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Biomedical subjects

F A Karlsson

Publications and source records attributed to F A Karlsson.

At least 19 recordsLinked to original sources
PubMed1992

21-Hydroxylase, a major autoantigen in idiopathic Addison's disease.

Sera from patients with idiopathic Addison's disease commonly react with the zona glomerulosa of adrenal cortex. We used high-resolution western blot analysis of an adrenal microsomal fraction to investigate the target of these antibodies. A protein with an apparent molecular weight of 54 kDa was recognised as the common and major component. Sera identifying this autoantigen (from 12 of 16 patients) also showed strong immunofluorescence staining of a steroid-producing human adrenal adrenocortical cell line, NCI-H295. On application of antisera specific for different cytochrome P450 steroidogenic enzymes (side-chain cleavage enzyme, 21-hydroxylase, 17 alpha-hydroxylase, 11 beta-hydroxylase) the mobility of the 54 kDa protein in western blots corresponded to that of 21-hydroxylase. This parallel behaviour was confirmed by immunoprecipitation, electrophoresis, and autoradiography with the various sera and 35S-methionine-labelled NCI-H295 cell lysates. Preabsorptions of 35S-methionine-labelled cell lysates with the antiserum to 21-hydroxylase, but not with the other enzyme antisera, abolished precipitation of the 54 kDa autoantigen with the patient sera. These results indicate that 21-hydroxylase (P450c21), prominent in the zona glomerulosa of the adrenal cortex, is a major autoantigen in idiopathic Addison's disease.

Addison Disease↗
PubMed1992

Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion.

This study examined the relationship between insulin secretion and expression of the 64 kDa/glutamic acid decarboxylase autoantigen in pancreatic islets. Islets isolated from Wistar rats were cultured for 3 days under different conditions: in 5.5 mmol/l glucose with or without alpha-ketoisocaproic acid or glipizide and in 28 mmol/l glucose with or without diazoxide. The 64 kDa/glutamic acid decarboxylase autoantigen was precipitated from lysates of [35S]-methionine-labelled islets with sera from patients with Type 1 (insulin-dependent) diabetes mellitus and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. In parallel, insulin contents of the islets and the media were determined as well as the rates of glucose-stimulated (pro)insulin biosynthesis. alpha-Ketoisocaproic acid and glipizide were found to stimulate the expression of the 64 kDa/glutamic acid decarboxylase autoantigen and also the rate of insulin secretion. Diazoxide on the other hand reduced the rate of the 64 kDa/glutamic acid decarboxylase autoantigen synthesis in parallel with an inhibition of glucose-stimulated insulin release. Under most of the conditions employed, (pro)insulin biosynthesis was not affected. The correlation found between the rate of insulin release and expression of the 64 kDa/glutamic acid decarboxylase autoantigen might provide an explanation for the earlier observed relationship between the functional demands on the Beta cells and their rate of destruction which may result in diabetes.

Animals↗
PubMed1992

Low plasma levels of insulin-like growth factor 1 (IGF-1) in male patients with idiopathic osteoporosis.

Experimental studies in vitro indicate that insulin-like growth factor 1 (IGF-1) could be of importance for normal bone growth and remodelling, but the clinical relevance of these observations is unknown. In 12 consecutive young to middle-aged male patients (mean age (+/- SD) 46 +/- 8 years, range 30-57 years) with symptomatic idiopathic osteoporosis, the plasma concentrations of IGF-1 were significantly lower than in healthy subjects (0.51 +/- 0.25 vs. 0.73 +/- 0.23 U ml-1; P less than 0.01). The bone mineral densities in the spine, the femoral neck, and the forearm were significantly different between patients and control subjects. There were positive correlations between the plasma IGF-1 concentrations and the bone densities of the spine and the forearm. Three of the patients received a 5-d course of human recombinant growth hormone (GH). During this short period significant increases in plasma IGF-1 levels and in biochemical indices of bone turnover (serum bone-specific alkaline phosphatase, urinary calcium excretion) were recorded. These observations indicate that circulating IGF-1 could have an important role in maintaining bone mass, and suggest that impairment of IGF-1 production is involved in the pathogenesis of osteoporosis.

Adult↗
PubMed1992

Hyperthyroid Graves' disease without detectable thyrotropin receptor antibodies.

