Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in acquisition of T cell tolerance to self-superantigens and processed DRα-derived peptide

We have established a set of transgenic mouse lines in which the HLA-DRA gene was expressed in different cell types. In one line (DRα-24), DRαEβ^b molecules were expressed on thymic medullary and cortical epithelial cells and all lineages of bone marrow-derived antigen-presenting cells (APC) except for thymic macrophages. By contrast, expression of the molecules in another line (DRα-30) was found on thymic medullary and cortical epithelial cells but not on bone marrow-derived APC in the thymus and periphery. To evaluate the role of thymic epithelial cells in acquisition of T cell tolerance, comparative analysis of DRα-24 and DRα-30 was performed. In DRα-30, T cells expressing TcR Vβ5 and Vβ11 were eliminated to comparable levels to those in DRα-24, suggesting that expression of the DRαEβ^b molecules on thymic epithelial cells are sufficient for clonal deletion of the self-superantigen-reactive T cells. In addition, CD4⁺ T cells from DRa-30 as well as those from DRα-24 were tolerant to DRα-derived peptide/I-A^b complex expressed on spleen cells from DRα-24 even in the presence of exogenous interleukin-2. These observations suggest that expression of the DRα chain in thymic epithelial cells could induce T cell tolerance directed toward naturally processed DRα-derived peptide bound to I-A^b molecules, probably via clonal deletion of the self-reactive T cells.     

Progressive congestive heart failure due to common iliac arteriovenous fistula: a case report

Arteriovenous shunt is one of the causes of heart failure, but heart failure caused by common iliac arteriovenous fistula is relatively rare. A 64-year-old man who developed acute heart failure due to venous perforation of a common iliac aneurysm and also had bilateral aneurysms (diameter 58 mm) was referred to our department. On admission, the patient complained of dyspnea and swollen left leg, so diuretic agent was administered to treat the heart failure. Cardiac catheterization showed a shunt rate of 80.6%, as well as 5.0 Qp/Qs and O2 step-up across perforation of the common iliac vein. Despite the therapy, pleural effusion and ascites exacerbated, and the heart failure became difficult to control, so surgical treatment was performed. The aneurysm was replaced with an artificial vessel, and the fistula was closed by direct suturing. Postoperatively, the symptoms disappeared, and the patient is in good health.     

Expression and significance of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 in an animal model of renal interstitial fibrosis induced by unilateral ureteral obstruction.

To evaluate the pathological roles of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1 in rat renal interstitial fibrosis, we examined the expression, localization and effect on growth of ADAMTS-1 in a normal rat kidney cell line (NRK-49F). Increased ADAMTS-1 mRNA expression was observed in the kidney by in situ hybridization after induction of unilateral ureteral obstruction (UUO) in male Wistar rats, the mRNA was localized in the renal tubular epithelial cells in the outer stripe of the outer medulla in the UUO kidney. On the other hand, no positive signals were observed in the sham-operated-kidney. Western-blot analysis of stable human embryonic kidney 293 (HEK293) transformant cells expressing rat ADAMTS-1 containing the V5 tag using anti-V5 tag monoclonal antibody revealed the presence of two post-translationally processed bands in the cells: an 87-kDa band with a metalloproteinase motif and 65-kDa band with a thrombospondin motifs. On the other hand, secretion of the 65-kDa protein into the culture supernatants from the transformant cells was confirmed. Treatment with the culture supernatant of the transformant cells potently reduced the uptake of 3H-thymidine in the NRK-49F cells, no such inhibitory effect was observed with the culture medium of the HEK293 cells. These results suggest that the UUO-induced expression of ADAMTS-1 in the rat renal tubular epithelial cells may actively contribute to the inhibition of DNA synthesis in the renal interstitial fibroblasts via the 65-kDa moiety with thrombospondin motifs.     

SYSTEMIC AMYLOID ARTHROPATHY ASSOCIATED WITH MULTIPLE MYELOMA

This is the first report of an autopsy case of systemic amyloid arthropathy associated with multiple myeloma in Japan. The patient was a 72-year-old male who had been suffering from multiple myeloma (IgA-lambda) with extensive arthropathy of the systemic joints. Autopsy examination revealed severe deposit of amyloid in the articular cavities of the systemic joints showing a feature of amyloidoma. Furthermore, numerous amyloid deposits were found in the wall of small blood vessels in the major organs. In the bone marrow, there were many atypical plasma cells and foamy cells both showing positive reaction for IgA and lambda light chain. No such atypical cells were observed in the other organs except for the bone marrow.     

