Shigenori Nakamura

Autoantibodies against thyroid hormones or iodothyronine. Implications in diagnosis, thyroid function, treatment, and pathogenesis.

Abstract The presence of antithyroid hormone autoantibodies in the sera of patients with thyroid and nonthyroid disorders is a well-known condition. When circulating thyroid hormones bind to the pa...

A case of Graves’ disease associated with polymyositis

A patient with Graves’ disease associated with severe muscle weakness who was finally diagnosed as polymyositis by pathological examination of the muscle is reported. A 28-year-old women was incidentally found to have hyperthyroidism when she consulted a hospital for the evaluation and treatment of anemia in 1979. She was treated with methimazole for approximately a month when she stopped the medication by herself. Approximately two yr later (Nov. 4, 1981) she consulted another hospital with complaints of palpitation and muscle weakness. Diagnosis of hyperthyroidism due to Graves’ disease and thyrotoxic myopathy were made, followed by the treatment with radioiodine (4 mCi of 131I). She was further treated with propylthiouracil (PTU). Four yr after the treatment, serum thyroid hormone concentration declined to the lower level than normal and serum TSH concentration increased. She was subsequently treated with synthetic I-T4. Despite the fact she became euthyroid with the treatment, muscle weakness as well as elevated concentrations of muscle enzymes were not improved. Muscle biopsy was made in July 1983, and she was diagnosed as immune polymyositis and treatment with prednisolone and cyclophosphamide in addition to PTU or I-T4, was started. With the treatment, serum LDH decreased to the normal range. However she still has muscle weakness and serum concentrations of CPK and aldolase are still in higher levels than normal range.

Thyroxine binding to human serum albumin immobilized on sepharose and effects of nonprotein albumin-binding plasma constituents

Abstract125I-thyroxine (125I-T4) binding to human serum albumin (HSA) covalently attached onto CNBr-activated Sepharose (HSA-Sepharose) was studied.125I-T4 binding to HSA-Sepharose was rapid and saturable. Nonlinear curve-fitting analysis of binding isotherms revealed two classes of binding sites. The values of dissociation constants of high and low affinity sites were 2.19±0.53×10−6 M and 2.69±0.78×10−5 M, respectively. The number of binding sites of the high and the low affinity sites were 1.28±0.46 mol/mol and 23.5±9.7 mol/mol of HSA, respectively. Fatty acids and bilirubin competitively inhibited the high-affinity binding of125I-T4 to HSA-Sepharose without affecting the low-affinity binding. 8-anilino-1-naphthalene sulfonic acid (ANS) inhibited the high affinity T4 binding via reduction of the binding capacity. Unlabeled T4 showed little inhibition of ANS binding to HSA, as measured by fluorescence intensity. These results suggest that ANS allosterically inhibits the high-affinity T4 binding to HSA-Sepharose.

Genetic Control of the Production of Anti-Thyroid Hormone Antibodies in Mice Immunized with Human Thyroglobulin

Various strains of mice with different H-2 and Igh-I allotypes were immunized with human thyroglobulin (HTg) and genetic control of the production of anti-thyroid hormone antibodies was examined. Anti-HTg antisera obtained from different strains of mice were examined for the presence of anti-thyroid hormone antibodies. At least one Ir-gene which controls the production of anti-T4 antibodies by immunization with HTg was identified in the I-A subregion. The presence of Ir-genes outside the H-2 was also suspected. Concerning the production of anti-T3 antibodies, only three strains (B10.A, C3H.SW, BALB/cJ) were high responders and therefore we were unable to identify the Ir-gene for them. These results indicate the presence of Ir-gene which controls the immune response in mice against thyroid hormone and suggest that the anti-thyroid hormone antibodies observed in various thyroidal and non-thyroidal disorders could be anti-HTg antibodies. The significance of genetic control of the production of anti-thyroid hormone antibodies in mice immunized with HTg is discussed.

Serum concentrations of osteocalcin in patients with hyperthyroidism, hypothyroidism and subacute thyroiditis

Serum concentration of osteocalcin (OC) was measured in sera from untreated patients with Graves’ disease, hypothyroidism due to Hashimoto’s thyroiditis, and subacute thyroiditis. Serum concentration of OC in Graves’ disease and hypothyroidism were 14.1+5.6 μ/L and 3.8±2.7 μg/L, respectively which were significantly different from that of healthy subjects (Graves’ disease, p<0.001, hypothyroidism, p<0.01). Serum concentration of OC in patients with subacute thyroiditis was 8.0+3.5 μ/L which was not statistically different from age-matched normal controls. Serial measurement of serum OC for 24 mo in 15 patients with Graves’ disease after initiation of antithyroid drugs disclosed that the decline of serum OC was obtained only 24 mo after antithyroid drug therapy. On the other hand, in hypothyroid patients, increased serum OC was observed after 1-2 months treatment of L-T4. Correlation coefficients between serum concentrations of OC and T3, T4, FT3 or FT4 in all the patients with thyroid disorders were 0.66, 0.51, 0.50 and 0.54, respectively, which were statistically significant (all, p<0.001). These results suggest that osteoblastic activity is enhanced in hyperthyroidism and suppressed in hypothyroidism. In hyperthyroid patients, despite of normalization of FT4 concentration in relatively short period (within 3-4 mo), it took 24 mo after initiation of antithyroid drugs for OC to normalize, suggesting not only thyroid hormone per se but also some unknown factor(s) participates in serum OC secretion. In contrast to thyrotoxic patients, rapid increase in serum OC after initiation of supplemental L-T4 treatment in hypothyroidism was observed, suggesting a direct effect of thyroid hormone on the osteoblasts in patients with hypothyroidism.

