Shun Matsuki

Cell-mediated cytotoxic islet cell surface antibodies to human pancreatic beta cells

SummarySera containing islet cell surface antibodies show a complement-dependent cytotoxic reaction against islet cells, but it has not yet been clarified whether islet cell surface antibodies exhibit cell-mediated cytotoxicity to these cells. By 51Cr release assay we investigated whether islet cell surface antibodies showed a cytotoxic reaction to human pancreatic B cells (JHPI-1 clone) in the presence of normal human lymphocytes. The sera from 14 islet cell surface antibody-positive, 16 islet cell surface antibody-negative Type 1 (insulin-dependent) diabetic patients and 18 islet cell surface antibody-negative healthy subjects were studied. Four sera containing islet cell surface antibodies showed specific cytotoxicity above the mean +3SD value of healthy subjects, and the mean specific cytotoxicity of islet cell surface antibody-positive sera differed significantly from that of both islet cell surface antibody-negative groups. These results suggest that this cell-mediated cytotoxic mechanism may play an important role in the pathogenesis of Type 1 diabetes.

Immunological aspect of non-obese diabetic mice: immune islet cell-killing mechanism and cell-mediated immunity

SummaryThe non-obese diabetic mouse is thought to be one of the best available animal models for human Type 1 (insulin-dependent) diabetes. By 51Cr release assay we investigated cell-mediated cytotoxicity to the islet cells of Balb/C mice, natural killer activity, and antibody-dependent cell-mediated cytotoxicity activity of spleen lymphocytes from pre-diabetic non-obese diabetic mice. The cell-mediated cytotoxicity to islet cells of non-obese diabetic mice was significantly higher than that of control ICR mice. In contrast, natural killer and antibody-dependent cell-mediated cytotoxicity activities of the spleen cells from the non-obese diabetic mice were significantly lower than those of ICR mice spleen cells. These results suggest that lymphocytes from non-obese diabetic mice were sensitized to the antigen of islet cells and that the non-specific cellular immunity of non-obese mice was reduced. They suggest also that this immune islet cell-killing mechanism may play an important role in the pathogenesis of diabetes in non-obese diabetic mice.

Renin and aldosterone in hypothyroidism: relation to excretion of sodium and potassium.

Changes in plasma renin activity (PRA) and plasma aldosterone (PA) were studied together with the urinary excretion of sodium and potassium in patients with hypothyroidism. The basal levels of PRA and PA were significantly less than those in normal subjects. However, there was no significant relationship between PRA and PA. The response of PRA after administration of 40 mg of frusemide in patients with hypothyroidism was significantly less than that in normal subjects, although the excretion of sodium was slightly higher than that in normal subjects. On the other hand, the excretion of potassium in patients with hypothyroidism was significantly lower than that in normal subjects. The responses of PA to various stimulations, such as ACTH, angiotensin II, potassium and frusemide, were equally suppressed. These results suggest that PRA and PA may be suppressed independently in hypothyroidism, probably due to dysfunction of juxtaglomerular cells and glomerulosa cells, respectively, and the possibility that suppression of PRA and PA in patients with hypothyroidism is related to exaggerated sodium excretion and a decrease in potassium excretion cannot be ruled out.

Erythrocyte Aging Changes Evaluated by the Deoxyuridine Suppression Test

Many hematologic studies have shown that the erythrocyte count decreases while the size of the individual cell increases in the aged. This study was performed in order to (1) evaluate changes in the blood erythrocyte level and mean erythrocyte size in the elderly and (2) evaluate use of the deoxyuridine (dU) supression test to determine whether deficiency of vitamin B12or folate plays any role in age‐related changes of hematopoiesis. Selected for study were 102 healthy men whose ages ranged from 20 to 79 years. The erythrocyte count and hemoglobin level decreased significantly, whereas the mean corpuscular volume and mean corpuscular hemoglobin increased after 70 years of age. Fresh bone‐marrow cells were obtained from 10 young (20–38 yr) and 10 aged (70–82 yr) men. Wickramasinghes dU suppression test was modified by application of an automatic cell harvester. The results were normal in both groups. Thus, the route of dU to dTMP in a DNA synthetic pathway appeared intact, and there was no evidence of B142or folate deficiency in the aged to explain the observed macrocytosis. However, 3H‐thymidine uptake by nucleated bone‐marrow cells was significantly decreased, and the ratio of 3H‐uridine to 3H‐thymidine uptake was greater in the old group than in the young group. These results could be explained by altered nucleic acid metabolism (unbalanced cell growth) or by a change in the proportion of the different fractions of nucleated cells.