Epidemiological survey of thyroid volume and iodine intake in schoolchildren,postpartum women and neonates living in Ulaan Baatar

OBJECTIVE: Although endemic goiter had been recognized in most parts of the country, there are few available data on iodine-deficiency disorders (IDDs) in Mongolia. This study aimed to characterize the current status of iodine deficiency in Ulaan Baatar, Mongolia's capital city. DESIGN: Cross-sectional, observational study designed and performed according to the surveillance methods for IDD prevalence recommended by WHO/UNICEF/ICCIDD. SUBJECTS: A total of 505 schoolchildren aged 9-14 years (237 girls and 268 boys) and 138 mothers and their neonatal infants were selected to clinical and biochemical examination of the thyroid in 1996 and 1999. MEASUREMENTS: The anthropometric measurements, thyroid volume determined by ultrasound, blood TSH and FT4 concentrations, urinary iodine concentration and iodine content of salt consumed in households. RESULTS: Median thyroid volumes based on age were generally higher than those in iodine-sufficient areas and comparative to those reported in mild iodine-deficiency areas. Application of the updated WHO/ICCIDD reference values in iodine-replete European schoolchildren to the Mongolian children aged 10-12 years resulted in a goiter prevalence of 43.3%. The median value of urinary iodine concentration was 152.5 micro g/l (1.20 micro mol/l) and 40.3% of children excreted iodine below 100 micro g/l. Iodized salt (> 40 ppm) was consumed in 63.1% of households and in the children using noniodized salt their urinary iodine concentration was lower than those using ionized salt. In postpartum women, median thyroid volume and urinary iodine concentration were 11.3 ml and 107 micro g/l (0.84 micro mol/l), respectively, and 46% of women excreted less than 100 micro g/l (0.79 micro mol/l) of iodine. Of their neonates, 17.8% had elevated blood TSH levels (> 5 mU/l). In a 1999 survey, the goiter prevalence and ratio of low iodine excretion in schoolchildren decreased to 29.8% and 31.3%, respectively, while median urinary iodine concentration remain unchanged (160 micro g/l; 1.26 micro mol/l). CONCLUSION: The present study clearly indicates the presence of mild iodine deficiency in Mongolia. Enlarged thyroid gland and normal iodine excretion observed in schoolchildren living in Ulaan Baatar may result from the residual effects of iodine deficiency previously and presumably still exist in the city. Slight reduction in the rate of children with enlarged thyroid and low urinary iodine excretion after the onset of national iodinization programme suggests incomplete normalization of thyroid volume in children and that the correction of iodine deficiency is now in progress in Ulaan Baatar. Further nationwide surveys together with monitoring the progress of the national programme eliminating IDD are required in suburban areas surrounding the city and also in rural areas.     

Understanding the mechanism of the age-change of thymic function to promote T cell differentiation

Immunological functions peak at around puberty and gradually decline thereafter with advancing age. The immunological decline mainly occurs in the T cell-dependent immune system and is generally associated with an increase in not only susceptibility to infections but also incidence of autoimmune phenomena. The age-related changes in T-cell dependent immune functions can be mainly ascribed to the physiological thymic involution which starts in the early phase of life. The age-related thymic involution can be ascribed to either extrinsic or intrinsic factors. Bone marrow stem cells can be one of the extrinsic factors for the thymic involution, but their role is estimated to be marginal as compared with alteration of the thymic microenvironment. With advancing age, the thymic capacity to promote T-cell differentiation declines together with a change in the composition of T-cell subsets produced. Such an alteration of the thymic environment is responsible for the age-related change in peripheral T cells in number and in composition. Age change is observed in several intrinsic factors in the thymic environment which influence proliferation of thymocytes. These thymic intrinsic factors can either promote or inhibit proliferation of thymocytes, and promoting factors generally decrease with age with a concomitant increase in inhibitory factors. Various endocrine hormones are important extrinsic factors influencing the thymic function. In fact, physiological thymic involution can be intervened by manipulation of the endocrine system, sometimes resulting in rejuvenation of immune functions to a certain extent. A specific strain of Buffalo rats has an unusual thymus, which does not involute with age, and the functions of the T-cell dependent immune system do not decline with age. Such animals having hyperplastic thymus are relatively resistant to various kinds of stress. Thus, restoration of immune functions in the aged animals appears to be beneficial for them in coping with various diseases associated with age.