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Biomedical subjects

R E Schmidt

Publications and source records attributed to R E Schmidt.

At least 163 records · Page 9Linked to original sources
PubMed1996

The IgG binding site of human FcgammaRIIIB receptor involves CC' and FG loops of the membrane-proximal domain.

Fc gamma receptors for the Fc part of IgG are the mediators for antibody effector functions. FcgammaRIII and FcgammaRII are low affinity receptors that, through the interaction with immune complexes, initiate a variety of immunological responses, such as phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators. We set out to define the IgG binding site on human FcgammaRIII. We assumed that potential beta-turns in Ig-like domains are the most probable determinants for ligand binding, and chimeric FcgammaRIIIB/FcepsilonRI receptors as well as single residue mutants were constructed in these regions of FcgammaRIIIB. Substitution of four amino acids in the membrane-proximal domain (Gln126, Arg156, Lys162, Val164) resulted in decreased binding of human IgG1. Lys162 and Val164 were found also to be crucial for the interaction with the IgG-binding inhibitory monoclonal antibody 3G8. In a putative three-dimensional model constructed in this study, these residues map on the CC loop (Gln126), on F beta-sheet (Arg156), and on the FG loop (Lys162, Val164). Our data are consistent with the study about human FcgammaRII (Hulett, M. D., Witort, E., Brinkworth, R. I., McKenzie, I. F. C., and Hogarth, P. M. (1994) J. Biol. Chem. 269, 15287-15293), suggesting that common structural determinants, i.e. FG loop or the GFC surface of the membrane-proximal domain, can be involved in interactions with IgG by both low affinity receptor classes FcgammaRII and FcgammaRIII.

Amino Acid Sequence↗
PubMed1996

Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms.

Increases in catecholamines have been shown to induce changes in migration of lymphocytes, in particular NK cells. To analyze the mechanisms of catecholamine-induced NK cell trafficking, normal healthy male human subjects and splenectomized individuals were infused with either adrenaline (0.10 microgram/kg/min), noradrenaline (0.15 microgram/kg/min), or NaCl i.v. for 20 min. Lymphocyte subsets (CD3+, CD4+, CD8+) transiently increased after administration of both catecholamines, with most pronounced increases (up to 600%) in NK cell numbers (CD16+ or CD56+) after infusion of adrenaline. These changes in NK cell numbers and function were accompanied neither by alterations in expression of adhesion molecules (CD11a), CD11b, CD31, CD43, CD44, CD62L) on NK cells nor by changes in plasma concentrations of soluble (s) adhesion molecules (sVCAM-1, sICAM-1, sE-selectin). Comparable increases in lymphocyte subsets were observed in splenectomized subjects, suggesting lymphocyte recruitment from other sources than the spleen. Furthermore, catecholamine-induced increases in lymphocyte subsets could be inhibited by pretreatment with the nonselective beta-adrenoceptor antagonist propranolol, but not by the beta1-selective antagonist bisoprolol. These data demonstrate that adrenaline and noradrenaline modulate the migratory capacity of human NK cells via spleen-independent beta 2-adrenoceptor mechanism.

Adrenergic beta-2 Receptor Antagonists↗
PubMed1996

Fc gamma-receptor III (CD 16) is involved in NK-B cell interaction.

CD16, the low affinity receptor for monomeric IgG (Fc gamma RIIIA), is a well characterized activation molecule on NK cells. In this study we investigated the role of CD16 in NK cell-mediated regulation of immunoglobulin production. Cocultures of the CD16+ human NK clone CNK6 and highly purified SAC/IL-2-activated B lymphocytes with various CD16 antibodies showed significantly diminished NK-enhanced immunoglobulin production in a dose-dependent manner, indicating that CD16 is relevant in NK-B cell interaction. Similarly, recombinant soluble CD16 incubated with B cells before cultures, suppressed the NK cell-stimulated B cell antibody response. Enhanced immunoglobulin production was also inhibited by Fc-specific F(ab')2 anti-body fragments. Coculture of NK cells with B lymphocytes resulted in induction of mRNA for IFN-gamma and TNF-alpha. The accumulation of mRNA for these cytokines was prevented by addition of CD16 and Fc-specific antibodies. It is proposed that interaction of CD16 on NK cells with B cell bound immunoglobulin leads to induction of cytokines in NK cells which stimulate immunoglobulin production by B cells.

