Autoantibodies to insulin as serum markers for autoimmune insulitis.
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Biomedical subjects
H Kolb
Publications and source records attributed to H Kolb.
Suppression of low-dose streptozotocin-induced diabetes by immunomodulatory lectins.
The effect of immunomodulatory lectins on diabetes development following low-dose streptozotocin treatment in inbred mice was studied. All lectins administered had been shown previously to suppress immune reactivity. Among plant lectins concanavalin A but not Lens culinaris or wheat germ agglutinin partially suppressed hyperglycaemia following low-dose streptozotocin. A similar inhibitory effect was found for the staphylococcal enterotoxin B. Finally, administration of an immunomodulatory lectin from vertebrates, electrolectin, also had a beneficial effect on the course of the disease. These findings indicate that some lectins have a suppressive effect on Type 1 diabetes in an animal model.
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Galactose-specific receptors on liver cells. II. Characterization of the purified receptor from macrophages reveals no structural relationship to the hepatocyte receptor.
We have isolated a galactose-specific receptor protein from rat liver macrophages by three techniques, all using EDTA extraction and subsequent affinity chromatography. The purified receptor has an apparent molecular mass of 30 kDa and exhibits hemagglutinating activity. Monospecific receptor-antisera produce one precipitation line with the macrophage receptor in Ouchterlony double diffusion but show no cross-reaction with the hepatocyte receptor. Sinusoidal cells, but not hepatocytes, are stained with monoclonal antibodies to the macrophage receptor, whereas anti-hepatocyte receptor antibodies stain hepatocyte surfaces but not sinusoidal cells. We conclude that the galactose-specific receptor from liver macrophages is structurally different from the hepatocyte receptor, although the two lectins share a similar binding specificity.
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Lack of evidence for liver lectins functioning as IgM or IgG-Fc-receptors.
We have tested whether mannose- and galactose-specific lectins on liver cells are able to bind antibody-antigen complexes and thus function as Fc-receptors. Rat hepatocytes and liver sinusoidal cells were isolated by collagenase perfusion and differential centrifugation. Rat erythrocytes were coated with purified IgM or IgG from rabbits immunized with rat erythrocytes. Both IgM and IgG coated erythrocytes bound to liver macrophages but not to hepatocytes. The binding of IgM and IgG coated red blood cells to liver macrophages could not be blocked by potent inhibitors for mannose- and galactose-specific macrophage lectins such as mannan, D-mannose-bovine serum albumin, N-acetyl-D-galactosamine, D-galactose-bovine serum albumin, or asialofetuin. Although lectin activity is calcium dependent and trypsin sensitive neither condition blocked rosette formation between liver macrophages and opsonized erythrocytes. Thus mannose- and galactose-specific lectins are not involved in the sequestration of IgM- or IgG-antibody-erythrocyte complexes in the liver.
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The distribution of photoreceptors, dopaminergic amacrine cells and ganglion cells in the retina of the North American opossum (Didelphis virginiana).
Quantitative light microscopic techniques have been applied to photoreceptors, ganglion cells and dopaminergic amacrine cells in the retina of the North American opossum Didelphis virginiana. This marsupial has a retina with a central areal specialization where ganglion cells reach a maximum density of 2900/mm2 and cone photoreceptors are concentrated. However, the retina is very much rod dominated and there is a ring of peak rod density approximately 2 mm around the area centralis (a.c.). At the a.c. the cone to rod ratio is 1:50 while in peripheral retina it is 1:120. Dopaminergic amacrines, revealed by induced fluorescence (Fa/Glu) techniques are extremely numerous in opossum retina reaching a peak density at the a.c. and distributed in a high density plateau covering much of tapetal superior retina. Opossum retina is compared to mammalian retinas, particularly cats, with the aim of understanding the evolution of mammalian retinal circuits.
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Autoimmune T-lymphocytes with specificity for pancreatic islet antigens.