Effect of 8-anilino-1-naphthalene sulfonic acid (ANS) on the interaction between thyroid hormone and anti-thyroid hormone antibodies

Effect of 8-anilino-1-naphthalene sulfonic acid (ANS) on the interaction between thyroid hormone and anti-thyroid hormone antibodies was examined. Addition of 5.1 x 10(6) or 6.3 x 10(6) molar excess of ANS, respectively, enhanced the binding of 125I-T3 or 125I-T4 to their respective autoantibodies. However, further increase in ANS concentration resulted in a decrease in binding. These results suggest that the optimum concentration of ANS for the detection of anti-thyroid hormone antibodies is 5 approximately 6 x 10(6) molar excess of ANS to 125I-T3 or 125I-T4. On the other hand, addition of 10(4) molar excess of ANS concentration decreased the binding of 125I-insulin to anti-insulin antibodies. It was therefore suggested that the effect of ANS could be a nonspecific one and likely due to its negative charge.

Autoimmune Recognition of Thyroglobulin and Thyroid Hormones in Rabbits

Two rabbits (RG-1, RG-2) were immunized with rabbit thyroglobulin (RTg) purified from thyroid glands of four other normal rabbits of the same strain, and bled serially. Antisera were obtained at different times after the first immunization and kept separately and studied. Production of anti-RTg as well as anti-thyroid hormone antibodies such as anti-thyroxine (T4) and anti-triiodothyronine (T3) antibodies was observed in both rabbits. Physicochemical parameters of anti-RTg antibodies with RTg, T4, and T3 were calculated in two selected antisera (70-day and 253-day) of each of the rabbits, using a Scatchard plot. Extraction of serial sera from both rabbits disclosed the presence of larger amounts of T3 and T4 in immune sera than in preimmune serum. Examination of pathology of thyroid glands and kidneys in both rabbits was negative for the lesions of autoimmune thyroiditis and immune nephritis. These results indicate that anti-Tg as well as anti-thyroid hormone autoantibodies can be raised without thyroid pathology in rabbit by immunization with autologous Tg.

GENETIC CONTROL OF MOUSE ANTIBODY PRODUCTION TO HUMAN THYROGLOBULIN

Genetic control of immune responses in mice against human thyroglobulin was studied using the enzyme‐linked immunosorbent assay and passive haemagglutination test. Our results revealed that mice of H‐2a, H‐2d, H‐2q, H‐2k and H‐2r haplotypes were high responders for antibody production to human thyroglobulin, while mice of H‐2b and H‐2s haplotypes were low responders. High responsiveness to human thyroglobulin was transmitted to F1 mice in a dominant fashion. Study of the genetic mapping of the immune responses to human thyroglobulin using various congenic mice showed thatI‐A subregion gene(s) control the immune response to human thyroglobulin.

Paraneoplastic Neurologie Syndrome and Autoimmune Addison Disease in a Patient with Thymoma

A 48-year-old man with autoimmune Addison disease developed the following paraneoplastic neurologic syndromes (PNNS): limbic encephalitis, opsoclonus/myoclonus, and sensorimotor and autonomic neuropathies. An anterior mediastinal mass detected on a chest computed tomographic scan was found on resection to be a noninvasive lymphocytic thymoma. The PNNS went into remission 1 year after the thymectomy. This is the first case of thymoma associated with autoimmune Addison disease and PNNS to be described in the literature.

Thyroid hormone metabolism and nuclear binding in Gunn rats

We examined the serum concentrations of total, free thyroid hormones and TSH, activity of hepatic T45′-deiodinase, and T3 binding to hepatic nuclei in homozygous (j/j) and heterozygous (j/+) Gunn rats. Both total T3 and free T3 (FT3) concentrations in sera from j/j rats were significantly lower than those of j/+ rats on 5–10, 15–20, and 25–30 days after birth. Both total T4 and free T4 (FT4) concentrations in j/j and j/+ rat sera were not significantly different on 5–10 days. However, in j/j rats they were significantly higher than those of j/+ rats on days 15–20 and 25–30. Serum reverse T3 (rT3) concentrations were higher in j/j than in j/+ rats on days 5–10, 15–20, and 25–30. Serum TSH concentration in j/j and j/+ rats on 15 days post-natal were 1.42±1.28 and 1.65±1.24 µg/l (mean±SD), respectively, wich were not significantly different from each other. T3 formation from T4 in hepatic microsomal fractions obtained 15 days after birth was significantly lower in homozygotes than in heterozygotes (4.89±1.18 vs 11.15±2.38 pmol/mg protein/min, p < 0.005). Binding constants (Ka) as well as maximal binding capacities (MBC) for T3 of hepatic nuclei from 15 day-old j/j and j/+ rats were similar (ka; 3.58×109vs3.15×109 M−1, MBC; 0.316 vs0.380 pmol/mg DNA). From these results we suggest that decreased conversion from T4 to T3 is one of the major reasons for high serum levels of T4 and rT3, and low levels of T3 in j/j rats, and that nuclear T3 binding and pituitary TSH secretion are unaltered in j/j rats.