patients with prolactinoma or ESS are probably secondary to the organic pituitary lesion and their significance in the development of the pituitary dysfunction is obscure.

The article is devoted to autoimmune diseases of the thyroid and apoptosis.

The capacity of lymphocytes isolated from diffuse toxic goiter (DTG) tissue to stimulate the proliferation of normal thyrocytes isolated from paranodular tissue adjacent to nodular euthyroid goiter was studied. Normal and DTG thyrocytes were incubated for 24 h with fetal calf serum (FCS) in various concentrations, DTG orparanodular lymphocytes, or both FCS and lymphocytes. The proliferation rate of normal thyrocytes in the presence of FCS alone increased with increase of the serum concentration, while the proliferation rate of DTG thyrocytes did not depend on the concentration of FCS. DTG lymphocytes, but not paranodular ones, stimulated the proliferation of normal thyrocytes. The growth-stimulating effect of DTG lymphocytes was paralleled by loss of normal thyrocytes sensitivity to growth factors (FCS). These data indicate a probable role of intrathyroid lymphocytes in increase of thyrocyte count characteristic of DTG and confirm a previous hypothesis on decrease in expression of surface antigens (receptors) on DTG cells under the effect of intrathyroid lymphocytes.

The clinical significance of measuring thyroid antibodies has been evaluated. With this aim in view, 47 patients with diffuse toxic goiter (DTG) (46 women and 1 man) aged 15 to 65 were examined. Antibodies to TTH receptors were detected in 85 patients with decompensated DTG by the radioligand method based on assessment of blocking of TTH binding to its receptor in the presence of patient’s serum. Antibodies to thyroglobulin (TG) were detected in 55.6% patients before therapy. Blood level of TG was increased in 42% of patients. Antibodies to the microsomal fraction (MS) were detected in 59% of patients. The activity of antibodies to TTH receptor depended on the disease severity, degree of the thyroid enlargement, and size of goiter. The incidence of antibodies to TG and their titers did not depend on the severity of thyrotoxicosis or size of goiter. The incidence of antibodies to MS increased only with enlargement of goiter. The incidence and titers of antibodies gradually decreased in the course of mercasolyl therapy of DTG. After 6 months antibodies to TTH receptors were found in 57% of patients, their activity being decreased, too. The incidence of anti-MS antibodies dropped to 45%, whereas the rate of detection of antibodies to TG was virtually the same. One year after therapy antibodies to TTH receptors were found in 29.4%> of patients. The rate of detection of antibodies to TG and MS decreased to 25 and 20%o, respectively. Hence, a high rate of detection of antireceptor antibodies in DTG and the relationship between the thyroid status and the titer of these antibodies confirm their leading role in the pathogenesis of the disease. The presence of antibodies to TG and MS in no more than half of the patients with DTG and absence of a clear-cut correlations between these antibodies and various clinical hormonal parameters of the disease indicates their significance solely as markers of the autoimmune process in the thyroid but does not specify the nature of its involvement. Antibodies to TTH receptors are the most informative immunological test for the diagnosis of DTG and the markers of immunological remission of the disease.

The significance and mechanisms of action of different antithyroid antibodies in diffuse toxic goiter (Graves' disease) and chronic lymphocytic thyroiditis (Hashimoto’s disease) arc analyzed. Antibodies immediately decreasing the level of cAMP in isolated thyrocytes were revealed in the sera of adolescents with juvenile struma, often resulting from lymphocytic thyroiditis. Complement-fixing cytotoxic antibodies are heterogeneous in patients with Graves' diseases and Hashimoto's thyroiditis. Thyrocytes from the tissue of diffuse toxic goiter are resistant to the cytolytic effect of such antibodies from patients with Graves' diseases but not from patients with Hashimoto's thyroiditis. The causes and mechanisms of development of resistance of thyrocytes from diffuse toxic goiter to antibody-dependent complement-mediated cytotoxicity of sera from patients with Graves' disease and the possibility of using this phenomenon as a differential diagnostic test are discussed.

Antibodies to adeno-pituitary cell surface antigen (PCSA) were studied in 40 untreated children with idiopathic growth hormone (GH) deficiency to elucidate the role of autoimmune disorders in the pathogenesis of GH deficiency. Antibodies to rat PCSA were assayed by ELISA. PCSA was detected in 15% of patients with GH deficiency, in contrast to that in healthy children and children with autoimmune thyroid diseases. The authors consider that in some cases GH deficiency may be caused by autoimmune hypophysitis. A family study revealed PCSA in 25% of mothers of patients with GH deficiency. In a population of healthy women PCSA was detected in 5.7% cases. Hence, a hereditary background of autoimmune abnormality cannot be completely ruled out.

Antibodies to adeno-pituitary cell surface antigen (PCSA) were studied in 40 untreated children with idiopathic growth hormone (GH) deficiency to elucidate the role of autoimmune disorders in the pathogenesis of GH deficiency. Antibodies to rat PCSA were assayed by ELISA. PCSA was detected in 15% of patients with GH deficiency, in contrast to that in healthy children and children with autoimmune thyroid diseases. The authors consider that in some cases GH deficiency may be caused by autoimmune hypophysitis. A family study revealed PCSA in 25% of mothers of patients with GH deficiency. In a population of healthy women PCSA was detected in 5.7% cases. Hence, a hereditary background of autoimmune abnormality cannot be completely ruled out.