Biomedical subjects

W L Sibbitt

Publications and source records attributed to W L Sibbitt.

63 records · Page 4Linked to original sources

PubMed1983

Natural killer cell in systemic lupus erythematosus. Defects in effector lytic activity and response to interferon and interferon inducers.

Spontaneous cytotoxicity mediated by natural killer (NK) cells is impaired in several human diseases including systemic lupus erythematosus (SLE). The precise mechanism(s) by which NK activity is suppressed in patients with SLE is generally unknown. The present study was designed to focus on cellular defects per se in NK cells from patients with SLE. It was observed that the usual enhancing effect of interferon (IF) and IF inducers was markedly impaired in SLE patients. Of 24 SLE patients studied, 17 had significantly decreased NK activity relative to controls. NK activity had a significant negative correlation with clinical activity score (r = -0.56, P less than 0.005) but was not correlated with corticosteroid dose, antinuclear antibody titers, total hemolytic complement (CH50), or sedimentation rate. Furthermore, significant depressions in NK activity correlated with variations in disease activity in six patients followed serially. Depressed NK function could not be reversed by prolonged in vitro incubation at 37 degrees C or with protease treatment. Furthermore, depressed NK activity was not altered by removal of glass adherent cells nor was a suppression of NK activity in normal controls seen by the addition of SLE peripheral mononuclear cells. No reversal of depressed activity to normal levels was seen by the addition of indomethacin nor did the supernatants from SLE cell cultures cause a suppression of normal NK function. NK activity in SLE patients did not respond normally to IF inducers (poly-I:C and concanavalin A) even if the SLE patients had normal NK function. The response of SLE cells to exogenous IF was also impaired. The number of effector-target conjugates was quantitated with several target cells (K562, Yac-1, Fravel) in SLE patients and controls. A significant correlation between the proportion of glass nonadherent mononuclear cells that formed effector-target conjugates with these various targets and the magnitude of NK lysis was observed. However, SLE and normal subjects had equal numbers of effector-target conjugates independent of NK function. Release of a soluble cytotoxic factor was induced with concanavalin A, and was markedly impaired in SLE patients relative to normal controls. Thus, impaired NK cell function in SLE does not appear to be related to cell-mediated suppressive mechanisms or to the deletion of effector cells; rather, the decreased NK activity may be related to an impaired release of a soluble cytotoxic factor.

Adult↗

PubMed1983

alpha-Interferon increases immunoglobulin production in cultured human mononuclear leukocytes.

Interferons (IFN) are known to modulate immune responses in either an inhibitory or a stimulating manner. The present study was initiated to investigate the mechanisms by which alpha-IFN modulates Ig production of human peripheral blood mononuclear cells (PBMC). IgG and IgM production was measured in pokeweed mitogen- (PWM) stimulated 7-day cultures of PBMC. Significant enhancement of IgM and IgG production was observed when alpha-IFN was added. Overnight preincubation followed by washing also produced significant enhancement. The effect of alpha-IFN was not obtained in the absence of PWM or T cells. The effect of alpha-IFN on cultures of B and T cells was not altered by irradiation of T cells (2000 rad). alpha-IFN was not shown to enhance the production of helper factor but did increase the responsiveness of B cells to helper factor if the B cells were preincubated with alpha-IFN. Finally, alpha-IFN did not increase the Ig production of PBMC induced by Epstein Barr virus (EBV), and the outgrowth of EBV-infected PBMC was not affected. Overall, these results show for the first time that the effect of alpha-IFN on PBMC is due to an enhanced responsiveness of B cells to helper factors produced by radioresistant T cells.

Adult↗

PubMed1983

Enhancement of natural cytotoxicity by beta-endorphin.