TSH receptor antibodies are generally held responsible for the stimulation of the thyroid that characterizes patients with Graves' disease. Here, we describe nine patients with hyperthyroidism (triiodothyronine 4.9, 3.2-6.7 nmol/L; median, range) who were referred for radioiodine treatment and who had increased thyroid radioiodine uptake values but lacked TSH receptor antibodies determined by a radioreceptor assay. Furthermore, when serum immunoglobulins were studied in a bioassay based on a rat thyroid cell line (FRTL-5), no evidence of stimulant activity was observed. Subsequent to radioiodine therapy, TSH receptor antibodies appeared in all nine patients. The antibodies competed for TSH in the radioreceptor assay and, of the eight patient samples studied with the bioassay, six stimulated cAMP production whereas another two blocked the latter. The results show that a small proportion of patients with active hyperthyroid Graves' disease, in this study 9 out of 130 cases, do not have detectable TSH receptor stimulatory antibodies. A local production of antibodies within the thyroid can be suggested, although a more likely explanation might be that the thyroid in Graves' disease is activated also by other mechanisms than antibody-dependent ones.

Adult↗
PubMed1992

Glucose regulation of the autoantigen GAD65 in human pancreatic islets.

Recent data suggest that the enzyme glutamic acid decarboxylase (GAD) may be a primary beta-cell antigen involved in the autoimmune response leading to insulin dependent diabetes mellitus (IDDM). Following three days culture of human islets at different glucose concentrations (5.6, 11 or 28 mM), there was a single 65 kDa/GAD band in the islet extracts, as assessed by immunoprecipitation both with serum from a newly diagnosed IDDM patient and a sheep anti-GAD serum. The synthesis of GAD was strongly stimulated at the higher glucose concentrations. Likewise, Western blot analysis indicated a glucose-induced increase of GAD in the islets. The data suggest that an enhanced function of human islet cells increases expression of GAD65. Possibly, this could exacerbate the autoimmune assault in the early stages of IDDM, and be of practical importance in attempts to ameliorate the autoimmune response towards the beta-cells in IDDM.

Autoantigens↗
PubMed1992

Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden.

The effect of age on ICA and thyrogastric antibodies at diagnosis of IDDM was evaluated in 633 consecutively diagnosed Swedish diabetic patients aged 15-34 yr and in 282 volunteers of the same age. ICAs were present in 61% (383 of 633) of the patients and in 2% (5 of 282) of control subjects. When the initial classification was considered, ICAs were detected in 69% (327 of 473) of patients with IDDM, 23% (19 of 83) of those with NIDDM, 50% (36 of 72) of those with unclassifiable diabetes, and 20% (1 of 5) of those with secondary diabetes. The frequency of ICA fell significantly (P less than 0.001) with age in IDDM patients from 77% (104/135) in those 15-19 yr old to 52% (50 of 96) in 30- to 34-yr-old IDDM patients. The low frequency of ICA in 30- to 34-yr-old IDDM patients was confined to men (42%, 28 of 66). The frequency of gastric (H+, K(+)-ATPase) antibodies was significantly (P less than 0.05) higher in IDDM patients (10%, 47 of 449) than in patients with NIDDM (3%, 3 of 80) and unclassifiable diabetes (4%, 3 of 72). In conclusion, the frequency of ICA at the diagnosis of IDDM in young adult subjects decreases with increasing age, particularly in men. The frequent finding of ICA in patients considered to have NIDDM or unclassifiable diabetes indicates that misclassification of diabetes is frequent in young adult patients recently diagnosed with diabetes.

Adolescent↗
PubMed1991

Peptic ulcer disease: absence of antibodies stimulating the histamine sensitive adenylate cyclase of gastric mucosal cells.

The possible presence of parietal cell stimulating antibodies was examined in sera from 57 patients with relapsing ulcer disease. The sera were obtained at the time of symptomatic relapse and all patients had ulcers confirmed by endoscopy. A sensitive assay based on adenosine 3':5' cyclic monophosphate (cAMP) production in isolated porcine gastric mucosal cells was used as a measure. cAMP production increased up to four hours of incubation and was histamine responsive; an approximately 20-fold increase was found with histamine 10(-4) mol/l. Sera from both patients and healthy control subjects showed some inhibitory effect on basal cAMP production compared with incubation in medium only, whereas immunoglobulin preparations had a weaker non-specific effect. No stimulation was found when the patients' sera and immunoglobulins (up to a concentration of 6 mg/ml) were examined. These results suggest that gastric acid hypersecretion in duodenal ulcer disease is not an effect of histamine receptor stimulating antibodies. The data thus argue against a recent hypothesis that severe chronic ulcer disease in some patients has an autoimmune origin.

Adenylyl Cyclases↗
PubMed1991

H+,K-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia.

The prevalence and development of antibodies to H+,K+-ATPase were investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 93% of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l (p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A, a product of the gastric chief and mucous neck cells (median, 8.5 micrograms/l; reference range, 10-90 percentile, 64.4-195.5 micrograms/l), and elevated serum gastrin values (greater than 55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K(+)-ATPase antibody titers (r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K(+)-ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H+,K(+)-ATPase antibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease.

Adult↗
PubMed1990

Hyperthyroidism and hypothyroidism in monozygotic twins: detection of stimulating and blocking THS receptor antibodies using the FRTL5-cell line.