The question is still unresolved whether in insulin-dependent (type I) diabetes T-lymphocytes mediate an autoimmune response towards pancreatic islets. We now present direct evidence in an animal model for autoimmune T-lymphocytes with specificity for islet antigens. Mice of strain C57BL/6 were immunized repeatedly with islet homogenates. Lymphocytes isolated from draining lymph nodes and the spleen show a specific proliferative response when challenged with mouse rat or islet antigens but do not respond to liver or spleen antigens. Islet antigen specific lymphoblasts have been maintained by in vitro culture for several weeks in the presence of T-cell growth factor containing medium.
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Electron microscopy of Golgi-impregnated photoreceptors reveals connections between red and green cones in the turtle retina.
Red and green cones of two turtle species (Pseudemys scripta elegans and Chelydra serpentina) retina have been stained with Golgi procedures and examined by light microscopy of whole-mount tissue and by electron microscopy of serial thin sections. By light microscopy, red and green single cones appear indistinguishable, but double cones can be readily identified. All Golgi-stained photoreceptors in turtle retina have a spray of telodendria radiating from their synaptic pedicles. The telodendria of single cones are 10-20 micron long and end in clusters of terminals, whereas double cones have 30- to 50-micron long telodendria in addition to a very short bush of telodendria arising from one side of the pedicle. Electron microscopy of the Golgi-stained cones allows them to be distinguished into red or green spectral types by the appearance of their oil droplets. Furthermore, the spectral identity of cones contacted by the telodendria of identified Golgi-stained cones can similarly be determined. Red single cones make telodendrial contacts with other red singles, both members of the double cones, and with green single cones. Green single cones likewise connect to many surrounding red cones, both single and double types, and a few other green singles. Both members of the double cone connect to neighboring red and green singles and occasionally to double cones. The telodendria of stained cones end on spectrally homologous or heterologous cone types at basal junctions, central elements of ribbon synapses or, sometimes, as lateral elements of ribbon synapses. However, all these synaptic contacts appear to be of the same type, i.e., narrow-cleft basal junctions. Small gap junctions occur between neighboring cone pedicles, regardless of spectral type, in the visual streak area of the retina. Large gap junctions occur between unidentified cone telodendria in the neuropil of the outer plexiform layer. The telodendrial connections between red and green cones in the turtle retina have the appearance of chemical synapses and suggest an anatomical pathway responsible for the mixing of red and green signals in red or green cones of the turtle retina as reported in the accompanying physiological paper by Normann, Perlman, and Daly (27).
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A17: a broad-field amacrine cell in the rod system of the cat retina.
A17 amacrine cells of the cat retina have been penetrated with horseradish peroxidase (HRP)-filled microelectrodes and their light responses recorded. These cells depolarize in sustained fashion to steps of light. Viewed in retinal wholemounts, HRP-injected cells have a spokelike radiating splay of very fine dendrites (0.1 micron diam) passing diffusely through all strata of the inner plexiform layer (IPL) to run primarily in strata 4 and 5. There are as many as 1,000 large, regularly spaced beads borne on the 500- to 1,200-micron diameter dendritic field. Cell body sizes range from 9 to 13 micron. In the electron microscope, the dendritic beads in sublamina b of the IPL are seen to synapse reciprocally with rod bipolar axon terminals. Dendritic beads in sublamina a rarely make synapses, but between the beads in this layer, input from at least three distinctive amacrine profiles occurs. Though diffuse at the light microscopic level, A17 thus appears to be structurally bistratified, with amacrine input in sublamina a and bipolar input in sublamina b. It is likely that A17 can be identified with AI. A17 signals are driven almost exclusively by rods. The spectral sensitivity peaks at 507 nm, identical with that of pigment epithelial cells. Light adaptation abolishes all but a small hyperpolarizing component of the signal. The overall intensity-response range is similar to that of AII amacrine cells. When receptive fields of A17 cells are mapped with slit stimuli, a broad, single-component curve is measured approximately covering the dendritic field. The receptive field is well described by a linear electrical model with a mean space constant of 259 +/- 97 micron (SD). On the other hand, responses to centered slit stimuli of varying width yielded space constants of only 38 +/- 29 micron. A17 amacrines are thus broad-field components of the cat's rod system but with very little capacity for spatial integration. Receptive-field measurements are not supportive of the notion of isolated dendritic regions.
