Mariko Sue

Fragments of Genomic DNA Released by Injured Cells Activate Innate Immunity and Suppress Endocrine Function in the Thyroid

Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines. Molecules necessary for antigen processing and presentation to lymphocytes are also induced in thyroid cells by injury. dsDNA strongly suppressed the expression of sodium/iodide symporter and radioiodine uptake. To identify molecules responsible for sensing cytosolic dsDNA, we directly identified the cellular proteins that bound a dsDNA Sepharose column by mass spectrometry. Our analysis identified histone H2B, which was previously demonstrated to be an essential factor that mediates the activation of innate immunity induced by dsDNA. Knockdown of histone H2B using specific small interfering RNA abolished cell injury-induced innate immune activation and increased sodium/iodide symporter expression. These results indicate that genomic DNA fragments released by cell injury are recognized by extrachromosomal histone H2B, which results in the activation of genes involved in both innate and acquired immune responses in thyroid cells and suppression of thyroid function. These results suggest that sterile thyroid injury, in the absence of infection, may be sufficient to trigger autoimmune reaction and to induce thyroid dysfunction.

Role of thyroglobulin on negative feedback autoregulation of thyroid follicular function and growth.

Thyroid function is tightly regulated by TSH. Although individual follicles are exposed to the same blood supply of TSH and express relatively homogenous levels of the TSH receptor, the function of individual follicles is variable. It was shown that thyroglobulin (Tg), stored in the follicular lumen, is a potent negative feedback regulator of follicular function. Thus, physiological concentrations of Tg significantly suppress thyroid-specific gene expression and antagonize the TSH-mediated stimulation that induces expression of thyroid-specific genes. Tg coordinately regulates both basal and apical iodide transporters in thyroid follicular cells. Recently, it was also reported that Tg could induce thyroid cell growth in the absence of TSH. These results indicate that Tg is an essential autocrine regulator of physiological thyroid follicular function that counteracts the effects of TSH.

Type 1 Diabetes Mellitus Associated with Pegylated Interferon-α Plus Ribavirin Treatment for Chronic Hepatitis C: Case Report and Literature Review.

Combined pegylated interferon (PEG-IFN)+ribavirin (RBV) therapy has been used as a primary treatment for chronic hepatitis C. However, IFN-induced autoimmune disease, including type 1 diabetes mellitus, has been highlighted as one of the problems with this therapy. Here we report the case of a patient who developed type 1 diabetes mellitus during combined PEG-IFN+RBV therapy for hepatitis C but who showed no exacerbation of diabetes despite continued use of IFN. A 63-year-old man with chronic hepatitis C and a nonresponder to previous IFNα treatments, was admitted to our hospital because of excessive thirst, polydipsia, and polyuria 24 weeks after the start of PEG-IFNα+RBV therapy. High levels of blood glucose and glycosylated hemoglobin and low levels of C-peptide and immunoreactive insulin were observed. The serum antiglutamic acid decarboxylase antibody titer was 27,700 U/mL. We diagnosed IFN-induced type 1 diabetes mellitus; however PEG-IFNα+RBV therapy was continued for 48 weeks. Serum HCV remains negative five years after this treatment. Intensive insulin therapy was started immediately after the diagnosis of type 1 diabetes. Although the patient initially required 22 U/day of insulin, the dosage could be gradually reduced after completion of PEG-IFNα+RBV therapy and blood glucose remained well controlled. Prediction of onset of type 1 diabetes mellitus on the basis of baseline measurement of pancreas-associated autoantibodies is difficult. Therefore, it would be advisable to consider the possibility of onset of type 1 diabetes mellitus in all patients receiving IFN+RBV therapy.

Central Adrenal Insufficiency and Diabetes Insipidus Misdiagnosed as Severe Depression

A 68 year-old Japanese man, who had been suffering from immobilization and disuse syndrome, was admitted to our hospital for evaluation of polyuria with polyposia, hyponatremia and low blood pressure. His plasma osmolality was greater than that of his urine. His endocrinological examination revealed low levels of plasma adrenocorticotropic hormone (ACTH) and cortisol, and a normal response of ACTH to the corticotrophin-releasing hormone (CRH) challenge. Plasma ACTH did not increase with insulin loading. A low plasma vasopressin (AVP) level and no response of AVP to a 5% saline administration were observed. We diagnosed central adrenal insufficiency with central diabetes insipidus. Six months after starting administration of hydrocortisone and 1-deamino-8D-arginine vasopressin, his psychological symptoms had improved, and 1.5 years after starting treatment, he was able to walk. In conclusion, it is not particularly rare for adrenal insufficiency to be misdiagnosed as depression. However, a correct early diagnosis is necessary, because, if adrenal insufficiency is not definitively diagnosed, the patients quality of life diminishes markedly.

Follicular thyroglobulin induces cathepsin H expression and activity in thyrocytes

Thyroglobulin (Tg) stored in thyroid follicles exerts a potent negative-feedback effect on each step of pre-hormone biosynthesis, including Tg gene transcription and iodine uptake and organification, by suppressing the expression of specific transcription factors that regulate these steps. Pre-hormones are stored in the follicular colloid before being reabsorbed. Following lysosomal proteolysis of its precursor, thyroid hormone (TH) is released from thyroid follicles. Although the suppressive effects of follicular Tg on each step of pre-hormone biosynthesis have been extensively characterized, whether follicular Tg accumulation also affects hormone reabsorption, proteolysis, and secretion is unclear. In this study we explored whether follicular Tg can regulate the expression and function of the lysosomal endopeptidases cathepsins. We found that in the rat thyroid cell line FRTL-5 follicular Tg induced cathepsin H mRNA and protein expression, as well as cathepsin H enzyme activity. Double immunofluorescence staining showed that Tg endocytosis promoted cathepsin H translocalization into lysosomes where it co-localized with internalized Tg. These results suggest that cathepsin H is an active participant in lysosome-mediated pre-hormone degradation, and that follicular Tg stimulates mobilization of pre-hormones by activating cathepsin H-associated proteolysis pathways.