Hironori Kimura

Exacerbation of Thyroid Autoimmunity by Interferon α Treatment in Patients with Chronic Viral Hepatitis

In the present studies, the long term effects of IFN alpha on thyroid function and thyroid autoantibodies were evaluated in 42 patients with chronic viral hepatitis type C treated with IFN alpha for at least 4 months. Before IFN treatment, 41 patients tested were all euthyroid. Five (12%) out of 24 patients tested had positive tests for thyroid autoantibodies. MCHA/TPOAb was detected in all 5 and TGHA/TGAb in 3 out of these 5 patients. Six to 10 x 10(6) units (U) of recombinant or natural IFN alpha were given intramuscularly daily for the first 2 to 4 weeks, followed by 3 to 10 x 10(6) U thrice weekly for the subsequent 14 to 22 weeks. Thyroid dysfunction and/or rises in titers of thyroid autoantibodies were observed in 6 patients during IFN alpha treatment; clinically overt thyroid dysfunctions, destructive thyroiditis and thyrotoxicosis of unidentified etiology, developed in 2 patients 4 to 5 months after start of IFN treatment, subclinical hypothyroidism with a slight increase in serum TSH concentrations but no serum thyroid hormone alternations was observed in 2 patients, and increases in titers of thyroid autoantibodies without thyroid dysfunction were found in 2 patients. Thus, IFN alpha exacerbated thyroid autoimmunity exclusively in all patients with positive tests for thyroid autoantibodies prior to treatment, but did not induce thyroid autoimmunity in thyroid autoantibody-negative patients. These data suggest that the prolonged IFN alpha therapy can lead to exacerbation of thyroid autoimmunity in susceptible (thyroid autoantibody-positive) patients.

Thyroid dysfunction in patients with amyloid goitre

Widespread amyloid deposition in the thyroid gland causes diffuse, clinically apparent enlargement of the thyroid (amyloid goitre: AG). The aim of this study was to clarify the abnormalities of thyroid function in patients with AG.

CD4+ T cell-mediated cytotoxicity toward thyrocytes: the importance of Fas/Fas ligand interaction inducing apoptosis of thyrocytes and the inhibitory effect of thyroid-stimulating hormone.

The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4+ T cells have been determined in thyroid gland from patients with Graves’ disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves’ disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular Vβ elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-γ (IFN-γ)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T cells toward IFN-γ-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-γ-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity of CD4+ T cells toward IFN-γ-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-γ in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4+ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4+ T cells.

Retinole acid inhibits human thyroid peroxidase and thyroglobulin gene expression in cultured human thyrocytes

The effect of retinoic acid (RA) on thyroid peroxidase (TPO) and thyroglobulin (Tg) gene expression was investigated in cultured human thyrocytes. Thyrocytes dispersed from Graves’ thyroid tissues were incubated with TSH 5mU/ml and RA 0, 0.01, 0.1,1.0 μM for 72 h respectively. The samples were then subjected to Northern gel analysis. Northern gel analysis using the specific cDNA probes showed that RA suppressed the accumulation of TPO and Tg mRNA stimulated by TSH in a time- and dose-responsive manner. Furthermore, RA inhibited forskolin and 8-Bromo-cyclic-AMP-induced TPO and Tg gene expression, suggesting a distal action site for these cAMP mediated gene expressions. Immunoprecipitation analysis using the specific monoclonal antibodies showed that TSH increased newly synthesized 100, 75, 36-kDa [35S] TPO. The increased de novo TPO was markedly inhibited by RA. Tg secretion from monolayer cultures was measured by radioimmunoassay. RA also inhibited TSH-in-duced Tg secretion in a dose dependent manner. RA did not affect [3H] thymidine uptake into primary cultured human thyrocytes. In conclusion, RA inhibits the synthesis of TPO and Tg via the suppression of thyroid-specific gene expression although the exact site of RA action on these genes in human thyroids remains to be further elucidated. These results suggest that RA may play a regulatory role in Tg and TPO gene expression, subsequently resulting in the suppression of thyroid hormone synthesis.

Impairment of the TSH signal transduction system in human thyroid carcinoma cells

In order to further evaluate the role of TSH in the proliferation and the differentiation of human thyroid carcinoma cells, we have analyzed the function of the TSH receptor in the established thyroid carcinoma cell lines NPA and WRO. The TSH signal transduction system in the carcinoma cells was also compared with that in normal thyroid cells. Although unresponsiveness to bovine and human TSH was demonstrated by measurement of cAMP production and [3H]thymidine incorporation after treatment of TSH, cAMP production was induced after stimulation of these cells by forskolin, cholera toxin, and isoproterenol. Specific binding to 125I-TSH was demonstrated in both NPA and WRO cells in addition to the existence of a TSH receptor mRNA and thyroglobulin mRNA species, although thyroid-specific gene expression in these cells was not regulated by TSH. These findings suggest that the unresponsiveness to TSH in these cells may be due to an abnormality of TSH receptor-G protein coupling rather than to a decreased level of TSH-receptor expression or a Gs protein abnormality.