Antibodies, Monoclonal↗
PubMed1996

Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice.

The family of receptors for IgG (Fc gamma R) plays an essential role in antibody-mediated effector functions of the immune system. However, the specific contribution of each of the Fc gamma R classes to in vivo immune reactions is still unclear. Here, we demonstrate that mice deficient for the ligand-binding alpha chain of Fc gamma RIII lack NK cell-mediated antibody-dependent cytotoxicity and phagocytosis of IgG1-coated particles by macrophages. Strikingly, these mice lack IgG-mediated mast cell degranulation, are resistant to IgG-dependent passive cutaneous anaphylaxis, and exhibit an impaired Arthus reaction. These results indicate a prominent role for Fc gamma RIII in inflammatory and anaphylactic responses, making this receptor a potential target in immunotherapy.

Animals↗
PubMed1996

Autoantibody against a 58 kD molecule in a patient with neutropenia and NK cell deficiency.

A patient with Evans' syndrome is described who developed intermittently an immunocytopenia consisting of autoimmune neutropenia and natural killer (NK) cell deficiency. During this time an autoantibody binding to a 58 kD antigen expressed on granulocytes, activated NK cells and Epstein-Barr virus (EBV) transformed B cells was present. Incubation of activated NK cells and NK cell clones with the autoantibody leads to a significant inhibition of NK activity. Therefore the autoantibody may detect a functionally important activation molecule.

Adult↗
PubMed1996

Epinephrine or norepinephrine fail to influence pituitary-adrenal secretion in man.

It is unknown whether plasma catecholamines have direct physiologic effects on pituitary-adrenocortical secretion in man. Therefore we investigated the effects of epinephrine and norepinephrine on plasma concentrations of adrenocorticotropin (ACTH), beta-endorphin and cortisol. Nineteen healthy male volunteers received infusions of either NaCl, epinephrine (0.10 micrograms/kg/min) or norepinephrine (0.15 micrograms/kg/min) for 20 minutes. 30 min before to 120 min after the infusion blood was continuously drawn to determine plasma levels of epinephrine, norepinephrine, and cortisol. In addition, ACTH and beta-endorphin plasma concentrations were analyzed at 6 time points before, during and after infusion. Infusion of catecholamines increased epinephrine and norepinephrine concentrations in physiological ranges as observed during intense psychological stress or exhausting physical exercise. However, these increases in catecholamine plasma levels neither affected concentrations of POMC-derived hormones nor plasma levels of cortisol. We conclude that in man, physiologic increases in circulating catecholamines have no influence on pituitary-adrenal hormone concentrations.

Adrenergic Agonists↗
PubMed1996

Modulation of the immunologic response to acute stress in humans by beta-blockade or benzodiazepines.

Acute stress evokes immediate responses in the cardiovascular endocrine, and immune systems. In particular, the number and activity of natural killer (NK) lymphocytes increase after stress. Here, we investigate the possibility to pharmacologically interfere with these stress-induced immunologic changes. Twenty-five healthy males were subjected to an acute stressor, a first-time tandem parachute jump. Subjects were randomly assigned to a beta-adrenoceptor antagonist (propranolol), a benzodiazepine (alprazolam), or placebo group. To analyze the role of the spleen in lymphocyte redistribution, splenectomized subjects performed a parachute jump. Propranolol, but no alprazolam, inhibited the heart rate increase during jumping. Increases in epinephrine and cortisol in the propranolol group were comparable to placebo, but were attenuated by alprazolam. The number and activity of NK cells significantly increased in the placebo group but not in the propranolol group immediately after stress. Alprazolam treatment did not alter the increase in NK cell numbers but did inhibit the increase in NK activity. In splenectomized subjects, NK cell numbers, but not NK activity, increased as in placebo subjects. We conclude that stress-induced changes in the immune system are controlled by beta-adrenergic mechanisms and only partly depend on the spleen; central interference with alprazolam differentially affects stress-induced changes in the NK cell compartment.