We present a rare history of monozygotic twin girls who at the age of 10 yr presented with hyper- and hypothyroidism, respectively. Both girls had antibodies against thyrotropin receptors as measured by a radioreceptor assay (230 U/l and 1400 U/l; reference range less than 7 U/l). The sera were further examined in a bioassay, based on a rat thyroid cell line (FRTL5), in which release of cAMP into medium was measured. The TSH receptor antibodies of the hyperthyroid twin displayed a ratio of radioreceptor to biological activity typical of Graves' disease. In contrast, the antibodies of the hypothyroid twin acted as pure antagonists at the TSH receptor level. The occurrence of TSH receptor antibodies in these monozygotic twins suggests a similar pathogenesis of Graves' disease and that of hypothyroidism due to thyroid blocking antibodies.

Adolescent↗
PubMed1990

Effects of interleukin 1 alpha on porcine thyroid follicles in suspension culture.

Interleukin 1, a product primarily of activated macrophages, was found to exert both a stimulatory and an inhibitory effect on porcine thyroid follicles in suspension cultures. A stimulatory effect on [125I] iodide incorporation into protein (iodination) was seen in cultures exposed to human recombinant interleukin 1 alpha (20 micrograms/l) for 1 h and (0.1 or 10 micrograms/l) for 18 h, whereas an inhibitory effect on iodination of interleukin 1 (10 micrograms/l) was registered after pre-incubation for 42 h and significant upon stimulation with TSH (200 mU/l). Cyclic AMP levels were stimulated in cells exposed to interleukin 1, however, significantly only after 42 h of pre-incubation, whereas TSH-stimulated cAMP response was inhibited by interleukin 1 already after 18 h of pre-incubation. The lumen of interleukin 1 incubated follicles was highly dilated and surrounded by a flattened epithelium. There were, however, no morphological signs of follicle disintegration or cellular cytotoxicity in the cultures exposed to interleukin 1. The data suggest that interleukin 1 might have a modulating role on thyroid function in autoimmune thyroid diseases associated with activation of intrathyroidal macrophages.

Animals↗
PubMed1979

Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody.

We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies resulted in a blockade of insulin binding and stimulation of 2-deoxy-glucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, no change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K(5), agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce a continuous biological response. Instead, there is desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action and to other situations in which there is long-term exposure of cells to antibodies that react with membrane components.

Adipose Tissue↗
PubMed1979

Thyrotropin is not a growth factor for human thyroid cells in culture.

Thyroid cells, obtained from both normal human tissue and benign nodular goiter, were cultured and maintained in vitro in 4-18 passages. Cultures with confluent cells accumulated cyclic AMP (10-150 times the basal amount) upon addition of bovine thyrotropin (100 milliunits/ml), indicating that the cells in culture maintained a thyrotropin-sensitive adenylate cyclase system. Addition of high doses of thyrotropin also induced a characteristic and reversible change in the morphology of the cells. The effect of thyrotropin on cell growth was studied in short- and long-term experiments. Thyrotropin reduced [(3)H]thymidine incorporation in a dose-dependent fashion in all cultures of thyroid cells. The maximal inhibition over a 24-hr period was about 50%. The thyroid cells were notably sensitive, and the half-maximal effect occurred at about 100 milliunits of thyrotropin per ml. In contrast, the hormone had no effect on [(3)H]-thymidine incorporation into human glial cells. Low doses of thyrotropin also had no effect on human fibroblasts and, at high doses, a stimulation of [(3)H]thymidine incorporation was seen. Thyroid cell cultures grown in the presence of 10 milliunits of thyrotropin per ml for 7-14 days had a slower growth rate and 24-36% lower cell numbers at saturation density than control dishes, indicating that the hormone also had a long-term effect on cell proliferation. The data agree with in vitro studies by others of the effects of corticotropin and lutropin on target cells and suggest that in vivo the primary action of pituitary trophic hormones on endocrine tissues is not stimulation of growth.

Cell Division↗
PubMed1979

A prospective study of urinary proteins in early infancy.

Urinary concentrations of protein, albumin, beta 2-microglobulin, alpha-amino nitrogen, and creatinine were determined in forty-one full-term infants on seven occasions up to six months of age. Except for beta 2-microglobulin the concentrations were highest on the first day, followed by a rapid decrease to a constant level within two weeks. Protein diminished approximately seven-fold, albumin twenty-fold, alpha-amino nitrogen three-fold and creatinine five-fold. By contrast, beta 2-microglobulin, a low molecular weight protein, first increased three-fold between day 1 and day 5, thereafter decreasing slowly 17-fold during the first three months of age. The data indicate that different kidney functions mature asynchronously.

Age Factors↗