The role of enkephalins, beta-endorphin, or other neuropeptides produced by the nervous system in the alteration of immune responsiveness is generally unknown. The present studies were undertaken to investigate the role of these neuropeptides in the modulation of human spontaneous cytotoxicity induced by natural killer (NK) cells. Natural cytotoxicity was measured by using a standard 51Cr release assay with radiolabeled K562 cells. NK activity was significantly enhanced by both beta-endorphin (30.5 +/- 11.5%, M +/- SE, relative enhancement at 50:1, effector:target (E:T) ratio, 10(-14)M beta-endorphin) and methionine-enkephalin (met-enkephalin) (27.4 +/- 9.7% relative enhancement at 10(-9)M). The magnitude of relative enhancement significantly correlated with increasing concentrations of beta-endorphin. Leucine-enkephalin, alpha-endorphin, and morphine did not augment NK activity. The enhancement of NK activity with beta-endorphin increased at all E:T ratios tested. Naloxone inhibited the augmentation of NK activity produced by beta-endorphin and met-enkephalin. By using a combination of a standard 51Cr release and soft agarose single cell analysis assays, beta-endorphin increased both the number of E:T cell conjugates and the number of active killer cells among target-binding cells. The maximal effector cell recycling capacity was increased by 170%. These studies provide new insight into the mechanisms by which neuropeptides produced by the nervous system can alter immune responsiveness.

Binding, Competitive↗

PubMed1983

Natural cytotoxicity in systemic lupus erythematosus: mechanisms of suppression by inhibitory serum factors.

Spontaneous cytotoxicity mediated by natural killer (NK) cells is impaired in several human diseases including systemic lupus erythematosus (SLE). The present study was designed to describe factors in SLE sera which suppress the NK function of unfractionated mononuclear cells and NK enriched suspensions. NK activity was determined in 19 SLE patients and 25 normal controls by a standard chromium release assay. Sera obtained from SLE patients suppressed normal NK activity by an average of 29.4%. The presence of anti-lymphocyte antibodies (ALA) of the IgM class which were reactive with unfractionated mononuclear cells or the NK cell enriched OKM1 positive subset correlated with serum-mediated suppression. NK inhibitory SLE sera did not interfere with normal effector-target conjugate formation. These results demonstrate the modulatory effects of immune aggregates and ALA on lymphocyte function in SLE. These factors suppress NK function without evidence of lymphocyte cell death or inhibition of NK effector cell binding to tumour targets.

Adult↗

PubMed1982

Cutaneous manifestations of rheumatoid arthritis.

Rheumatoid arthritis is a systemic disease which can have multiple cutaneous manifestations. In particular, rheumatoid vasculitis may be difficult to diagnose because of the wide array of clinical presentations. Early recognition can assist the physician in diagnosis and in determination of the proper therapy. Every physician caring for patients with rheumatoid arthritis should be aware of these common dermatologic complications.

Adolescent↗

PubMed1978

Studies of cell subpopulations mediating mitogen hyporesponsiveness in patients with Hodgkin's disease.

Hodgkin's disease (HD) is associated with a deficit in T-cell immunity characterized by skin test anergy and decreased lymphocyte responses to phytohemagglutinin (PHA). To investigate this mitogen hyporesponsiveness in HD, we separated peripheral blood mononuclear cells on Ficoll-Hypaque gradients and determined their response to various suboptimal concentrations of PHA. As was expected, patients with HD demonstrated marked mitogen hyporesponsiveness relative to normal controls; however, if the cell suspensions were first passed through glass wool columns to remove adherent cells, the PHA responsiveness of the hyporesponsive HD cells was markedly increased. In contrast, the responsiveness of normal controls was decreased so that the responses of nonadherent normal and HD cells were statistically indistinguishable. Evidently, a glass wool-adherent suppressor cell had been removed from patients with HD, while a glass wool-adherent cell which enhanced mitogenic responses had been removed from normal controls during column passage. Previous to column depletion, patients with HD had decreased proportions of E-rosettes and increased proportions of cells with surface alpha-fetoprotein; however, the proportion of these cells was not changed after column passage. Significant changes with column depletion of glass wool-adherent cells in HD were recorded in the proportions of monocytes (13.2 vs 5.8%) and lymphocytes with C-3 receptors (12.6 vs. 7.8%). The only significant change in normal controls was a decrease in the proportion of monocytes (10 vs. 1.7%). To determine if glass-adherent cells would have a suppressor effect, HD-adherent cells were added in progressively increasing numbers to mononuclear cell suspensions depleted of glass wool-adherent cells. PHA responsiveness returned toward predepletion levels. In summary, patients with HD possess a glass wool-adherent suppressor cell which is responsible at least in part for in vitro mitogen hyporesponsiveness.

