3-メルカプトピルビン酸硫黄転移酵素(3MST)の結晶学的研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 清水 敏之, 東京大学教授 船津 高志, 東京大学准教授 花岡 健二郎, 東京大学特任准教授 加藤 大, 東京大学講師 大戸 梅治University of Tokyo(東京大学

Clinical follow-up of the first SF-1 insufficient female patient

Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future

NK Cells Are Not Required for Spontaneous Autoimmune Diabetes in NOD Mice

NK cells have been shown to either promote or protect from autoimmune diseases. Several studies have examined the role of receptors preferentially expressed by NK cells in the spontaneous disease of NOD mice or the direct role of NK cells in acute induced disease models of diabetes. Yet, the role of NK cells in spontaneous diabetes has not been directly addressed. Here, we used the NOD.NK1.1 congenic mouse model to examine the role of NK cells in spontaneous diabetes. Significant numbers of NK cells were only seen in the pancreas of mice with disease. Pancreatic NK cells displayed an activated surface phenotype and proliferated more than NK cells from other tissues in the diseased mice. Nonetheless, depletion of NK cells had no effect on dendritic cell maturation or T cell proliferation. In spontaneous disease, the deletion of NK cells had no significant impact on disease onset. NK cells were also not required to promote disease induced by adoptively transferred pathogenic CD4+ T cells. Thus, NK cells are not required for spontaneous autoimmune diabetes in NOD mice

The utility of the new generation of humanized mice to study HIV-1 infection: transmission, prevention, pathogenesis, and treatment

Substantial improvements have been made in recent years in the ability to engraft human cells and tissues into immunodeficient mice. The use of human hematopoietic stem cells (HSCs) leads to multi-lineage human hematopoiesis accompanied by production of a variety of human immune cell types. Population of murine primary and secondary lymphoid organs with human cells occurs, and long-term engraftment has been achieved. Engrafted cells are capable of producing human innate and adaptive immune responses, making these models the most physiologically relevant humanized animal models to date. New models have been successfully infected by a variety of strains of Human Immunodeficiency Virus Type 1 (HIV-1), accompanied by virus replication in lymphoid and non-lymphoid organs, including the gut-associated lymphoid tissue, the male and female reproductive tracts, and the brain. Multiple forms of virus-induced pathogenesis are present, and human T cell and antibody responses to HIV-1 are detected. These humanized mice are susceptible to a high rate of rectal and vaginal transmission of HIV-1 across an intact epithelium, indicating the potential to study vaccines and microbicides. Antiviral drugs, siRNAs, and hematopoietic stem cell gene therapy strategies have all been shown to be effective at reducing viral load and preventing or reversing helper T cell loss in humanized mice, indicating that they will serve as an important preclinical model to study new therapeutic modalities. HIV-1 has also been shown to evolve in response to selective pressures in humanized mice, thus showing that the model will be useful to study and/or predict viral evolution in response to drug or immune pressures. The purpose of this review is to summarize the findings reported to date on all new humanized mouse models (those transplanted with human HSCs) in regards to HIV-1 sexual transmission, pathogenesis, anti-HIV-1 immune responses, viral evolution, pre- and post-exposure prophylaxis, and gene therapeutic strategies

Clinical Features of Type B Insulin Resistance in Japanese Patients: Case Report and Survey-Based Case Series Study

Type B insulin resistance (TBIR) is an extremely rare disease characterized by marked hyperglycemia and insulin resistance and often coexists with autoimmune diseases. The characteristics, symptoms, blood glucose patterns, comorbidities, and treatments of TBIR all vary and are not defined. In this study, we described a case of TBIR that developed 6 months after DPP-4 inhibitor administration and immediately after the patient caught a cold. Treatment using prednisolone and insulin-like growth factor-1 was effective. We also conducted an observational survey-based case series study in a Japanese cohort comprising 21 cases. The average age of onset of TBIR was 62.3±14.8 (17–84) years, and 61.9% of subjects were male. The majority of patients (90.4%) were 50 years old and over. During the study period, there was a high percentage (85.7%) of episodes of hypoglycemia, which was the trigger for diagnosis in more than 50% of cases. Glycemic patterns included 7 cases of hyperglycemia (33.3%), 10 cases of hypoglycemia (47.6%), and 4 cases of both hyperglycemia and hypoglycemia (19.1%). In the hypoglycemic group, 90.0% of patients were male. Furthermore, 71.4% of cases were antinuclear antibody positive, and 81.0% of cases were complicated with autoimmune disease. Systemic lupus erythematosus (38.1%) and Sjögren’s syndrome (23.8%) were relatively common as coexisting autoimmune diseases. Treatment was based on prednisolone use, which was used in 88.9% of patients. On the other hand, the effect of IGF-1 was limited. Overall, the prognosis of TBIR was good