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Administration of silica prevents diabetes in BB-rats.
Administration of silica to young BB-rats almost completely prevented the development of spontaneous diabetes. Only 1 of 31 silica-treated rats developed hyperglycemia, whereas 9 of 31 in the untreated group did so. Since silica is highly specific in its action against macrophages, our observations indicate an important role of these cells in the pathogenesis of the disease.
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[A 64-year-old patient with diffuse bleeding tendency and pancytopenia].
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Anti-Bacterial Agents↗
[Cyclosporin A in type I diabetes mellitus].
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Adolescent↗
Effect of cyclosporin A on low-dose streptozotocin diabetes in mice.
The effect of cyclosporin A administration on diabetes development following multiple low-dose streptozotocin treatment was determined in inbred mice. When given daily at a dose of 12 or 60 mg/kg body weight the drug induced an earlier development of hyperglycemia and led to persistently higher blood glucose levels. Enhancement of diabetes by cyclosporin A was also seen when the drug was given only after termination of treatment with streptozotocin.
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Dopamine-containing amacrine cells of rhesus monkey retina parallel rods in spatial distribution.
Dopamine-containing amacrine cells of rhesus monkey were found everywhere outside of the foveola in whole, flat retinas by the formaldehyde-glutaraldehyde fluorescent method. There were about 7500 such cells in a single retina and their density, determined by cell counts and measured by a nearest neighbor method, was minimal in foveal and peripheral regions and maximal at 3 mm from the center of the fovea. Compared to density distributions of other retinal neuron types, dopamine-containing amacrine cells correlated only with rods, which also had a peak density at 3 mm eccentricity. Cones and ganglion cells peaked in the foveal pit, or within 1 mm of it, respectively. As the distribution of dopamine-containing cells followed that of rods, it is suggested that dopamine could be involved in the rod neuronal circuitry of primates.
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Direct excitatory interactions between cones of different spectral types in the turtle retina.
Cone linear sensitivities to red and green stimuli were measured intracellularly in the dark- and light-adapted turtle retina. Test flashes of small diameter were used to minimize horizontal cell feedback. Light adaptation was achieved with either green or red background illumination. The ratio of cone sensitivities to red and green light depended on the color of the background light and differed from the ratio measured in the dark. Electron microscope studies of Golgi-stained turtle cones revealed direct synaptic connections between red and green cones mediated by cone telodendria. These data indicate that the red cone photoresponse is not univariant as has been previously supposed and suggest that mixing of signals from different spectral classes of cones can occur via direct excitatory connections between cones.
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Correlation of islet cell antibodies and HLA-DR phenotypes with diabetes mellitus in adults.
In a cross-sectional study, sera of 81 adult diabetic in-patients were tested for the presence of pancreatic islet cell antibodies (ICA), both IgG and complement-fixing. All patients had been well controlled initially with oral hypoglycaemic agents and therefore had been classified as having Type 2 (non-insulin-dependent) diabetes. However, 14 were subsequently classified as Type 1 (insulin-dependent) because they became insulin-dependent within 2 months of diagnosis. Ten of these patients (71%) were ICA-positive. Sixty-seven patients had been non-insulin-dependent for at least 1 year after diagnosis. Circulating ICA were present in 18 patients and 16 of these (89%) required insulin therapy. Secondary oral hypoglycaemic agent failure developed within a mean period of 3.7 years after diagnosis. In contrast, in the ICA-negative sub-group (n = 49) insulin treatment became necessary in 29 patients. Secondary oral hypoglycaemic agent failure of these patients had developed after a mean period of 8.4 years, which was significantly longer than in the ICA-positive patients (p less than 0.01). Complement-fixing-ICA were detected only in sera with an ICA-IgG titre of at least 8, and its prevalence was similar in the sub-groups tested, i.e., the Type 1 diabetic patients and the patients with secondary oral hypoglycaemic agent failure. With HLA-DR typing, a significant excess of the DR3 antigen and heterozygous DR3/DR4 phenotypes was found in ICA-positive patients with secondary oral hypoglycaemic agent failure and in the Type 1 diabetic patients, which was comparable with the frequencies reported in juvenile-onset Type 1 diabetes.