Adrenergic beta-Antagonists↗
PubMed1996

Time kinetics of the endocrine response to acute psychological stress.

A first-time parachute jump was chosen as a model to evaluate the endocrine response to acute psychological stress. In 43 inexperienced tandem parachutists, blood was drawn continuously from 2 h before to 1 h after the jump and analyzed at 10-min intervals for plasma concentrations of epinephrine (E), norepinephrine (NE), cortisol, GH, PRL, and TSH. In addition, heart rate was recorded throughout the experiment. There was a significant increase in heart rate and E concentrations during the jump itself. NE, cortisol, GH, PRL, and TSH peaked with a latency of 10-20 min. Apart from cortisol and TSH concentrations, which were still elevated 1 h after the stress event, plasma levels of the other endocrine variables normalized within 1 h following the jump. Statistically significant cross-correlations could be observed between E and NE (r = 0.60, no time lag) and between E and PRL (r = 0.58, 10-min time lag) only. Even in a very homogenous group of subjects and under well-controlled conditions, endocrine responses to acute psychological stress show considerable variations.

Adult↗
PubMed1996

Effect of aminoguanidine on the frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic autonomic ganglia of rats with streptozocin-induced diabetes.

Aminoguanidine, which prevents formation of advanced glycation end products and is a relatively selective potent inhibitor of the inducible (versus constitutive) isoform(s) of nitric oxide synthase, has been reported to ameliorate structural and functional abnormalities in peripheral somatic nerves in rats with streptozocin (STZ)-induced diabetes. In the present studies, the effects of aminoguanidine treatment on ultrastructural changes in the autonomic nervous system of rats with STZ-induced diabetes were examined. The frequency of neuroaxonal dystrophy, the neuropathological hallmark of sympathetic autonomic neuropathy in diabetic rats, increased 9- to 11-fold in the superior mesenteric ganglia of 7- and 10-month STZ-diabetic rats compared with that in age-matched controls. Administration of aminoguanidine continuously from the time of induction of diabetes at a dose equal to or in excess of that providing a salutary effect in the diabetic somatic peripheral nervous system did not alter the severity of diabetes as assessed by plasma glucose level, 24-h urine volume, and levels of glycated hemoglobin. Chronic aminoguanidine therapy did not diminish the frequency or affect the ultrastructural appearance of neuroaxonal dystrophy in diabetic or age-matched control rat sympathetic ganglia after 7 or 10 months of continuous administration. Our findings (under these experimental conditions) do not support a role for aminoguanidine-sensitive processes in the development of sympathetic neuroaxonal dystrophy in diabetic rats. Glycation-linked aminoguanidine-insensitive processes, however, such as the formation of early glucose adducts (Schiff bases and Amadori products) with intracellular and/or extracellular proteins and amine-containing lipids, superoxide anion generation during subsequent autoxidation of these glucose adducts, and non-glycative processes, remain potential pathogenetic mechanisms for diabetic autonomic neuropathy.

Animals↗
PubMed1996

[Stress and the immune system].

Research in psychoneuroimmunology has demonstrated that biopsychosocial factors such as psychological stress can influence the immune system. Chronic stress has been associated with the suppression of the immune function. In contrast, acute psychological stressors and physical exercise have been shown to transiently enhance immune responses. These stress effects on immunity seem to be mediated via endocrine factors, since hormones, neurotransmitters, and neuropeptides can interact with cellular components of the immune system. In summary, experimental and clinical evidence suggests a functional relationship between stress, immunity, and diseases.