Hodgkin Disease↗

PubMedDate not supplied

A possible role for MRI in polyarteritis nodosa: the "creeping fat" sign.

We describe a case of polyarteritis nodosa with diffuse abnormalities in subcutaneous fat by magnetic resonance imaging. These abnormalities returned to normal following treatment. Magnetic resonance imaging may have a role in the identification and diagnosis of systemic vasculitis.

Adipose Tissue↗

PubMedDate not supplied

A commentary on 10 years of aldose reductase inhibition for limited joint mobility in diabetes.

This investigation examines the clinical response to long-term treatment of the diabetic syndrome of limited joint mobility (LJM) using an aldose reductase inhibitor (ARI) in comparison to historical controls, and proposes a potential role of aldose reductase (AR) genotype and expression in the clinical response to ARI. Clinical parameters, including quantitative hand movement and electromyogram, were followed over a decade of continuous ARI treatment with sorbinil (400 mg/day) in two patients with insulin-dependent diabetes mellitus (IDDM) and severe compromising LJM, and compared to the published 10-year prospective investigation of untreated IDDM diabetic patients with LJM. Both subjects were homozygous for the Z-2 AR allele (A-C)23 that has been linked with microvascular complications of DM. Cellular AR mRNA/beta-actin ratios for both treated patients while on ARI therapy were approximately one-half the value observed in untreated patients with the complications of nephropathy or neuropathy. This is the longest reported experience of ARI intervention for any diabetic complication, documenting sustained correction of LJM, lack of side effects, and a potential molecular basis for the therapeutic response.

Actins↗

PubMedDate not supplied

Oncogenes, growth factors, and autoimmune diseases (review).

Autoimmune diseases are benign proliferative diseases characterized by the expansion and activation of the autoreactive immune cells and the proliferation of connective tissue elements. Because both cytokines and oncogenes products are necessary for expansion of immune cells, it is possible that inappropriate activation of oncogenes might influence cytokine and lymphokine secretion as well as the expression of immune response genes necessary for the development of autoimmunity in a susceptible individual. At least four gene families of the immune system are involved in the induction and perpetuation of autoimmunity: 1) genes associated with the major histocompatibility complex, 2) germline immunoglobulin genes, 3) T cell receptor genes, and 4) complement genes. The hypothetical genetic locus responsible for the induction of autoimmunity is the "rheumogene". Oncogenes are obvious candidates for rheumogenes and activation of such genes may be necessary for the development of autoimmunity. Certain protooncogenes are activated in systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, progressive systemic sclerosis, and dermatomyositis, supporting this hypothesis. However, the activation of oncogenes in autoimmunity is not associated with gene translocation, deletions, point mutations, loss of regulatory sequences, or amplification, indicating that autoimmunity involves different mechanisms of oncogene activation than do many malignancies. Oncogene expression in autoimmune diseases tends to mimic the expression of oncogenes in normal activated lymphocytes, macrophages, and fibroblasts. Rheumogenes, if they exist, may be disordered regulatory genes which suppress or enhance the expression of cellular oncogenes in a non-malignant fashion. The existence of regulator gene demethylation and the presence of DNA-binding proteins specific for oncogene regulator sequences provide support for the concept of that regulator gene dysfunction, rather than oncogene activation per se is the more primary event in autoimmune diseases.

Animals↗