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Synaptic organization of the outer plexiform layer of the turtle retina: an electron microscope study of serial sections.
Neural connections in the outer plexiform layer of the Pseudemys turtle retina have been studied by electron microscopy of serial ultrathin sections. While the distinguishing features of the photoreceptors have been described elsewhere, in this paper we describe the patterns of connectivity between identified second order neurons and identified photoreceptors or amongst second order neurons themselves. Basal telodendria emitted from double cone pedicles interconnect the two members of the double cone. Three morphologically different types of junction are made between bipolar cells and cone pedicles. H1 horizontal cells can be distinguished from H2 horizontal cells and synapses occur between them. Axon terminals of H1 cells are presynaptic to H1 cell bodies. Photoreceptors, H1 cell bodies and H1 axon terminals engage in electrical junctions while chemical synapses occur from both types of horizontal cell to bipolar cells. On rare occasions, bipolar cell dendrites were seen to be presynaptic to other bipolar cell dendrites. The significance of some of these contacts for the electrophysiological findings on the OPL of the turtle retina is discussed.
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Chronic insulitis after partial islet damage by passive insulin antibody transfer.
The effect of passive insulin antibody transfer into recipient mice was reevaluated. Mice of inbred strains BALB/c, C57Bl/6 and DBA/2 received 10 injections of hyperimmune guinea pig insulin antiserum within 2 weeks. Ten days later the animals were sacrificed. It was found that up to 40% of animals had developed chronic lymphocytic infiltrations of pancreatic islets (insulitis) without showing diabetic symptoms. It is concluded that repeated damaging of islet tissue by passive insulin antibody transfer may result in chronic, possibly autoimmune insulitis. Our observation supports the concept that partial damage of pancreatic islets by environmental factors may trigger an organ-specific progressive islet cell destruction process mediated by immune cells.
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GalNAc/Gal-specific rat liver lectins: their role in cellular recognition.
By investigating the presence and distribution of GalNAc/Gal-specific receptors on liver cells in vitro and in vivo, we provided evidence that the hepatocyte is not the only liver cell expressing receptor activity but that receptors of similar specificity are found on liver macrophages and also on endothelial cells. The receptor distribution in the plasma membrane is strinkingly different between the three cell types, as judged from the binding pattern of colloidal gold particles coated with asialofetuin or lactosylated serum albumin. Binding to hepatocytes occurs as single particles statistically distributed, binding to liver macrophages in a clustered arrangement all over the cell membrane and binding to endothelial cells also in a clustered arrangement but restricted to coated pits only. The different receptor distribution results in different binding and uptake abilities. Whereas hepatocytes bind and take up molecules and small particles (5 nm) only, the clustered receptor arrangement of endothelial cells and macrophages enables them to effectively bind and ingest larger particles. Ligands larger than 35 nm can be taken up by the macrophages only. The different receptor arrangement results also in different capacities of cell contact formation. Although in vitro liver macrophages and hepatocytes can both bind desialylated cells the macrophage needs much less galactosyl groups exposed on erythrocytes to establish stable contacts than the hepatocyte. The contacts formed by hepatocytes stay reversible for 30 min at 37 degrees C, whereas the contacts formed by the liver macrophages become irreversible after 10 min at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
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