Animals↗
PubMed1995

Transganglionic response of GAP-43 in the gracile nucleus to sciatic nerve injury in young and aged rats.

Sciatic nerve axotomy induces the transganglionic expression of the growth associated protein GAP-43 and neuropeptide Y (NPY) in lumbar DRG projections to the gracile nucleus. Four weeks after axotomy young animals had developed delicate GAP-43 and NPY-immunoreactive axonal sprouts in the gracile nuclei; however, an identical insult to aged (14-26 months) animals resulted in the labeling of swollen dystrophic elements and fewer delicate axonal sprouts. Unilateral sciatic transection in young rats with subsequent frustration of regeneration for 8 months resulted in ipsilateral gracile neuroaxonal dystrophy as assessed by ultrastructural, immunohistologic and quantitative morphometric techniques.

Aging↗
PubMed1995

Exogenous NT-3 mitigates the transganglionic neuropeptide Y response to sciatic nerve injury.

Peripheral sciatic nerve transection injury produces a marked increase in immunoreactive NPY in rat lumbar DRG and, as a 'transganglionic' response, in their central axonal projections to the dorsal spinal cord and gracile nuclei. Local application of neurotrophin-3 (NT-3) using implanted silicone chambers applied to the proximal transected sciatic nerve stump significantly diminished the transganglionic NPY response in the gracile nucleus and spinal cord but did not affect the CGRP transganglionic response. Conversely, local application of NGF affected the transganglionic CGRP response to axotomy but did not substantially affect transganglionic gracile NPY upregulation.

Animals↗
PubMed1995

The low affinity Fc gamma RIIa and Fc gamma RIIIb on polymorphonuclear neutrophils are differentially regulated by CD45 phosphatase.

Stimulation of human polymorphonuclear neutrophils through ligation and cross-linking of the low affinity Fc gamma RIIa and Fc gamma RIIIb using mAb Fab and F(ab')2 fragments led to transient intracellular calcium mobilization and activation of the respiratory burst. Fc gamma RIIIb engagement resulted in a different pattern of intracellular calcium flux, and induction of the respiratory burst was significantly more effective than in the case of Fc gamma RIIa. These data demonstrate that the capacity of Fc gamma RIIIb to transduce transmembrane signals itself contributes to full cell activation. Treatment with a mAb F(ab')2 fragment recognizing CD45 phosphatase suppressed Fc gamma R-induced calcium mobilization in a dose-dependent manner. An ongoing intracellular calcium mobilization was immediately terminated when activation was followed by co-cross-linking Fc gamma R and CD45. This suggests that the initial steps of Fc gamma R signal transduction pathways are influenced by the state of tyrosine phosphorylation. Combined cross-linking of both receptors, however, was hardly susceptible to CD45. Also, inhibition of respiratory burst by CD45 in the case of Fc gamma RIIIb was minimal compared with that for Fc gamma RIIa. Signal transduction pathways of low affinity Fc gamma RIIa and Fc gamma RIIIb are differentially regulated by CD45, underlining the essential function of Fc gamma R-mediated tyrosine phosphorylation in polymorphonuclear neutrophil activation.

Adult↗
PubMed1995

Mineralization of the globus pallidus following excitotoxic lesions of the basal forebrain.

The excitotoxin N-methyl aspartic acid was injected into the rat nucleus basalis to destroy basal forebrain cholinergic (BFC) neurons. In long-term survival experiments (up to 11 months post-lesion), conspicuous mineralized deposits were found in the globus pallidus and to a lesser extent in the thalamus. Deposits stained in a manner consistent with a composition of calcium and iron. Typically, deposits were absent from the center of the injection site, where BFC cell loss was most severe, but were present within the ventral and lateral globus pallidus where there was substantial sparing of BFC neurons. The similarity of this pathology to basal ganglia calcification and its relationship to Alzheimer's Disease and Down's syndrome is discussed.

Alzheimer Disease↗