Idiopathic portal hypertension associated with systemic sclerosis and Sjögren’s syndrome

We report a patient with idiopathic portal hypertension (IPH) associated with systemic sclerosis (SSc) and Sjögren’s syndrome. A 72-year-old Japanese woman was admitted to our hospital because of Raynaud’s phenomenon, sclerodactyly, and dyspnea. The patient had splenomegaly, esophageal varices in the absence of extrahepatic portal obstruction, and cirrhosis of the liver. Immunological studies revealed positive anti-nuclear antibodies and high titers of anti-Scl-70, anti-SS-A, anti-centromere, and anti-mitochondrial M2 antibodies. Histological examinations of the liver biopsy specimen revealed stenosis and loss of small portal veins without findings of primary biliary cirrhosis. The patient was diagnosed as having IPH associated with SSc and Sjögren’s syndrome. These observations suggest an immunological role in the pathogenesis of IPH.

Thyrotropin binding specificity for the thyrotropin receptor

Recently, highly purified bovine thyrotropin (bTSH) of pituitary origin, as well as recombinant human (h) TSH free of lutropin (LH) contamination, has been reported to activate the LH/choriogonadotropin receptor (LH/CGR). These data challenge the concept of TSH specificity for its own receptor. We, therefore, re-evaluated these data using, as targets, the recombinant hTSH and rat LH/CGRs stably expressed in Chinese hamster ovary (CHO) cells. Partially purified bTSH (2 IU/mg protein) and, to a lesser degree, highly purified bTSH (30 IU/mg protein) increased intracellular cAMP levels in CHO-LH/CGR cells (an EC50 of 0.2 and > 20 mIU/ml, respectively). In contrast, recombinant hTSH (up to 1 IU/ml) did not. All three TSH preparations increased cAMP levels to the same extent in CHO-TSHR cells (an EC50 of 0.3 mIU/ml). Furthermore, we observed only nonspecific, low affinity TSH binding for CHO-LH/CGR cells and also for CHO cells transfected with the expression vector alone (a Kd of 100 nM), although both high and low affinity TSH binding was demonstrated in CHOT-SHR cells (a Kd of 0.3 and 100 nM, respectively). These data indicate that even highly purified bTSH of pituitary origin contains significant amounts of LH, and that TSH itself does not appear to activate the LH/CGR.

Multiple endocrine neoplasia type 2 with malignant pheochromocytoma — Long term follow-up of a case by131I-meta-iodobenzylguanidine scintigraphy—

The case of a 33-year-old Japanese man, who has Multiple Endocrine Neoplasia Type 2 (MEN IIa) (Sipple’s syndrome) with malignant pheochromocytoma, is reported. He had survived for twelve years since the initial diagnosis of malignant pheochromocytoma. Within this period, he had undergone131I-meta-iodobenzylguanidine scintigraphy twice, in 1983 and 1990. This is the first case in Japan of a longterm surviving patient with malignant pheochromocytoma followed up by131I-MIBG scintigraphy. Although he had no exacerbation of clinical symptoms or urinary catecholamine levels, second scintigraphy clearly showed an increase in the tumor size, new metastasis of the malignant pheochromocytoma and exacerbation of the medullary thyroid carcinoma. Compared with any other roentgenological device and hormonal data,131I-MIBG scintigraphy was seen to be a good tool for evaluating the localization and the progression of tumors.131I-MIBG scintigraphy is a useful procedure not only for initial diagnosis but also for judging progression in a case of advanced malignant pheochromocytoma.

Subnormal secretion of parathyroid hormone prevents age-related bone loss

Parathyroid hormone (PTH) is a key factor involved in the systemic regulation of bone resorption. It is well known that a high turnover of bone occurred together with the reduced bone mass in patients with hyperparathyroidism. However, the effect of subnormal secretion of PTH on age-related bone loss has not been extensively investigated. Recently, some investigators and us have focused on the effect of suppressed PTH secretion and have demonstrated that patients with subnormal secretion of PTH preserved a relatively higher bone mineral densities than age- and sex-matched controls. We believe that these results will give a new insight into the mechanism of age-related bone loss or osteoporosis. Further studies are needed to evaluate the mechanisms of this protective effect of suppressed PTH secretion on bone mass.

Association of subacute cutaneous lupus erythematosus in a rheumatoid arthritis patient with Sjögren's syndrome

Abstract In this paper, we report a case of rheumatoid arthritis (RA) with Sjögrens syndrome (SS) in which the patient developed subacute cutaneous lupus erythematosus (SCLE). A 72-year-old woman, who had a 10-year history of RA and SS, developed annular erythematosus skin lesions involving her face, neck, and extremities. Serological tests showed that anti-SS-A/Ro antibodies and anti-DNA antibodies were elevated. Histological examination of the skin lesions demonstrated the liquefaction degeneration of the epidermal basal layer and perivascular mononuclear cell infiltration. The diagnosis of SCLE was made based on the clinical features and skin histological findings. The disease was well controlled with intralesional and systemic corticosteroids and became quiescent. This case report demonstrates the concurrence of sero-positive RA, SS, and SCLE, which seems to be quite rare.