Control of Aldosterone in 17α-Hydroxylase Deficiency

The control mechanism of aldosterone in 3 patients with 17α-hydroxylase deficiency was compared to that in a patient with a deoxycorticosterone-producing tumor. The basal levels of plasma renin activity (PRA) and plasma aldosterone (PAC) were decreased in 2 of the 3 patients with 17α-hydroxylase deficiency and in the patient with a tumor. However, in the third patient with accelerated hypertension, those levels were normal. In the 3 patients with low PRA and PAC, PAC was stimulated by various procedures, although the responses were lower than those in control subjects. In the patient with accelerated hypertension, the responses were similar to those of the control subjects. After 6 months’ treatment with dexamethasone, the low levels of PRA and PAC gradually returned to the lower limit of normal in 2 of the patients with 17α-hydroxylase deficiency. These results suggest that the suppression of PAC in patients with 17α-hydroxylase deficiency is probablydue to a suppression of the renin-angiotensin system.

A case of 17alpha-hydroxylase deficiency with symptoms mimicking testicular feminization.

A case of 17alpha-hydroxylase deficiency mimicking testicular feminization is reported. Different from the complete form of testicular feminization in which androgens are normal or elevated and end-organ insensitivity to androgens is supposed, this case had a negligible amount of androgens and responded to the injection of testosterone propionate with a positive nitrogen and phosphate balance.

Renin and the Juxtaglomerular Apparatus in Diabetic Nephropathy

In order to study the role of the renin‐angiotensin system in patients with diabetic nephropathy, renin release and the juxtaglomerular apparatus were studied in 17 diabetic patients with proteinuria and in 23 without proteinuria; 8 normal subjects were used for controls. Despite hypertension and marked arteriosclerosis, plasma renin activity (supine posture) was normal; however, the renin response to salt restriction and upright posture was less in the diabetic patients with proteinuria than in the controls. Renal renin content, determined at autopsy, was also normal. Examination of the juxtaglomerular apparatus in the diabetic patients with proteinuria revealed hyalinization of the afferent and efferent arterioles in most of the glomeruli and various degrees of destruction of the juxtaglomerular cells. The findings suggest that renin production is not increased in diabetic patients with proteinuria plus marked vascular damage, and that the renin‐angiotensin system in patients with diabetic nephropathy apparently does not play an important role in the exacerbation of hypertension or the degree of vascular damage.

Studies on the Mechanism of Secretion of Adrenal Steroid Hormones from Adenomas of Primary Aldosteronism and Cushing's Syndrome

The mechanism of secretion of adrenal steroid hormones from adenomas of primary aldosteronism and Cushings syndrome was studied in 10 patients with primary aldosteronism and in 3 patients with Cushings syndrome in in vivo and in vitro experiments. In all of the 10 patients with primary aldosteronism, ACTH stimulated aldosterone secretion from the adenomas more significantly than did angiotensin II and III. DOC and cortisol which were contained in the adenomas were also stimulated more significantly by ACTH than by angiotensin II and III. Responses of the adenomas of Cushings syndrome to various stimulations were less than those of primary aldosteronism. Secretion of cortisol and aldosterone from the adenomas of Cushings syndrome was stimulated by ACTH and angiotensin II to a similar degree. From these studies, it seems that secretion of adrenal steroid hormones from adenomas of primary aldosteronism is more sensitive to extradrenal stimulations than that of Cushings syndrome, and ACTH is the main factor in the control of the secretion of adrenal steroid hormones from the adenomas.